Correspondence: Dr H. McNamara, Perinatal Research Room F440, Womens Pavillion Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada.
The main problem with preterm labour is our lack of progress in the successful management of this condition. We need to reassess our approach to this problem because preterm labour is not a disease, but an event, which may result from multiple independent pathways. This problem has also been affected significantly by medical advances such as infertility treatments and changes in neonatal survival at the limit of viability. The specific challenges that we face in managing preterm labour include: problems with definition; aetiology, including genetic and infection components; diagnostic problems, such as true versus false labour and role of cervical length and fetal fibronectin; and specific interventions according to the antepartum, intrapartum and postpartum challenges. In order to address the main issue, and make future progress in the management of preterm labour, we should consider the implementation of a ‘Postpartum Preterm Labour Diagnostic Workup Protocol’. These data/workup results could be entered on web-based databases for each preterm labour ‘event’. An international research team could analyse data relating to specific aetiological patterns and subgroup analyses, leading to the collaborative development of ‘aetiology specific’ management modalities. This approach requires a close collaboration between clinicians and researchers, in order to make significant progress in this difficult area, and ultimately improve perinatal outcomes.
The main problem with spontaneous preterm labour is the lack of progress in the successful management of this condition. We need to be aware that preterm labour is not a disease, but an event, which may result from single or multiple, independent or interdependent pathways. Preterm labour is often the final step in a multifactorial process. It has been suggested that in some women, a single risk factor such as uterine distension due to a triplet pregnancy is sufficient to produce preterm labour, while in others, a combination of individually lesser risk factors may result in preterm labour1. Overall, the lack of progress in the management of preterm labour may be attributed to both clinical and research issues, which are interrelated.
Medical advances, such as infertility treatments, have significantly affected the problem of preterm labour. These advances have been associated with an increase in the incidence of preterm delivery, especially in multiple pregnancies. Furthermore, improvements in neonatal care have resulted in an increased neonatal survival at the lower limit of viability, increasing the impact of preterm birth and its consequences.
There are various challenges to the management of preterm labour, which have not been subjected to rigorous scientific review. These challenges may require an individualised approach for different patients, using expert committees or guidelines as the ‘backbone’ of the management plan. In highlighting the current problems and challenges in the management of preterm labour, we hope to open the discussion of how best to progress in the management of this difficult condition.
Clinical Problems and Preterm Labour
The clinical problems associated with our lack of progress in the management of preterm labour include the definition of preterm labour, diagnosis of the condition, aetiology and challenges relating to the treatment of the condition.
Problems Relating to the Definition of Preterm Labour
What is the definition of preterm labour in terms of gestational age (<37 weeks gestation)? What is the ‘clinically significant’ definition of preterm labour (<32–34 weeks gestation)? Are these definitions, the same? If not, why not? These are questions that need to be revisited by both clinicians and researchers involved in the management of preterm labour.
At 34 weeks gestation and above, neonatal survival rates in tertiary centres are considered equal to survival rates at term. However, ‘survival’ may not be the appropriate end point to be considered. Long-term adverse neonatal sequelae occur mainly in infants born <34 weeks gestation, but these adverse sequelae are not found exclusively in this group. In our institution, we do not generally perform detailed follow-up examinations on preterm infants >34 weeks gestation. Most long-term follow-up programmes only follow preterm infants born ≤28 weeks gestation. At the other end of the spectrum, there have been a number of reports of respiratory distress syndrome occurring at 37–38 weeks gestation in infants delivered by elective lower segment caesarean section2 and recent work suggests that even ‘mild’ prematurity may contribute to infant mortality3.
Another problem relating to the definition of preterm labour between 24 and 34 weeks gestation is the difference in aetiology, diagnosis, cause-specific management and neonatal outcomes across this gestational age range. There are sufficient differences to preclude women in preterm labour being considered as a homogeneous group.
Problems Relating to the Diagnosis (‘Identification’) of Preterm Labour
Since we propose that preterm labour is not a disease, but rather an ‘event’, it may be more appropriate to replace the term ‘diagnosis’ with the term ‘identification’ in this context.
