The Prediction and Prevention of Spontaneous Preterm Birth (SPB)

Fetal fibronectin testing
Fetal fibronectin (Ffn) is a protein found in amniotic fluid, placental tissue and the extracellular substance of the decidua basalis next to the placental intervillous space. The virtual disappearance of Ffn from the vaginal secretions by 22 weeks coincides with the fusion of the chorion and decidua capsularis with the decidua parietalis of the uterine wall; the reappearance of fibronectin before labour may represent the seperation of the chorion from the decidua prior to the onset of labour.

In women with uncomplicated pregnancies ending at term, Ffn can be detected in the cervical secretions of only 4% of pregnancies between 21 and 37 weeks². Ruptured membranes, recent (<24 hours) sexual intercourse, antepartum haemorrhage or vaginal examination may invalidate the test result by creating a false positive result³.

Unfortunately, Ffn testing in asymptomatic women i.e. not contracting is not a clinically useful test since it lacks the necessary accuracy⁴. However, in women experiencing preterm contractions, a negative test reduces the likelihood of delivery within 7-10 days from 3% to less than 1%; a positive test increases the likelihood of delivery from 3% to 14%4. A negative test therefore might form the basis for withholding interventions, with subsequent reductions in hospital admissions and inter-hospital transfers⁵. Ffn testing is available as a bedside test providing a result within minutes of testing so represents a potentially useful clinical test to differentiate between true and false preterm labour.

Cervical ultrasound
The assessment of cervical length using ultrasound is superior to digital examination as a predictor of SPB. The precise mechanism(s) whereby the length of the cervix influences the risk of SPB are not fully established but mechanical resistance of the cervix to delivery, and resistance to the ascent of micro-organisms are likely to be relevant.

The cervix is visualised best with transvaginal ultrasound (TVS) and this method also avoids the artefactual elongation of the cervix that is sometimes seen in the presence of a full maternal bladder when scanning trans-abdominally.

A number of studies have evaluated cervical length and risk of SPB and there is agreement that risk of SPB increases as cervical length decreases. However, it would appear that cervical length measurement alone is unlikely to become a clinically useful predictor of preterm spontaneous birth in asymptomatic women (ie not contracting), whether ‘high’ or ‘low’ risk; anywhere between 15% and 75% of high risk women with short cervical length will deliver preterm⁶. However, amongst contracting women a high negative predictive value can be expected to be useful since this would indicate a low risk of preterm birth and permit observation or discharge rather than intervention; the availability of a transvaginal scanning service is often a limiting factor in these circumstances.

Other potential predictors of SPB
Biological markers have been considered as predictors of SPB including maternal oestriol (E3), corticotrophin releasing hormon, relaxin, inflammatory cytokines and matrix metalloproteinase 9 (MMP-9). The most promising of these appears to be MMP-9 where elevated levels have been identified in amniotic fluid in association with labour and premature rupture of membranes. Further studies are required to determine whether MMP assays will become a clinically useful tool or not.

Prevention of preterm labour / delivery
The primary aim of predicting the risk of preterm labour is to target appropriate interventions to prolong delivery and to allow appropriate transfer and/or acceleration of fetal pulmonary maturity by the administration of maternal corticosteroids.

Progesterone
Progesterone is a smooth muscle relaxant and is a logical therapy for the prevention of preterm uterine activity. A recent meta-analysis of randomised trials comparing progesterone with placebo in women at increased risk of SPB demonstrated a halving of the incidence of delivery before 34 weeks gestation⁷. Treatment with progesterone may be unpleasant but appears to be safe for mother and child and such an intervention is gaining popularity amongst obstetricians in the UK. The use of progesterone in multiple pregnancies is not established and cannot currently be recommended.

Cervical cerclage (cervical stitch)
Women with a short cervix are at increased risk or preterm delivery. What appears to be more controversial is when, and in what group of patients, to use cervical cerclage is appropriate to prevent preterm delivery. Cerclage is traditionally offered to women with a history of one or more mid-trimester losses or other features suggestive of an ‘incompetent cervix’ but the diagnosis of cervical incompetence is imprecise so many sutures are placed for little benefit. Cervical length assessment is a more objective assessment of cervical function but in women with a short cervix, 29% will deliver <35 weeks if a stitch is inserted compared to 35% with no cerclage . This is a very modest reduction indicating that cerclage is likely to benefit only a small minority of women.

