Preterm labour occurs between the 27th and 34th week of pregnancy. New, novel biomarkers will form the basis of future prevention, screening and treatment strategies
Lynne Sykes and TG Teoh
Parturition Research Group,
Institute of Reproductive and
Developmental Biology,
Imperial College, London, UK
Phillip R Bennett
St Mary’s Hospital,
Imperial College Healthcare NHS Trust, London, UK
Preterm labour is a major cause of neonatal morbidity and mortality. This article discusses the current understanding of the pathophysiology of preterm labour and the current predictive tools and strategies for its prevention. We also explore the potential future strategies for both the prediction and the prevention of preterm labour.
Definition
Preterm labour is defined as a labour occurring between the 24th and 37th week of pregnancy and can be further classified as extremely preterm (24–27 completed weeks), very preterm (28–31 completed weeks) and late preterm (32–36 completed weeks). The singleton preterm delivery rate in England over the last decade has been between 5.7 and 6.7%, with a transient increase to 7.5% between 2005 and 2006.(1)
Neonatal morbidity and mortality is dramatically increased in neonates born preterm. A total of 77% of neonatal deaths reported in the UK in 2006 were born preterm.(2) Short-term complications of prematurity include necrotising enterocolitis, sepsis, respiratory distress and periventricular haemorrhage, and long-term sequale include chronic lung disease and neurodevelopmental impairment. The financial cost to the NHS is increased the earlier the gestation of delivery. The estimated cost of hospitalisation for a term infant is £584 compared with £317,166 for an extremely preterm neonate. The projected financial burden for all babies born preterm per year is estimated at £2.946 billion for the subsequent 18 years.(3) With the introduction of antenatal corticosteroids and the improvement of neonatal intensive care provision, neonatal morbidity and mortality have decreased over the last few decades. However, major advances in the prevention of preterm labour are still required.
Pathophysiology
Preterm birth is a complex clinical syndrome with multiple aetiologies. Spontaneous preterm rupture of membranes (ROM) and labour account for the majority of preterm deliveries, and in most cases the cause is not identified. Identifiable causes of preterm labour include placental abruption and cervical insufficiency, the latter classically presenting as painless dilatation of the cervix. Infection and inflammation are associated with preterm labour and are independent risk factors for brain injury. Although the initial triggers of preterm labour are not fully understood, the biochemical pathways that result in the rupture of foetal membranes, uterine contractility and cervical dilation are common to those activated in term labour.
During pregnancy the uterus remains quiescent. At the onset of labour a cascade of biochemical changes occurs, and the uterus becomes a contractile organ. As labour approaches, foetal membranes become a rich source of prostaglandin synthesis via the enzyme cyclooxygenase-2 (COX-2). Matrix metalloproteinases (MMPs) produced by foetal membranes lead to programmed proteolysis and rupture of the membranes. Premature activation of MMPs are thought to contribute to preterm ROM. Matrix metalloproteinases and prostaglandins also contribute to cervical ripening. The cervix functions as both a mechanical and immunological barrier. As labour approaches there is an influx of leukocytes, and the cervix undergoes extensive remodelling leading to dilation.
A common factor in these biochemical changes is the transcription factor nuclear factor kappa B (NF-κB). Nuclear factor kappa B is classically associated with inflammation controlling the expression of cytokines such as interleukin- (IL) 1β, tumour necrosis factor (TNF) alpha, IL-8 and IL-6. Nuclear factor kappa B also appears to play a pivotal role in the transcriptional regulation of contractile associated genes in the myometrium and foetal membranes, for example connexin 43, the oxytocin receptor and COX-2.
Current screening methods for the prediction of preterm labour
History and examination
The most commonly applied screening method for assessing risk of preterm labour is history and examination. A history of prior mid-trimester loss or preterm labour can increase the risk of preterm labour to 25–30%. Symptoms of threatened preterm labour increase the risk of early delivery, yet in 70% of cases the pregnancy continues until term.(4) Cervical length assessment by digital examination is not considered to be as reliable as ultrasound; however, it still plays a role in assessing for other signs of cervical ripening in women presenting with threatened preterm labour.
