SEARCH

SEARCH BY CITATION

Introduction

  1. Top of page
  2. Introduction
  3. Methods
  4. Results
  5. Conclusion

The objective of this review of the literature is to analyse recent evidence demonstrating that firstly, preterm labour is best considered as a set of complex diseases. Secondly, common causes of preterm labour have distinct, but frequently overlapping pathophysiological pathways. Thirdly, these pathways can be frequently identified in early pregnancy. Finally, tocolytic treatment is likely to be the most effective when used in combination with the treatment of the primary pathophysiological mechanisms or in the absence of identifiable causes of preterm labour (‘idiopathic’ preterm labour).

A further strategic goal is to consider how ‘primary prevention’ strategies can effectively reduce the occurrence of preterm labour, thus making tocolysis with oxytocin analogues, or other tocolytic agents, appear more effective in clinical practice. A summary of the primary causes of preterm labour is shown in Table 1.

Table 1.  Primary causes of preterm birth.
Pathogenic causes
Infection/inflammationBleeding/thrombosis
CervicalEarly stress
Uterine [DOWNWARDS ARROW] BMI
Substance abuseShort conception cycle <1 year
Multiple pregnancyAge <17 or >35 years
Medical causes
a) Fetal, b) Maternal, c) Mixed, d) Teratogenic
   Infection/inflammationWork/standing
   Substance abuseBleeding/thrombosis
   Multiple pregnancyNutrition
   Extreme stressUterine over distension

Methods

  1. Top of page
  2. Introduction
  3. Methods
  4. Results
  5. Conclusion

Multiple sources of information including unpublished studies were examined. In order to provide clinical context for considering use and effectiveness of tocolysis, we conducted an ‘expert’ systematic analysis to calculate population attributable risks (PAR) of clinically closely attributable causes/pathways of prematurity (<34 weeks) in representative populations in Denver, Colorado, USA.

Results

  1. Top of page
  2. Introduction
  3. Methods
  4. Results
  5. Conclusion

Complex Diseases

‘Complex diseases’ are caused by interactions between individuals' genomic endowment interacting with environmental or other factors to cause disease, including preterm labour and preterm birth (PTB). During pregnancy, such processes can be ‘extra complex’ because of maternal, fetal, and trophoblast interactions. Paternal factors can also cause or predispose to disease in pregnancy because of differentially expressed paternal genes in trophoblast tissues (‘imprinting’).

Pathological Pathways

Overall, five, main pathological pathways to prematurity were identified:

  • 1
    infection/inflammation
  • 2
    cervical factors
  • 3
    bleeding/thrombosis
  • 4
    multiple pregnancy
  • 5
    presumed endocrine/paracrine related disorders.

In an urban ‘safety net’ hospital, infection/inflammation and bleeding related mechanisms were most common (PAR >55%). In a large private hospital, multiple gestation and ‘idiopathic’ or presumed endocrine/paracrine mechanisms were most commonly identified (PAR >50%). Evidence of differing primary pathways to preterm labour/preterm delivery in diverse populations may account for the variances in the results of tocolytic treatments reported previously. The use of tocolysis in cases where infection/inflammation or bleeding/thrombosis are immediate causes of preterm labour/preterm birth is less likely to be effective than with other aetiologies.

Analyses of the recently published studies showed that infection/inflammation, endocrine/paracrine, substance abuse, and cervical function related pathways to prematurity can be identified and potentially treated in the earliest trimesters of pregnancy. Markers of early pregnancy intrauterine infection/inflammation include 15–18 week amniotic fluid interleukin (IL)-6, tumour necrosis factor (TNF)-α, matrix metalloprotease (MMP)-8, C-reactive protein and the presence of microorganisms or their products in amniotic fluid. Findings in early pregnancy of elevated levels of CRH or E3 predict increased risks of preterm labour/preterm birth, as do shortened cervix and cervical funneling.

Smoking, substance abuse, low body mass index (BMI) (<20), intrauterine growth restriction, and elevated cervical fetal fibronectin are also findings associated with preterm labour/preterm birth, which can be identified in early pregnancy. Taken together, such factors account for consistently large proportions of preterm births in differing populations.

Primary prevention strategies focusing on early pregnancy or preconception screening and treatment or prevention of causes of preterm birth are now being investigated. Possible approaches include the identification and elimination/mitigation of genitourinary infection/inflammation, short cervix, substance abuse, and possible stress-related mechanisms (abuse, excess standing, fatigue, etc.), or nutrition and prevention of multiple pregnancies due to assisted reproduction.

Tocolysis

Systematic care of these potentially preventable causes of preterm labour/preterm birth can increase the likelihood of successful tocolysis by increasing chances that remaining causes of preterm labour can be more effectively treatable by oxytocin analogues and other tocolytics. This analysis also suggests that tocolysis should be combined with clinical examination and focused treatment for primary as well as secondary pathophysiological preterm labour mechanisms.

Conclusion

  1. Top of page
  2. Introduction
  3. Methods
  4. Results
  5. Conclusion

From the results of this analysis, we can conclude that:

  • 1
    Common primary causes of preterm labour/preterm birth are frequently detectable and possibly remediable in early pregnancy or, possibly, before conception
  • 2
    Secondary prevention strategies, such as tocolysis, are most likely to be more effective if principal pathophysiological process can be specifically identified and effectively treated along with tocolytic treatment
  • 3
    Evidence-based ‘screen, treat, prevent’ approaches employed early in pregnancy, or possibly during preconception care, can increase the observed efficacy of tocolytic treatment.

These and other approaches focusing on the prevention of preterm labour/preterm birth are now being evaluated in well-controlled trials.