There has been considerable discussion regarding the existence of ‘false’ labour, and specifically ‘false’ preterm labour, inferring that labour is a dichotomous true/false phenomenon. Should we instead consider labour, specifically preterm labour, as a ‘continuum’ (e.g. level a, b, c etc.), where we may encounter patients at various ‘levels’ of preterm labour, anywhere from the initial ‘subtle’ onset to stages further along in the process? Could cervical length +/− fetal fibronectin be used, in assigning patients to different levels along the continuum, leading to a greater understanding of the evolution and multiple aetiologies of preterm labour? It is a commonly held belief that 50% of preterm labour diagnoses are ‘incorrect’. However, this really means that 50% of preterm labour diagnoses do not result in preterm delivery, which is an entirely different issue.
Is the term ‘idiopathic’ preterm labour used appropriately? In general, the term ‘idiopathic’ should only be reserved for cases where all causes have been investigated and negative results are available. Unknown cause implies that we have performed a complete but fruitless search for a cause. Often, this is not the case. As suggested by Lettieri and colleagues, we need to invest both time and resources in the diagnosis of the primary cause of preterm labour, in each individual patient4.
The course of pregnancy and delivery affords three ‘time-windows’, antepartum, intrapartum and postpartum, which may be seen as multiple opportunities to attempt accurate ascertainment of the cause of all clinically relevant preterm labour events.
Problems Relating to the Aetiology of Preterm Labour
Current research in this area is focused on attempting to elucidate pathways to preterm labour, and identify single or multiple causes along these pathways and their potential inter-relationships. This type of study requires a combination of different strategies from both clinical research and basic research disciplines5.
For instance, the contribution of both genetic components6 and infective components7 to preterm labour are continually under investigation. These areas may contribute to knowledge regarding the aetiology of preterm labour, either independently or in combination. In terms of other factors, such as socio-economic status, social behaviour and stress-related issues5,8, we need to re-examine whether these ‘social’ issues are causal, confounding or modifying effects of other causal components. These inter-relationships are key to understanding the multiple inter-related aetiologies of preterm labour.
Problems Relating to the Treatment of Preterm Labour
In order to tailor management to a specific cause of preterm labour, it is essential to have invested both time and resources in elucidation of specific cause(s). We may need to revisit the issue of specificity of treatment. Should treatment be specific to both a) the ‘level’ of preterm labour on the ‘continuum’ and b) the identified cause(s)? The ‘one size fits all’ approach to the treatment of preterm labour clearly does not work, and this is one of the reasons for our lack of progress in this area. In general, it may be that the treatment of preterm labour appears unsuccessful because we are not specific in which subgroups, by level/cause, we target with specific treatments, when such treatments are in the research and development phase.
It is possible that we could be more successful if we used combination treatments selectively, so that combination therapy is ‘cause-driven’ e.g. triplets = bed rest and tocolysis; infection = antibiotics and tocolysis etc. It may be that treatments, previously discarded because of overall lack of efficacy, may be very efficacious in selected appropriate subgroups with preterm labour.
After specifically targeted treatment is used, we need to record carefully treatment outcomes, so that we may learn what is successful in preventing preterm birth in these specific subgroups. This will further advance our knowledge relating to aetiology, which, in turn, drives the search for new therapeutic options.
Research and Preterm Labour
Our progress in the clinical management of preterm labour is dependent on our conducting appropriate and productive research in this area and our effective translation of such research findings into clinical practice. However, the clinical problems previously described have a significantly negative effect on our ability to advance through research in the area of preterm labour. Furthermore, there are specific research problems which also need to addressed.
Problems Relating to the Definition of the Study Outcome
The distinction between preterm labour and preterm birth should be clear to researchers in this area. We need to be specific about the outcomes of importance. If we are studying preterm deliveries, then the outcome measure is ‘preterm birth’. However, if we are interested in the prediction and prevention of preterm labour, then the outcome measure is ‘preterm labour’, whether or not it results in preterm birth. Definitions of study outcomes need to be detailed and specific.
Problems Relating to the Definition of the Study Exposure
If the outcome is preterm birth, we may need to be specific about the exposure/determinants and differentiate between spontaneous preterm birth and iatrogenic preterm birth. The constructs for these outcomes, spontaneous preterm birth and iatrogenic preterm birth, may be quite different, in terms of exposure, risk factors and patient profiles.
