Cervical insufficiency: prediction, diagnosis and prevention

Authors


Maternal and Fetal Health, Division of Reproduction and Endocrinology, St Thomas’ Hospital Campus, King's College London, Westminster Bridge Road, London SE1 7EH, UK Email: manju.chandiramani@kcl.ac.uk

Abstract

  • • Predicting preterm birth secondary to cervical insufficiency is based mainly on previous history.
  • • Prediction has become more effective with the use of transvaginal ultrasonography and fetal fibronectin.
  • • Prophylactic and reactive interventions remain largely unevaluated or ineffective.
  • • A combination of interventions, including cerclage, progesterone, antibiotics and tocolytics, are routinely used in the clinical management.

Learning objectives:

  • • To understand how predictive tools can guide clinicians in identifying ‘at-risk’ women.
  • • To be aware of the limitations of research into diagnosis and prevention.

Ethical issues:

  • • How can the risk/benefit of uncertain interventions be balanced in women at high risk?

Please cite this article as: Chandiramani M, Shennan AH. Cervical insufficiency: prediction, diagnosis and prevention. The Obstetrician & Gynaecologist 2008;10: 99–106.

Introduction

The incidence of preterm birth, defined as before 37 weeks of gestation, continues to rise even in the developed world, where it accounts for 12.5% of infants (>500 000 annually in the USA) being born preterm. The yearly cost is in excess of $26.2 billion for the USA.1 Amongst low-risk European women aged 20–40 years, there has been a 51% increase in spontaneous early delivery in the last decade,2 reinforcing the fact that clinicians have been unable to reduce rates.3 Assisted reproductive techniques and multiple pregnancies have contributed to the rise. Iatrogenic causes (hypertension, diabetes, antepartum haemorrhage, intrauterine growth restriction) account for a significant proportion (30%) of preterm birth, particularly at earlier gestations; these are increasing.4 Spontaneous preterm birth is often associated with infection/inflammation and preterm, prelabour rupture of membranes.

Advances in neonatal medicine and antenatal corticosteroid use have significantly reduced neonatal morbidity and mortality. Our ability to predict women who will deliver preterm has improved through the use of cervical length assessment and fetal fibronectin testing. These are often targeted at women with poor past obstetric history. The varied causes of spontaneous preterm birth make it unlikely that a single measure will be effective in prevention. As a result, women tend to be managed with a combination of prophylactic (cerclage, progesterone, antibiotics) and reactive (emergency cerclage, antibiotics, corticosteroids, tocolytics and timely in utero transfer to maternity units with adequate neonatal facilities) measures. This review focuses on cervical insufficiency as a cause of spontaneous preterm birth and its prediction, diagnosis and prevention.

Aetiology

Regardless of the cause, spontaneous preterm birth is a consequence of premature cervical changes of effacement and dilatation. Because clinicians tend to encounter women late in this pathological process, it is often difficult to ascertain whether the cervix is truly ‘weak’ or whether another process has contributed to its change. As a result, cervical insufficiency is a diagnosis often made retrospectively after a woman has had a second trimester miscarriage or spontaneous preterm birth. Cervical insufficiency, defined as the inability of the cervix to retain a pregnancy in the absence of contractions or labour, is likely to represent a continuum,5 influenced by a number of factors. The incidence of true cervical insufficiency has been estimated to be 1%.6

Normally, the cervix maintains the fetus within the uterine cavity, providing mechanical strength and support and acting as a barrier from ascending infection. A weak cervix can lack the inherent baseline strength necessary to function in this way and to resist change or deformation described as effacement, funnelling and dilatation.7 As the pregnancy progresses and the fetus becomes heavier, the mechanical stress can result in cervical shortening. In turn, this increases the likelihood of exposure to ascending infection and stimulation of an inflammatory process, culminating in a spontaneous preterm birth. A threshold seems to be breached that differentiates those who go on to deliver preterm, as even a short cervix (<10 mm) with a closed external os often results in a term pregnancy.8 If another stimulus unrelated to cervical ‘weakness’ results in cervical shortening, the ‘last straw’ may still be membrane exposure precipitating infection and delivery.

Prediction

Women with inherent cervical weakness are difficult to identify. Some are identified on the basis of a previous preterm birth or second trimester loss, while others have factors in their history that alert clinicians to question the inherent cervical strength. Cervical disease resulting from congenital disorders (diethylstilbestrol [DES] exposure) and surgical or cervical trauma (surgical termination of pregnancy, repeated dilatation and curettage, loop electrosurgical excision procedure [LEEP], cold knife conisation, trachelectomy) all increase the likelihood of cervical weakness and subsequent adverse pregnancy outcomes. The mechanism whereby toxic substances, such as cigarettes or illicit drugs, cause early birth is unclear but probably related to other factors.

