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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Origins of Tocolysis
  5. Development of Tocolysis
  6. Is Tocolysis Superfluous?
  7. Measuring the Benefits of Tocolysis
  8. Summary
  9. References

In 1950, the World Health Organisation (WHO) defined prematurity as a birthweight of 2500 g or less and in 1961 as a gestational age of less than 37 weeks. The time in between marks an era in which there was growing recognition of the importance of gestational age at birth and how to influence it. The latter was facilitated too by the development of tocography, which permitted some semi-objective measurement of uterine contractility. Along with it, came a growing interest in agents that could control uterine contractility beyond the earlier classical approaches of hormones and gastrointestinal spasmolytics. Hence, the early 1960s saw much research interest in agents, such as nylidrine, isoxsuprine, and orciprenaline that could suppress uterine contractility as one of their many beta-agonist properties. Subsequently, two approaches would be used to shift the balance towards uterine function over and above the influence on other bodily functions. One consisted of supplementing these drugs with agents, such as calcium antagonists and beta-receptor blockers that were hoped to suppress non-uterine actions. The other was a search for drugs in the same class with greater uterospecificity and more selective binding to uterine as opposed to other receptors. Neither of these approaches has ever fully fulfilled the hopes that were pinned on them, but they resulted in the availability of a large number of agents to suppress uterine contractility. The advent of prostaglandins as regulators of uterine contractility and the ability to suppress their biosynthesis saw another range of attempts to suppress uterine activity. They included aspirin, sodium salicylate, flufenamic acid, sulindac and indomethacin, but some were clearly based on a defective understanding of how uterine prostaglandin synthesis can be influenced. In the meantime, a flurry of other agents came and went, often more than once, testifying to the ingenuity of clinicians in trying to solve a problem that is poorly understood. Some, such as relaxin and ethanol, came and disappeared. Others, such as calcium antagonists, entered the scene as protectors against the non-uterine effects of other agents, went, and re-entered the scene in their own right. Still others, such as magnesium sulphate, came, lingered around, and became credited with effects in preterm labour that do not depend on affecting uterine contractility. Amidst this all arose the term tocolysis, coined in 1964 by Mosler from the Greek stems ‘τκζ’ and ‘λυɛιν’, to epitomise all of this ingenuity.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Origins of Tocolysis
  5. Development of Tocolysis
  6. Is Tocolysis Superfluous?
  7. Measuring the Benefits of Tocolysis
  8. Summary
  9. References

The definition of prematurity has remained a controversial and debatable issue ever since one of the earliest recorded incidences of premature birth. In 19071, Simpson referred to a birth on December 25th, 1642 when a widow gave premature birth to a male child who was ‘so small that he could have been put into a quart mug’. The infant survived and grew up to be Sir Isaac Newton, who described gravity. At the time Simpson was not concerned as to why Newton was born small. As far as Simpson was concerned it was simply a premature birth. Reed and Stanley (1977)2 stated that prematurity is a term used to describe various combinations of being born too early or too small or both. Unfortunately, we are still struggling with the definition of prematurity today.

Tocolysis found its origins in prematurity and is still in search of its maturity. The history of tocolysis predominantly consists of premature actions and immature thoughts.

Origins of Tocolysis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Origins of Tocolysis
  5. Development of Tocolysis
  6. Is Tocolysis Superfluous?
  7. Measuring the Benefits of Tocolysis
  8. Summary
  9. References

After the Second World War, the World Health Organisation (WHO) was founded. In 1950, the WHO defined prematurity as a birthweight of 2500 g or less. The definition was derived from an idea by a Finnish paediatrician who trained in Berlin3. He wrote a long treatise showing that babies weighing 2500 g or less did substantially worse than babies weighing more. However after 1950, physicians became aware that weight and maturity were not necessarily related. The classic study by McKeown and Record4 illustrated that there was a difference between weight and maturity. In 1961, the WHO revised the definition of prematurity to a gestational age of less than 37 weeks. During this period we saw the first attempt at genuine tocolysis with relaxin in 19555. In 1961 we saw the first publication whereby a beta-agonist, isoxuprine, was used to stop uterine contractions6. The term tocolysis did not emerge until 1964 where it was coined by Mosler7 at the Symposium on Physiology and Pathology of Uterine Contractility from the Greek words τκσ (contraction) and λυɛιν (to untie or destroy). By 1969, the WHO8 realised the confusion created by the term ‘prematurity’ and so revised the definition so that <2500 g was referred to as low birthweight and <37 weeks gestation became known as preterm.