Antibiotics
Since the late 1970s, intrauterine infection has been increasingly implicated as a cause of preterm labour. Several randomized clinical trials have assessed the role of bacterial vaginosis (BV) treatment in prevention of preterm birth. Several large, well conducted research studies have provided conflicting evidence regarding the treatment of asymptomatic vaginal infections^9,10.

It appears that antibiotics used for the prevention of preterm birth are more likely to be successful if they are used in women with abnormal genital tract flora (rather than other risk factors for preterm birth) and if they are used early in pregnancy prior to infection. However, there is no convincing evidence of the benefit of antibiotics in the prevention or treatment of preterm labour in the absence of ruptured membranes.

Tocolytics
Tocolytics are drugs used to suppress uterine contractions. The most widely used tocolytics are betamimetics (Ritodrine, salbutamol) which delay delivery by up to 48 hours but have a high frequency of unpleasant maternal side effects. Calcium channel blockers such as nifedipine are popular alternatives associated with fewer maternal side-effects and are associated with equivalent efficacy¹¹.

The only tocolytic licensed for use in the UK is Atosiban. This is an oxytocin antagonist and has been compared in several trials against both betamimetics and calcium channel blockers¹². The side effects of Atosiban are less than with other tocolytic agents but it appears to be no more effective than calcium channel blockers in preventing preterm labour and the relatively high cost of Atosiban has hindered its more widespread use. There is no evidence to support the use of tocolytics as prophylaxis (i.e. in women at high risk but not contracting) or beyond 48 hours of presentation in apparent preterm labour.

Conclusion
Spontaneous preterm birth remains a significant challenge for health professionals involved in maternity care. Current methods of prediction are imprecise and prevention strategies of limited impact. The role of prophylaxis with progesterone supplementation is likely to grow but more research is necessary to identify the sub-group of women who are most likely to benefit from this treatment.

1. Lumley J; The epidemiology of preterm birth; Baillieres Clin. Obstet. Gynecol 1993; 7, 447-98
2. Lockwood CJ, Seneyi AE, Dische R et al; Fetal Fibronectin in cervical and vaginal secretions as a predictor of preterm delivery; N. Engl. J. Med 1991; 325, 669-74
3. McKenna DS, Chung K, Iams JD; Effect of digital examination on the expression of fetal Fibronectin; J Reprod Med 1999; 44,796-800
4. Honest H, Bachmann LM, Gupta JK, Kleijnen J, Khan KS; Accuracy of cervico-vaginal fetal Fibronectin test in predicting spontaneous preterm birth: systematic review; BMJ 2002; 325, 301-4
5. Joffe GM, Jacques D, Bemis-Heyes R et al; Impact of the fetal Fibronectin assay on admissions for preterm labour; Am J Obstet Gynecol 1999; 180, 581-6
6. Owen P, Mackemzie F; The prediction of preterm labour; Preterm Labour Managing Risk in Clinical Practice ed. Norman J, Greer I; published Cambridge University Press 2005
7. Coomarasamy A, Thangaratinam S, Gee H, Khan KS. Progesterone for the prevention of preterm birth: a critical evaluation of evidence; Eur J Obstet Gynecol Reprod Biol 2006 Dec; 129(2): 111-8
8. Berghella V, Odibo AO, To MS, Rust OA, Althuisius SM; Cerclage for short cervix on ultrasonography; meta-analysis of trials using individual patient level data; Obstet Gynecol 2005 Jul; 106(1): 181-9
9. Shennan A, Crawshaw S, Briley A, Hawken J, Seed P, Jones G, Poston L; A randomised controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal Fibronectin: the PREMET study; BJOG 2006 Jan; 113(1): 65-74
10. Varma R, Gupta JK; Antibiotic treatment of bacterial vaginosis in pregnancy: multiple meta-analyses and dilemmas in interpretation; Eur J Obstet Gynecol Reprod Biol 2006 Jan 1; 124(1):10-4
11. King JF, Flenady VJ, Papatsonis DN, Dekker GA, Carbonne B; Calcium channel blockers for inhibiting preterm labour; Cochrane Database Systematic Review 2003 (1)
12. Papatsonis D, Flenady V, Cole S, Liley H; Oxytocin receptor antagonists for prevention of preterm labour; Cochrane Database Systematic Review 2005 Jul 20 (3)

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