History

A previous preterm birth or second trimester loss is a significant factor that contributes to a woman's risk of subsequent preterm birth. In a study9 of 1711 multiparous women with a singleton pregnancy, women with a prior spontaneous preterm birth had a 2.5-fold increase in the risk of spontaneous preterm birth in their index pregnancy over those with no prior spontaneous preterm birth (21.7% versus 8.8%; P ≤0.01). This means that almost a quarter of women who have had a previous early spontaneous preterm birth (at 23–27 weeks of gestation) will deliver at less than 28 weeks of gestation in a subsequent pregnancy.

Another study,10 of 154 809 women, demonstrated that if the first pregnancy resulted in a spontaneous preterm birth, affected women were more likely not only to deliver preterm spontaneously (adjusted odds ratio [OR] 3.6, 95% CI 3.2–4.0), but also iatrogenically (OR 2.5, 95% CI 2.1–3.0) in the subsequent pregnancy. Similarly, if the first pregnancy resulted in an iatrogenic delivery, they were over 10 times more likely to have an iatrogenic preterm birth in their second pregnancy, highlighting that the two clinical subtypes may share common aetiologies. How often these events are primarily related to a cervical problem is simply not known.

In a Scottish study11 of 84 391 first births, the risk of spontaneous preterm birth among nulliparous women was positively associated with the number of previous therapeutic abortions and smoking, amongst other things. Two or more previous miscarriages were more strongly associated with extreme preterm delivery, i.e. birth between 24–28 weeks, compared with births between 29–36 weeks. In another study,12 women with a history of LEEP, cold knife conisation and cryotherapy all independently had shorter cervical lengths than low-risk controls and similar lengths to women with previous spontaneous preterm birth. In women with a history of LEEP, a cervix <30 mm on transvaginal ultrasonography predicted preterm birth with a positive predictive value of 54% and a negative predictive value of 95%.12 This strongly suggests that any form of cervical treatment, probably related to degree of trauma, could increase risk.

Despite the fact that risk factors including maternal characteristics (previous miscarriages, terminations of pregnancy, smoking, etc.) and second trimester serum screening have been shown to be associated with preterm birth, models using this information probably do not have the predictive ability for any degree of spontaneous preterm birth, which would allow useful population-based screening.11 Similar findings have been found using other independent risk scoring systems, with low sensitivities of about 20% and low positive predictive values of about 30% for preterm birth.13

Cervical length assessment, fetal fibronectin and infection screening

A recent systematic review14 of available evidence has shown that cervical evaluation by transvaginal ultrasonography (Figure 1a and Figure 1b), fetal fibronectin (Figure 2a, Figure 2b and Figure 2c) and interleukin-6 in amniotic fluid are the best methods for predicting preterm birth. In both low- and high-risk pregnancies, the risk of preterm birth increases exponentially with decreasing cervical length. As a result, detection of cervical shortening and funnelling on transvaginal ultrasonography is a better predictor of preterm birth than relying on history alone. In fact, with cervical shortening to ≤15 mm, there is almost a 50% risk of spontaneous preterm birth at ≤32 weeks.15 Interventions to improve outcome in women with a short cervix remain unproven.

Figure 1a.

Transvaginal ultrasound scan with calipers placed at the internal and external os and a cervical length of 26 mm

Figure 1b.

Transvaginal ultrasound scan with calipers showing a cervical length of 52 mm following preconception transabdominal cervical cerclage. Note level of stitch differs significantly between Figure 1a and b

Figure 2a.

Fibronectin kit

Figure 2b.

Vaginal swab in buffer for 10 minutes

Figure 2c.

Negative fibronectin test showing only the control line

As the cervix shortens in symptomatic and asymptomatic women, the presence of fetal fibronectin (fFN), a glycoprotein physiologically found in high concentrations in cervicovaginal secretions prior to term but absent between 22–35 weeks of gestation, can be an effective biochemical investigation to use alongside cervical length assessment. It has a negative predictive value of about 99% for predicting preterm birth within 7 days in symptomatic women, with a positive predictive value of about 20%.16,17 A positive test in asymptomatic women has a likelihood ratio of 15 for delivery at <30 weeks of gestation (Table 1).18 Because of its ability to predict accurately those women who are unlikely to deliver in upcoming weeks, management can be targeted appropriately, avoiding unnecessary corticosteroid administration and lengthy inpatient stays, resulting in the judicious use of healthcare resources.