By this time, tocolysis was now firmly established thanks to a diverse range of pharmacological agents, some of which were better than others. Some of the tocolytic agents introduced appeared to have complex relationships with one another. This was often confusing due to different names given to the same drugs. For example, buphenine, was also known as rolidrine, dilatol, nylidrine, dihydrine and arlidine, however this tocolytic agent belonged to a much larger family of tocolytics called the beta-agonists that share many similar attributes. Other large groups are also related, such as those agents that influence prostaglandin synthesis e.g. indomethacin, sulindac, naproxen.

Development of Tocolysis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Origins of Tocolysis
  5. Development of Tocolysis
  6. Is Tocolysis Superfluous?
  7. Measuring the Benefits of Tocolysis
  8. Summary
  9. References

The development of tocolysis was driven forward by three factors. The first was the interest in perinatal mortality, which began just after the Second World War. This could be attributed either to doubts surrounding the advances made in maternal mortality or whether it was felt that the population of Europe needed to be replenished. The second factor was the discrepancies noted between birthweight and gestational age. Finally, the emergence of tocography allowed for the semi-objective measurement of contractility.

The history of tocolysis began with relaxin, which was introduced by Abramson and Reid (1955)5. A 100% success rate, defined as progression to 36 weeks gestation, was achieved in all of the five women treated. However, Decker (1958)9 highlighted two major flaws with the study; firstly there were too few cases included and, secondly, there was no control group. At the same time McCarthy et al. (1957)10 studied the use of relaxin but included a control group. Fifteen women were allocated to receive IV relaxin followed by several IM injections versus the ‘standard treatment’ and he found no difference at all. It was not clear whether this meant that relaxin did not work or that the standard treatment, which consisted of innumerable hormones and analgesic agents in various amounts at the discretion of the attending physician, was slightly better. At the same time, others investigated whether relaxin could cause contractions and enhance cervical ripening and therefore be used for the augmentation of labour. Another tocolytic, which was investigated, but did not belong to any particular pharmacological family, was ethanol. Ethanol was introduced by Fuchs11 during the mid-sixties and, despite the alternatives available, was still undergoing investigation in 198112. It was reported that for ethanol to be effective you needed to achieve blood levels between 1.2 and 1.8 g/l. However, this caused depression and incontinence in women and required the routine use of an anti-emetic drug.

Magnesium sulphate was first introduced in 1965 by Dumont13, and although it has never been shown to be useful as a tocolytic agent, it has subsequently made a comeback as a cerebro-protective agent. However, the recent results of the MAGPIE trial suggest that it will disappear again at least for the treatment of preterm labour14.

For the calcium antagonists, nifedipine was introduced in 197715 and has also been paid more interest of late. However, the lack of good quality evidence available for these tocolytics and reports of cardiovascular side effects may limit their usefulness in the treatment of preterm labour.

Of the beta-agonists, fenoterol, which was introduced in Germany in 1970, is worth considering because in 1982 Jung proclaimed that it was the most widely used and best-explored beta-agonist agent in Europe16. This depends on what we mean by best explored, as this has never really been evaluated properly. Within 10 years of its introduction it was used in combination with calcium antagonists17, prostaglandin synthesis inhibitors18, beta-receptors blockers19 and magnesium sulphate20 to counteract some of its side effects or to enhance its activity.

In summary, the wide range of tocolytic agents in use is testament to the fact that we still do not have an ideal drug available. There are a number of conflicting opinions regarding the true benefits of tocolysis. Most physicians believe either that tocolysis is an excellent tool or that it is useless, with few doctors voicing an opinion in between. This attitude to tocolysis was very marked during the 1980s when France was very pro-tocolysis to the extent that 46% of primigravidae received prophylactic tocolytics, however, in contrast, therapeutic nihilism was so great in Ireland that they did not even have tocolytics on the market.