Transvaginal ultrasound assessment of cervical length
Cervical length screening can be adopted in high-risk women. The shorter the cervix, the higher the risk of preterm labour. A cervical length of <25mm in asymptomatic high-risk women has a positive predictive value of 70% for delivery <35 weeks if detected at 14–18 weeks and 40% if detected at 18–22 weeks.(5) In women presenting with threatened preterm labour, a recent meta analysis concluded a cut off of 15mm gives a positive predictive value of 60% and a negative predictive value of 96% for delivery within one week if presenting <34 weeks of gestation.(6)
Qualitative foetal fibronectin
Foetal fibronectin is an extracellular matrix glycoprotein secreted by the chorion. If any biochemical disruption to the foetal membranes occurs, this glycoprotein can be detected in the posterior fornix. A negative result places both asymptomatic and symptomatic women at low risk of preterm labour. A systematic review of 26,876 women revealed a likelihood ratio (LR) for positive results of 4.01 (95% confidence interval [CI] 2.39–5.49) for predicting birth <34 weeks in asymptomatic women, with a corresponding LR for negative results of 0.78 (95% CI 0.72–0.84). In symptomatic women, the LR for a positive result was 5.42 (95%CI 4.36–6.74) for delivery within 7–10 days and 0.25 (95%CI 0.2–0.31) for a negative result.(7) Cost savings are seen with the introduction of foetal fibronectin testing as a result of a reduction in hospitalisation, administration of corticosteroids and in utero transfers to tertiary referral centres in women with a negative result.(8)
Current strategies for the prevention of preterm labour
Cerclage
Cervical cerclage for the prevention of preterm delivery was first described in the 1950s and involves the placement of a purse string suture around the cervix. It aims to provide mechanical support to the cervix and helps to reduce the risk of ascending infection by prevention of cervical shortening. Cervical cerclage is placed electively at around 12 weeks in women with a strong history suggestive of cervical insufficiency or is placed if the cervix becomes short as detected by ultrasound. A multicentre randomised trial of history-indicated cervical cerclage in women with three or more mid-trimester losses of preterm births showed a reduction in the risk of PTB <33 weeks from 32 to 15%.(9) For high-risk women with a short cervix (<25mm), a meta-analysis of 208 women concluded a statistically significant reduction in the rate of preterm delivery <35 weeks with cerclage placement (relative risk 0.61; 95%CI 0.4–0.92).(10) There is also evidence that cervical cerclage in women at high-risk results in a statistically significant reduction of a composite of perinatal mortality and morbidity.(11)
Progesterone
There have been several large trials looking at the potential benefits of vaginal progesterone to reduce the rates of preterm delivery using gestational age of delivery as a primary outcome. Until recently, there have been no studies showing a statistically significant benefit to the neonate. A large, multicentre, randomised controlled trial including mainly women without a prior history of preterm birth has shown a 45% reduction in preterm labour at <33 weeks using 90mg vaginal progesterone in women with a short cervix of 10–20mm.(12) A composite of neonatal indices were also reduced, including a 60% reduction in respiratory distress syndrome. We eagerly await results from the multicentre trial OPPTIMUM, a randomised controlled trial of high-risk women which is specifically powered for neonatal outcome.
Tocolytics
A short course of tocolysis for women with threatened preterm labour is given to allow time for the administration of corticosteroids to stimulate foetal maturation; however, no long term neonatal benefits from tocolytics have been demonstrated. This is partly because most women in threatened preterm labour were not destined to labour; conversely, for those women that really did need tocolysis, once uterine contractility is established it is likely that the multiple biochemical pathways involved are too advanced to be overcome by transient inhibition of the contractions. Nifedipine and atosiban are the most commonly used tocolytics in the UK. There is no evidence that atosiban is superior to nifedipine, and with the trend towards an improvement in perinatal morbidity, low side effect profile and direct cost comparison, nifedipine is a reasonable first-line tocolytic.
Future strategies for the prevention of preterm labour – advances in the prediction of those at risk
Advances in transvaginal ultrasound
Introduction of three-dimensional ultrasound allows us to take multiplanar measurements and can therefore more accurately identify the endocervical canal, with the added benefit of measuring other parameters such as cervical volume, vascularity index (VI), flow index and vascularity–flow index. The VI represents the presence of blood vessels in the tissue, and the flow index is average intensity of flow in the vessels. In women who have had previous cervical treatment we may find that reduced vascularity is directly proportional to the degree of scarring, which may provide a novel measure of risk of preterm labour in this population. A study of three-dimensional ultrasound in high-risk women is currently being undertaken at Imperial College NHS Healthcare Trust.
Advances in the development of biochemical biomarkers
A recent meta-analysis of novel biomarkers examined 72 studies and evaluated 30 novel biomarkers for the prediction of preterm labour.(13) The authors concluded that cervico-vaginal proteomic profile, cervico-vaginal prolactin and amniotic fluid MMP 8 had a LR of >10. Four other biomarkers had moderate predictive accuracy including IL-6 and angiogenin in amniotic fluid and human chorionic gonadotropin (HCG) and phosphorylated insulin-like growth factor binding protein-1 (p-IGFBP-1) in cervico-vaginal fluid. The value of quantitative foetal fibronectin is being evaluated in a double blinded study, EQUIPP, to determine if the positive predictive value of the test can be improved.
With the developing interest in the role of inflammation in preterm labour, many proinflammatory cytokines have been investigated for their potential use as biomarkers. For example, a high concentration of cervico-vaginal and serum IL-6 is associated with a higher risk of preterm labour. Maternal serum IL-6 has also been shown to increase the risk of neonatal intraventricular haemorrhage and chronic lung disease.(14) One of the most common causes of inflammation is infection, and approximately 30% of preterm deliveries are associated with an infective process.(15) However, this is likely to be an underestimate as standard culturing methods do not detect all organisms. Bacterial detection rates could be improved with technology that combines amplification of the 16s ribosomal RNA gene by polymerase chain reaction (PCR) and very deep sequencing of the PCR products. We are currently examining the potential of this technique for predicting preterm labour in a high-risk cohort.