Table 1. Fetal fibronectin at 24 and 27 weeks of gestation as a predictor of spontaneous preterm birth at <30 weeks of gestation18Thumbnail image of

Although cervical insufficiency has cervical ripening as its predominant feature, it may not always be caused by a primary cervical problem but, rather, by an inflammatory or infective process.19 Intrauterine infection has been implicated in up to 50% of women with a clinical presentation consistent with acute cervical insufficiency.20 The presence of a subclinical infection can trigger cytokine production and the synthesis and release of prostaglandins, which can precede cervical change. The relationship between inflammation and preterm birth is supported by the association of positive intrauterine cultures and elevated cord blood interleukin-6 with polymorphonuclear infiltrations of the free membranes, chorionic plate and umbilical cord.21

Although it is possible to screen for vaginal organisms and inflammatory markers, studies have been limited in their ability to predict women accurately based on these tests. For instance, the organisms that cause bacterial vaginosis, which affects up to 35% of asymptomatic pregnant women,22 have been associated with adverse pregnancy outcome. In fact, the presence of bacterial vaginosis before 20 weeks of gestation has been found to be an independent risk factor for delivery of an infant with low birthweight, preterm delivery of a low birthweight infant, indicated preterm delivery and clinical chorioamnionitis.23 The timing and diagnosis of bacterial vaginosis appears to be significant: a recent study by Guerra et al.24 showed that early screening (prior to 10 weeks of gestation) and diagnosis of bacterial vaginosis in pregnant women who had experienced a previous preterm birth, increased the risk of a second trimester miscarriage or a preterm birth when bacterial vaginosis was present (OR 4.56; 95% CI 2.54–8.93) although the presence of bacterial vaginosis in the second trimester did not significantly increase the risk of preterm birth.

Diagnosis

Unfortunately, there are no prepregnancy tests to reliably confirm cervical insufficiency in at-risk women. In the past, clinicians have suggested a variety of tests including: assessment of the width of the cervical canal by hysterosalpingogram; ease of insertion of cervical dilators of various diameters; force required to withdraw a Foley catheter with its bulb inflated through the internal os; and different methods to measure force required to stretch the cervix using an intracervical balloon.25 None of these has been validated in rigorous clinical studies. The obvious flaw with these techniques is the failure to account for the effects of pregnancy on the dynamic capabilities of the cervix.

With the advent of transvaginal ultrasonography and measurement of cervical length features such as shortening, effacement and dilatation with the presence of funnelling and prolapse of the membranes, have enabled clinicians to predict outcome long before symptoms occur, but we do not know if this is indicative of a primary cervical problem. Between 20–28 weeks most women have a median cervical length of 35 mm which decreases gradually, as pregnancy advances, to about 30 mm at term. Without any reliable, objective method of distinguishing cervical insufficiency from other causes of premature cervical change, management is pragmatically based on combining features within the history (e.g. previous painless dilatation, cervical surgery) with ultrasound findings.

Prevention

Although prediction of cervical weakness has evolved and become more precise with the use of transvaginal ultrasonography, fetal fibronectin assays and the use of molecular markers, preventative measures resulting in prolongation of pregnancy with improved neonatal and longer-term outcomes remain more elusive. Nonetheless, preventative methods that are employed include the avoidance of predisposing factors where possible, ranging from the avoidance of surgical trauma to the cervix and smoking cessation. Whether reduction of physical activity and work, cessation of sexual activity and the prophylactic use of cervical cerclage, progesterone and antibiotics are beneficial, remains unclear.

A diagnosis of precancerous changes in the cervix is associated with an increased risk of preterm birth and the type of treatment confers a small additional risk: the use of diathermy is associated with an adjusted OR of 1.72, compared with 1.1 for women treated using laser ablation.26 Additionally, in the case of surgical termination of pregnancy and surgical or medical management of early miscarriage, there may be some value to using prostaglandin analogues such as misoprostol with antiprogesterone priming with mifepristone27 to avoid excessive dilatation force, haemorrhage and resultant cervical trauma, which can weaken the cervix considerably.

Cervical cerclage

There are no established guidelines of indications for cervical cerclage and the decision is often made by a senior obstetrician with some degree of specialist knowledge. In women with true cervical weakness, as evidenced by multiple midtrimester losses or early deliveries associated with risk factors such as extensive cervical trauma, current evidence regarding the decision to perform elective transvaginal cervical cerclage is conflicting.28–30 Although there does seem to be an overall reduction in the rates of preterm birth in some studies, this does not necessarily translate into improved neonatal outcomes. Despite this, it is a widely accepted practice in these very high-risk women where the benefit of cerclage outweighs risk. There is little evidence to support the use of cerclage in women with two or fewer previous midtrimester losses (or preterm births) as an isolated finding, although clinicians are frequently compelled to do so by their need to help.