Is Tocolysis Superfluous?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Origins of Tocolysis
  5. Development of Tocolysis
  6. Is Tocolysis Superfluous?
  7. Measuring the Benefits of Tocolysis
  8. Summary
  9. References

There are three arguments, which can be used to address the validity of tocolysis. The first is based on the population receiving these drugs and relates to the fact that despite the existence of a plethora of drugs, an actual reduction in preterm birth has not materialised.

The second issue is based on the individual per se and the fact that there has been no improvement in infant outcome following tocolytic treatment. Finally, it could be suggested that advances in neonatal care will make tocolysis surplus to requirements both at the population and individual level. However, this third argument can be immediately discounted since there are significant neonatal complications that arise from prematurity and long-term costs involved despite advances in neonatal care.

The incidence of preterm birth has remained unchanged despite advances in perinatal care. Data from Australia indicate that the incidence of preterm birth has increased over the last number of years from 6.2% to 7.1%. In Belgium, the study centre for perinatal epidemiology has shown that throughout the nineties, the incidence of preterm birth increased by 0.1% per year, which equates to 1% over 10 years. However, these observations have little to do with tocolysis. Increases in preterm birth are related predominantly to multiple pregnancy, reproductive technology, advanced maternal age and obstetric intervention, which occurs earlier in pregnancy. While all four are independent they are to some extent interrelated. Even without these influential factors could we still have seen an influence from tocolysis on the rate of preterm birth? If we concentrate only on viable pregnancies i.e. a live fetus without lethal malformations, we see that multiple birth and elective deliveries have both increased and hence contribute to the rise in the number of preterm births. The contribution from spontaneous singleton pregnancies has subsequently fallen. Half of the spontaneous singleton preterm births are associated with pathology in the mother or the baby, which doesn't warrant a delay in delivery or prolongation of pregnancy. Of the remaining small proportion of spontaneous preterm births without pathology, half of these cases begin with ruptured membranes. Therefore, the argument of whether tocolytics work in the population is not valid because there is only a small fraction of the population that is eligible for treatment. Whether the tocolytic works in a population or not is secondary because the most fundamental issue is whether it benefits the individual.

On the subject of infant outcome, the interpretation of study results is important. There is a large difference between the statements that ‘tocolysis has no effect’ or ‘no effect could be demonstrated’. However, these terms are often confused. The reason that no effect can be demonstrated is that by itself tocolysis has no effect. The only effect stems from the time gained in utero. A gain of 3 weeks from 34 to 37 weeks will be associated with little effect compared with a delay from 24 to 27 weeks. However, at earlier gestational ages much fewer preterm births occur. Furthermore a short delay in birth will not demonstrate much of an effect. In the placebo-controlled, Canadian ritodrine trial21, only 30% of the women in the trial were very preterm i.e. 70% were above 32 weeks, and just over 10% were extremely preterm. There was no requirement to give corticosteroids and all of the women in the trial were already in a tertiary-care centre. It is therefore impossible to expect to show an improvement in perinatal outcome.

Despite this, we can draw positive conclusions from the study. For every 90 women in the trial there was one less case of cerebral palsy and one less case of neonatal mortality. Hence, although not statistically significant in terms of reducing preterm birth, we can state that tocolysis did confer some clinical significance. We can approach these findings from another angle by asking, ‘How many caesarean sections would you be prepared to do to avoid one case of cerebral palsy plus one neonatal death?’ I would guess substantially more than 90. Therefore, the fact that tocolysis has not demonstrated statistical significance in terms of reducing the rate of preterm birth and improving neonatal outcome is ultimately influenced by other factors, such as, the restricted population who were eligible for treatment, the gestational age and the use of corticosteroids.

Measuring the Benefits of Tocolysis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Origins of Tocolysis
  5. Development of Tocolysis
  6. Is Tocolysis Superfluous?
  7. Measuring the Benefits of Tocolysis
  8. Summary
  9. References

The recommended duration of tocolytic treatment can also be scrutinised as this was initially proposed several years ago following a review of the early beta-agonist studies. It was suggested that the beta-agonists were only capable of working for 48 hours. These early studies led to many misleading assumptions, such as, that corticosteroids don't work before 24 weeks or after 34 weeks and that beta-agonists do not work before 24 weeks and only for 24 or perhaps 48 hours. This strict adherence to these cutoff points is misjudged, because we cannot assume that the uterus and fetus have an ‘on/off switch’, which responds during specific periods of treatment or at particular gestational ages.