Problems relating to the definition of the study population
The study population, and whether it is a general population or a selected population affect the relevance of study results. However, in the case of preterm labour, we may need to move our focus to the study of subgroups or restricted populations. This strategy may provide valuable information, for example, in terms of treatments that are effective in one subgroup with preterm labour, and not in other subgroups identified with the same ‘end-point’ condition.
Challenges in the Management of Preterm Labour
The specific challenges to the clinical management of preterm labour may be subdivided, by their timing in terms of pregnancy and delivery. Antepartum challenges include controversial issues such as: management at the limit of viability; emergency cervical cerclage; maternal transport; inpatient versus outpatient management; management at 32–37 weeks; and psychosocial assessment and therapy. There are many intrapartum challenges, which are discussed individually in detail by other authors. In addition, institution of placental examination, beginning in the intrapartum period, should be considered in all cases of preterm labour and preterm birth, in order to elucidate possible aetiological components. In terms of postpartum challenges, important progress in the area of preterm labour may be possible if we expand postpartum care delivery in the following areas: special parental consultation; and full postpartum diagnostic workup.
The majority of the challenges in the management of preterm labour relative to obstetrical practice occur in the antepartum period. These include, but are not limited to, the following particularly challenging areas
Preterm Labour: Management at the Limit of Viability
The management of families dealing with preterm labour at the limit of viability requires a joint approach involving both the obstetrician and the pediatrician, if possible together at the same time. This critical and sensitive issue is addressed in a Joint Statement9 from the Canadian Pediatric Society (CPS) and Society of Obstetricians and Gynecologists of Canada (SOGC), which is summarised in Table 19. The aims in joint management are to:
Table 1. Limit of viability.
< or = 22 weeks: not viable
1. compassionate care
2. no active treatment
3. no caesarean section
23–24 completed weeks: varied outcomes
1. consider expected results at resuscitation
2. limited benefit of caesarean section for infant
3. potential harm of caesarean section to the mother
25–26 completed weeks: most survive
1. any required neonatal care
2. caesarean section if indicated
1offer parents therapeutic choices before delivery occurs
2provide parents with full information on likely outcomes
4minimise parental and infant suffering when infant resuscitation and/or treatment are not in the infant's best interest.
The management itself is then tailored to the individual couple with consideration for the best interests, of the health of the mother, the best interests of the fetus, and the personal views of the now fully informed parents. It is especially important that treatment of all infants with a gestational age of 22–26 weeks should be tailored to the infant and the individual family9.
Preterm Labour and Emergency Cervical Cerclage
Unfortunately, rigorous scientific examination of the use of emergency cervical cerclage has not been undertaken. However, a recent report suggests that the technique may be of value in carefully selected cases10. It has been suggested that an emergency cervical cerclage should be considered only if all of the following criteria are fulfilled11:
2no significant bleeding
3abnormal dilatation of the cervix
4minimal uterine activity that subsides following bed rest and intravenous hydration
5absence of intra-amniotic infection
612 hour observation shows no change from above clinical status
7possibility of improvement in neonatal prognosis.
Preterm Labour and Maternal Transport
The critical issue in maternal transport is the clarification of which team, ‘sending’ or ‘receiving’, is responsible for the patient during the transfer process? In considering maternal transport in the setting of the management of preterm labour, there are two major questions that need to be addressed: a) who should be transported? and b) when should the transport take place?
Once the decision has been taken that the patient should be transported, the following factors must be considered12:
1availability of neonatal intensive care beds/neonatal care
2estimate of length of time before delivery
3estimate of transfer time
4availability of space for mother at tertiary center/perinatal care
7availability of two qualified transporting staff; one for the mother, one for the baby, should complicated delivery occur en route
8cervical dilatation: reassess immediately prior to transfer; if the cervix is dilated greater than 6 cm, transport is generally not advised.
If, after consideration of the above factors, a decision is taken to proceed with the maternal transfer, it is advisable to attempt inhibition of labour with tocolytics during transport, and prior to the arrival at the tertiary centre12.