The ‘omics’ collectively describes the study of the genome (DNA), transcriptome (mRNA), proteome (proteome) and metabolome (metabolites). A recent small study characterised the proteomic profile of cervico-vaginal fluid of five women delivering preterm in comparison with a cohort that delivered at term.(16) From this profile, two proteins, desmoplakin isoform-1 and stratifin, had a sensitivity of 100%. We are examining the metabolomic profile of blood and urine in high-risk women in early pregnancy. With the aid of mass spectrometry and nuclear magnetic resonance spectroscopy, we hope to identify novel biomarkers for both cervical shortening and preterm labour.
Future strategies for the prevention of preterm labour: advances in potential future treatments
Future therapeutic options for the prevention and treatment of preterm labour will need to overcome several key challenges. The safety profile for therapeutic agents in pregnancy is dependent on establishing transplacental transfer and assuring no risk of teratogenicity. Secondly, the decision to prevent preterm labour must be supported by assurance of foetal wellbeing and absence of infection. By targeting the inflammatory pathways in conjunction with the labour-associated biochemical pathways, there is potential to provide anti-inflammatory neuroprotection as well as preventing preterm labour. An anti-inflammatory prostaglandin, 15dPGJ2 (which inhibits NF-κB in cultured myocytes and amniocytes), has shown promising results in an animal model of preterm labour.(17)
Conclusions
Current treatments have proved disappointing in terms of delaying preterm labour and improving neonatal outcome as a result of the complexity of the preterm parturition syndrome. Despite clear evidence that both cervical cerclage and progesterone can reduce the risk of preterm labour, the focus is now on determining if this translates to an improvement in neonatal outcome. This review has highlighted the need for continued research into the pathophysiology and prevention of preterm labour. Future strategies for the prevention of preterm labour are likely to be developed from the discovery of novel biomarkers that will serve as both screening tools and novel therapeutic targets.
References
- Sykes L et al. Targeting immune activation in the prevention of preterm labour. Eur J Obstet Gynaecol 2011;6(2):100–6.
- Acolet D, Springett A, Golightly S. Confidential Enquiry into Maternal and Child Health (CEMACH) Perinatal Mortality 2006: England, Wales and Northern Ireland. CEMACH:London 2008.
- Petrou S, Eddama O, Mangham L. A structured review of the recent literature on the economic consequences of preterm birth. Arch Dis Child Fetal Neonatal Ed 2011;96(3):F225–32.
- King JF et al. Beta-mimetics in preterm labour: an overview of the randomised controlled trials. Br J Obstet Gynaecol 1988;95(3):211–22.
- Berghella V et al. Cervical ultrasonography compared with manual examination as a predictor of preterm delivery. Am J Obstet Gynecol 1997;177(4):723–30.
- Sotiriadis A et al. Transvaginal cervical length measurement for prediction of preterm birth in women with threatened preterm labor: a meta-analysis. Ultrasound Obstet Gynecol 2010;35(1):54–64.
- Honest H et al. Accuracy of cervicovaginal fetal fibronectin test in predicting risk of spontaneous preterm birth: systematic review. BMJ 2002;325(7359):301.
- Dutta D, Norman JE. The efficacy of fetal fibronectin testing in minimising hospital admissions, length of hospital stay and cost savings in women presenting with symptoms of pre-term labour. J Obstet Gynaecol 2010;30(8):768–73.
- Final report of the Medical Research Council/Royal College of Obstetricians and Gynaecologists multicentre randomised trial of cervical cerclage. MRC/RCOG Working Party on Cervical Cerclage. Br J Obstet Gynaecol 1993;100(6):516–23.
- Berghella V et al. Effectiveness of cerclage according to severity of cervical length shortening: a meta-analysis. Ultrasound Obstet Gynecol 2010;35(4):468–73.
- Berghella V et al. Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth: a meta-analysis. Obstet Gynecol 2011;117(3):663–71.
- Hassan SS et al. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomised, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2011;38(1):18–31.
- Conde-Agudelo A et al. Novel biomarkers for the prediction of the spontaneous preterm birth phenotype: a systematic review and meta-analysis. BJOG 2011;118(9):1042–54.
- Sorokin Y et al. Maternal serum interleukin-6, C-reactive protein and matrix metalloproteinase-9 concentrations as risk factors for preterm birth <32 weeks and adverse neonatal outcomes. Am J Perinatol 2010;27(8):631–40.
- Challis JRG. Mechanism of parturition and preterm labor. Obstet Gynecol Surv 2000;55(10):650–60.
- Shah SJ et al. Identification and quantification of preterm birth biomarkers in human cervicovaginal fluid by liquid chromatography/tandem mass spectrometry. J Proteome Res 2009;8(5):2407–17.
- Pirianov G et al. The cyclopentenone 15-deoxy-delta 12,14-prostaglandin J(2) delays lipopolysaccharide-induced preterm delivery and reduces mortality in the newborn mouse. Endocrinology 2009;150(2):699–706.