The concept of delaying delivery for 48 hours with beta-agonists is derived from a systematic review of tocolytics22,23. We wanted to know what evidence existed to suggest a delay of birth, was there evidence for a reduction in the incidence of preterm birth and an improvement in infant outcome. While looking at the delay of birth, we had to decide upon some options. A delay of 24 hours was agreed as an ideal period of time to allow for in utero transfer to a tertiary centre. However, 48 hours was deemed to be more useful as this would allow a whole course of corticosteroids. One and 2 weeks and 10 days were initially suggested as ideal targets that could equate with real perinatal benefits. However, we soon had to abandon the 2-week, 10-day and 1-week parameters as there were no data in the literature. Therefore, we were left with the outcomes after 24 and 48 hours, which revolutionised the world. When the Canadian trial was undertaken these parameters were used as an outcome measure. The data showed a statistically significant increase after 24 and 48 hours. Yet data over 7 days also showed a difference of 9%, although not statistically significant (Table 1). Therefore, we should not be constrained by or over-reliant on arbitrary cutoff points when investigating the effects of tocolysis. As new tocolytic agents are introduced, the window of tocolytic opportunity may widen allowing earlier treatment for longer periods with the possibility of demonstrating real improvements in neonatal mortality and reductions in preterm birth.

Table 1.  Length of time to delivery after starting treatment (Canadian Ritodrine trial).
 Ritodrine (n= 352)Placebo (n= 356)Difference (95% CI) %
  1. *P < 0.001.

<24 hours25 (7.1)70 (19.7)−12.6 (−17.5 to −7.7)*
<48 hours75 (21.4)126 (35.4)−14.0 (−20.6 to −7.4)*
<7 days134 (38.2)168 (47.2)−9.0 (−14.8 to −3.2)
Delivery <32 weeks104 (48.8)123 (58.0)−9.2 (−18.6 to 0.2)
Delivery <37 weeks24 (68.2)245 (68.8)−0.6 (−7.4 to 6.2)

Summary

  1. Top of page
  2. Abstract
  3. Introduction
  4. Origins of Tocolysis
  5. Development of Tocolysis
  6. Is Tocolysis Superfluous?
  7. Measuring the Benefits of Tocolysis
  8. Summary
  9. References

The history of tocolysis is based on premature actions and immature thoughts, but there is no point looking at the history if all we are going to do is repeat it. We should realise that tocolysis is still looking for its maturity and that we need to begin thinking about tocolysis with more maturity than we have done thus far.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Origins of Tocolysis
  5. Development of Tocolysis
  6. Is Tocolysis Superfluous?
  7. Measuring the Benefits of Tocolysis
  8. Summary
  9. References
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    McKeown T, Record RC. Observations on fetal growth in multiple pregnancy. J Endocrinol 1952;8: 386401.
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    Abramson D, Reid DE. Use of relaxin in treatment of threatened premature labor. J Clin Endocrinol 1955;15: 206209.
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    Dumont M. Traitement des douleurs utérine gravidiques par le lactate de magnésium. Lyon Méd 1965;213: 15711582.
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    Andersson KE, Ingemarsson I, Ulmsten U, Wingerup L. Inhibition of prostaglandin-induced uterine activity by nifedipine. Br J Obstet Gynaecol 1979;86: 175179.
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    Trolp R, Irmer M, Bernius U, Pohl C, Steim H, Hillemanns HG. Tokolyseerfolge unter Fenoterol-Monotherapie und Fenoterol in Kombination mit einem kardioselektiven β-Blocker. Geburtshilfe Frauenheilkd 1980;40: 602609.
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    Spätling L. Orale Magnesium-Zusatztherapie bei vorzeitiger wehentätigkeit. Geburtshilfe Frauenheilkd 1981;41: 101102.
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    King JF, Keirse MJNC, Grant A, Chalmers I. Tocolysis—the case for and against. In: BeardRW, SharpF editors. Preterm Labour and its Consequences. London : Royal College of Obstetricians and Gynaecologists, 1985: 199208.
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