The guidelines for maternal transport in the SOGC Advanced Labour and Risk Management Course (ALARM) include urging the obstetrician to be aware of the risks associated with the decision to conduct a maternal transport in the setting of preterm labour14. The guidelines advise that this decision should be based on evidence that is convincing, compelling and, most importantly, clearly documented. It is also critical to document in detail all communications between the sending/receiving obstetrician and also, communications between other clinicians at both relevant centres, including the establishment of a mutually acceptable transport plan14.
The best location for a preterm delivery is an adequately prepared tertiary referral centre, but the worst location for a preterm delivery is in a vehicle during transport. There should be clear agreement as to the unit responsible for the patient during transport, and this is occasionally a matter for discussion. This is particularly important if maternal transport is undertaken in the presence of possible contra-indications15.
The contra-indications to maternal transport may differ slightly from one area to another. In Canada, the contra-indications to maternal transport in the setting of preterm labour include14:
1inability to stabilise mother
2acute fetal distress requiring delivery
4weather conditions hazardous for travel
5no experienced attendants available to travel with the mother.
Preterm Labour: Inpatient Versus Outpatient Management
When the acute episode of preterm labour has subsided, and the patient remains undelivered, a management plan for the remainder of the pregnancy is required15. This should include the important decision regarding components of inpatient and outpatient management. The duration of hospitalisation following the acute event is governed by: cervical status; complicating diagnosis (cause?); gestational age; and home environment.
Prior to instituting outpatient management, problems that should be considered include:
5home uterine activity monitoring (HUAM).
A recent randomised controlled trial has examined this issue in a selected population of 250 women, following resolution of the acute episode of preterm labour16. In this study, there were no significant differences reported between the inpatient group and the outpatient group in terms of the following outcomes: mean gestational age at delivery; mean birth weight; and proportions of babies born before term. This group concluded that home care management following an acute episode of preterm labour is an efficient and acceptable alternative to hospital care, in a selected group of patients16.
Preterm Labour: Management at 32–37 Weeks
In many centres, treatment of preterm labour is discontinued at 32 weeks gestation, while in others it is not indicated after 34 weeks gestation. However, respiratory distressed syndrome (RDS) may occur at 37–38 weeks2, and other reports suggest that infant mortality and morbidity related to prematurity continues to be a problem in this subgroup of patients3.
In a recent retrospective study17 of 207 infants born between 34–36 weeks gestation, the results in Fig. 1 were obtained. In this study group, there was a decrease in both the incidence of RDS (15% reduced to 3.2%) going from 34 to 36 weeks gestation, and a decrease in the severity of the condition at 36 weeks gestation. However, it was concluded that neonatal complications of prematurity are still prevalent at 34–36 weeks, and it was suggested that we consider continuation of therapeutic management of preterm labour at a later gestational age17.
Preterm Labour and Psychosocial Assessment/Therapy
Preterm labour poses a great threat to the psychological progression of pregnancy. In theory, the increased psychological stress could, in turn, lead to the physiologic response of increased circulating catecholamines, with further compromise of uteroplacental blood flow and reduced fetal oxygenation18.
Other authors advise that every effort should be made to reassure the patient and to give anticipatory guidance, in order to reduce stress as much as realistically possible. Honest, realistic responses to questions may give the couple the information they need in their daily lives to cope with the events surrounding preterm labour19.
If preterm delivery is anticipated, it is critical that the couple be prepared psychologically, as well as physically for the delivery and possible outcomes. Also, plans should be instituted for psychological support in the postpartum period, where indicated.
Further challenges to clinical management occur in the intrapartum period. Other authors address these challenges individually. However, we need to realise the potential impact of placental examination, instituted in the intrapartum period, on the ability to address future questions relating to aetiology, during the antepartum period of subsequent pregnancies.
Preterm Labour and Placental Examination
Pathological examination of the placenta should be considered in all cases of preterm labour and preterm birth, in order to rule out acute/chronic inflammatory processes and lesions compatible with immunopathological conditions. It has been demonstrated that three placental abnormalities are significantly more frequent in placentae from patients with preterm labour20:
Decidual vasculopathy has been associated with maternal autoimmune or alloimmune disorders21. It has been suggested that chronic villitis may be due to a feto-maternal immunopathological condition22 or a congenital infection23. In a study by Lettieri and colleagues4, immunopathology such as decidual vasculopathy or chronic villitis, combined with maternal immunoserological findings, suggested a possible immunological cause in 30% of preterm labour cases.