Anecdotally, other forms of cerclage, involving mobilising the bladder (Shirodkar cerclage) or insertion via laparotomy (transabdominal cerclage) may improve outcome but there is little prospective evidence to support this. Figure 1a and Figure 1b shows the suture site on ultrasound using an abdominal and vaginal approach. Cervical length remains a good predictor even in these women.8 Mersilene® (Ethicon Ltd., Livingston, UK) tape is often the suture material of choice in preventing the suture from tearing out (Figure 3). It is unknown whether other materials confer any risk/benefit (see Figure 4). A loop with two knots is frequently left to facilitate removal of the purse string (McDonald) cerclage (Figure 5).

Figure 3.

Material of choice – Mersilene tape with two needles

Figure 4.

Suture after removal at 37 weeks showing two knots (nylon)

Figure 5.

Suture after removal at 37 weeks showing two knots (Mersilene tape)

An alternative approach to elective cerclage is insertion once an insufficient cervix, defined by the presence of dynamic changes of shortening, funnelling, dilatation or prolapse of membranes, is detected on transvaginal ultrasonography. However, there is conflicting evidence regarding the benefit of ultrasound-indicated31–34 and rescue cerclage,35–37 possibly because of the poor selection of women likely to benefit. Further research is needed in this area. In women who have evidence of an evolving pathological process, it is also unclear at what cervical length to intervene. Elevated inflammatory markers such as interleukin-8 (IL-8) may identify those women at risk38 but interventions in these women need to be trialled.

Progesterone

Recently, the use of progesterone, which is responsible for maintaining myometrial quiescence during pregnancy, has been advocated in the prevention of preterm birth in women at risk. The evidence on the correct dosage, agent, gestational age at initiation and cessation of intervention and the long-term maternal and neonatal adverse effects is, however, limited. Two randomised clinical trials39,40 have reported significant reduction in preterm birth with the use of progesterone. In a Cochrane meta-analysis41 of 988 women assessing the benefits and risks of progesterone administration during pregnancy, there was a reduction in the risk of preterm birth at <37 weeks (6 studies; relative risk 0.65, 95% CI 0.54–0.79). Some clinicians use it in conjunction with cervical cerclage in high-risk women, although it remains unclear whether this confers benefit in terms of both prolongation of pregnancy and neonatal outcome. Recent trials have targeted progesterone for the short cervix and the results are promising, suggesting a reduction by almost half in preterm births <34 weeks in singleton pregnancies.42 Further UK-based trials evaluating neonatal outcome are ongoing. Until improved outcome is established, progesterone use should remain in the research setting.

Antibiotics

As infection is likely to be the final event that precipitates preterm birth, it is reasonable to presume that treating organisms detected on vaginal swabs will prevent the stimulation of a complex inflammatory response with the concomitant release of cytokines. The presence of abnormal vaginal flora and bacterial vaginosis in early pregnancy increases the risk of miscarriage and preterm birth23,24 but there is conflicting evidence regarding treatment. In a Cochrane review43 of 5300 women examining the effects of antibiotic treatment of bacterial vaginosis in pregnancy, antibiotic therapy did not significantly reduce the risk of preterm birth at <37 weeks of gestation, although it did eradicate bacterial vaginosis and seemed to be of benefit to women with a previous preterm birth. Okun et al.44 found no evidence to support its use in pregnancy to reduce the risk of preterm birth, while other studies suggest a 40–60% reduction in the incidence of preterm birth, even in low-risk women.45 Although early preterm birth is likely to have an infectious component, the use of ineffective antibiotics in inappropriate women at incorrect gestations can contribute to the controversy regarding their use. Based on their potential actually to increase the risk of preterm birth,46 the authors recommend that antibiotics are not used routinely in asymptomatic high-risk women until better evidence regarding the correct antibiotic and gestation at which to use it is clear.

Conclusion

Transvaginal ultrasound and fetal fibronectin have improved our ability to predict women who will have an early delivery based on premature cervical change, which may, in part, be the result of primary cervical disease. Certain aspects of prophylactic prevention should be better targeted to decrease risk factors for developing cervical insufficiency, including lifestyle changes (smoking) and better priming of the cervix to avoid surgical trauma. Without better evidence to guide practice, however, cerclage and the use of progesterone and antibiotics are largely targeted according to risk and clinician preference. It remains clear that more evidence is desperately required, particularly with regard to interventions. Until this is available, we would advocate ‘first do no harm’.

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