Finally, we are faced with specific challenges to management of preterm labour in the postpartum period, an area that does not receive adequate attention in terms of the overall management of preterm labour. This is an area where changes in our approaches could theoretically lead to major advances, and progress in the management of preterm labour. The challenges in the postpartum period include special parental consultation and full postpartum diagnostic workup.
Preterm Labour: Special Parental Consultation
The special parental consultation should involve joint discussion, where possible, with the obstetrician and the paediatrician, regarding the delivery and potential neonatal outcomes. This is especially important for parents whose infants have died or have suffered major morbidity. The aim here is to come up with answers for the parents in terms of why this occurred and whether it is likely to happen again. At this point, the issue of continued psychological assessment/therapy should be addressed.
This consultation offers the opportunity to review results from investigations in both the mother and the infant, in order to piece together the possible steps that led up to the event of preterm birth15. Results of all investigations should be discussed, with particular reference to any modification of risk factors/medical conditions prior to subsequent pregnancies. If the aetiology of preterm labour/preterm birth is known, the problem should be treated aggressively before the next pregnancy. If no such answer is available, we should proceed immediately to the full postpartum diagnostic workup.
Preterm Labour: Full Postpartum Diagnostic Workup
The full postpartum diagnostic workup should include both basic investigations (anaemia/infection), and those investigations relating to causes of preterm labour/preterm birth, which are not possible during pregnancy, such as full urinary tract investigation and hysterosalpingogram. The existing model that we suggest for the postpartum diagnostic workup for preterm labour/preterm birth15, is similar to the protocol already instituted in the postpartum period to meticulously investigate the cause of stillbirth. According to one previous study, an exhaustive evaluation plan after delivery can identify possible causes in the majority, 96% of cases, of ‘idiopathic’ preterm labour, where preterm delivery occurred in spite of tocolysis and in the presence of intact membranes4. If we were to complete a detailed diagnostic work-up after every preterm delivery, an example of which we have previously published15, we might be able to elucidate different pathways, aetiologies or combinations of aetiologies responsible for preterm birth and ultimately make a detailed study of the aetiology of preterm labour. This, in turn, could facilitate the discovery of new strategies, alone or in combination, which would allow progress in the management of preterm labour, with positive implications for both individual patients, and all pregnant women in the future.
Preterm Labour: The Way Forward
We need to acknowledge that the ‘one size fits all’ approach to the management of preterm labour is not appropriate, so that we do not continue to discourage physicians, researchers, and most of all, our patients, regarding potential future progress in the management of this condition. We need to institute a fundamental change in our approach to the difficult and complicated issue of preterm labour and this will require new ways of addressing the problem.
Previous authors have compared preterm labour to cardiovascular disease (CVD) in terms of management challenges24. They have suggested that both preterm labour and CVD are multifactorial conditions with various clinical presentations. Management of CVD has been classified into primary, secondary and tertiary levels and it has been suggested that we adopt the approach in Fig. 2 in the management of preterm labour24.
In examining this model, it appears that most of our current efforts in clinical practice are directed at ‘tertiary care’, where our patients are already in preterm labour and we attempt to prevent preterm delivery. Since the best possible management of preterm labour is its prevention, i.e. primary care, we could make significant progress in this area if we invested more resources in the primary care area relative to preterm labour and its prevention. However, in order to address prevention, further knowledge regarding possible aetiologies is required, as preventive strategies will be determined by specific aetiologies in specific groups. Primary care/prevention is particularly important in preterm labour secondary to infection, where it may not be desirable to prevent either preterm labour or preterm delivery due to risk to the infant from the infective process.
Ultimately, in terms of preterm labour, we need to consider: 1) HOW? (‘level’ of preterm labour i.e. contractions, cervical change, ruptured membranes, combinations? where is patient on proposed ‘continuum’ of preterm labour?), 2) WHEN? (gestational age), 3) WHY? (aetiology). If we know how, when and why, then it is possible to design a specifically tailored management programme for that individual patient. Furthermore, we can record and disseminate our outcome results, which will further advance knowledge regarding both aetiology and specific successes in the management of preterm labour, leading to appropriate modification of management options in the future.