Abstract
Preterm birth is defined by the WHO as birth before 37 completed weeks of gestation. The incidence varies across countries but is currently approximately 8% of all births in the United Kingdom and 11% worldwide. Being born too soon can confer significant clinical deficits throughout life, leading to neuro-developmental disorders such as cerebral palsy, learning impairment and visual disorders; problems which are more likely to occur with greater severity at earlier gestations of birth [1]. Preterm birth may also affect long-term physical health, with a higher risk of cardiovascular disease, and lays a huge emotional and economic burden on affected families [2]. Figure 39.1 is adapted from the EPICURE longitudinal study of morbidity and mortality of preterm infants and demonstrates that with each week of increasing gestation, rates of disability and death decrease substantially. This underlines the importance of timely treatment aimed at preventing and ameliorating the effects of preterm birth.
Key Facts
Preterm birth is common and is a syndrome with causes including infection, inflammation, utero-placental bleeding and cervical weakness.
Risk factors for preterm birth include previous preterm birth, cervical excisional surgery, rupture of membranes and previous full-dilatation caesarean section.
The diagnosis of preterm labour can be made via clinical recognition of the presentation of regular uterine contractions and cervical changes on examination.
Predictive techniques to diagnose likelihood of preterm birth such as a combination of cervical length ultrasound and quantitative fetal fibronectin will aid more targeted treatment regimens for women with symptoms of preterm labour.
Management may include antenatal corticosteroid therapy, magnesium sulphate infusion, antibiotic therapy and tocolysis.
Consideration should always be given for in utero transfer to aim for delivery at the appropriate level of neonatal unit according to gestational age of pregnancy.
The timely use of emergency cerclage where indicated can reduce the rate of preterm birth.
Introduction
Preterm birth is defined by the WHO as birth before 37 completed weeks of gestation. The incidence varies across countries but is currently approximately 8% of all births in the United Kingdom and 11% worldwide. Being born too soon can confer significant clinical deficits throughout life, leading to neuro-developmental disorders such as cerebral palsy, learning impairment and visual disorders; problems which are more likely to occur with greater severity at earlier gestations of birth [1]. Preterm birth may also affect long-term physical health, with a higher risk of cardiovascular disease, and lays a huge emotional and economic burden on affected families [2]. Figure 39.1 is adapted from the EPICURE longitudinal study of morbidity and mortality of preterm infants and demonstrates that with each week of increasing gestation, rates of disability and death decrease substantially. This underlines the importance of timely treatment aimed at preventing and ameliorating the effects of preterm birth.
Figure 39.1 Extreme preterm survival with and without significant disability as per gestational age. Note that figures are taken from UK centres up to 2006 and survival at the extremes of prematurity has improved considerably since that time. Disability rates, however, have been slower to improve.
Preterm birth may be divided into two types: spontaneous (70%) and indicated (30%). Indicated (or caregiver initiated) preterm births are those whereby delivery has been expedited by a clinician due to concerns regarding maternal or fetal health for conditions such as preeclampsia or fetal growth restriction. This often occurs in the absence of labour and discussion of these situations is outside the scope of this chapter. Spontaneous preterm birth (s-PTB) is preceded by spontaneous preterm labour (s-PTL), the presentation and diagnosis of which are discussed in detail in the text that follows. s-PTL can occur in the presence or absence of amniotic membrane rupture; however, it is important to note that membrane rupture without signs of preterm labour (premature prelabour rupture of membranes [PPROM]) should be distinguished as a separate clinical entity; as the management of this situation can differ from established s-PTL.
Although multiple pregnancies are at increased risk of preterm labour and birth, the evidence regarding the diagnosis and management of these patients is complex and often differs from the singleton situation. Therefore, the information provided in this chapter refers only to the diagnosis and management of established preterm labour for singleton pregnancies.
Aetiology and Risk Factors
The aetiology of spontaneous preterm birth and labour is complex and multifactorial. Preterm birth is a syndrome and best understood as the final endpoint of a number of possible pathological events. It can be initiated by an array of disease processes including uterine over-distension, utero-placental haemorrhage or ischaemia, maternal stress, cervical insufficiency and inflammation with or without clinically apparent infection [3].
A history of preterm birth in a previous pregnancy conveys the strongest risk factor for preterm birth in a subsequent pregnancy. This risk increases with earlier gestation of previous preterm birth or if more than one previous pregnancy has been complicated by preterm birth. Additional risk factors include late or second trimester pregnancy loss from 16 to 23 weeks, or PPROM in previous pregnancies or the index pregnancy [4].
Previous excisional cervical surgery is associated with subsequent preterm birth. Such associations may be confounded by the fact that similar demographic factors complicate both CIN and preterm birth (smoking, low socioeconomic status); however, the association is stronger if multiple long loop excisional biopsies of the transformation zone (LLETZ) have been taken or a deep excisional biopsy (10–15 mm) has been removed [5]. Emerging evidence also suggests that caesarean section performed at full dilatation may also pose a significant risk for preterm birth in subsequent pregnancies [6].
Diagnosis of Established Preterm Labour
Interventions aimed at the treatment and prevention of preterm birth can improve neonatal and long-term outcomes; however, they are also costly and may carry significant side effects. Thus, the most accurate means of identifying which patients with a threatened presentation of spontaneous preterm labour will go on to deliver can avoid exposure of both fetus and mother to unnecessary treatment with potentially negative effects.
In low-resource settings a diagnosis of established preterm labour can be made using a defined criterion such as a patient presenting before 37 weeks of completed gestation with regular uterine contractions combined with cervical modifications (effacement or shortening) as observed on vaginal or Cusco’s speculum examination. This is defined by NICE as progressive cervical dilatation from 4 cm with regular contractions [7]. In well-resourced settings modern techniques such as cervical length ultrasound scanning or biomarkers from the cervico-vaginal fluid should also be employed, as these can allow for more accurate and predictive diagnosis so that a more targeted treatment regime can be instituted.
Cervical Length
Transvaginal ultrasound measurement of cervical length is an easy to perform and effective screening test in women with signs and symptoms of preterm labour. The shorter the cervix the higher the risk of spontaneous preterm birth. Various thresholds are described for what constitutes a positive test. The most persuasive evidence supports the use of a cut off of <15 mm to predict delivery within both 48 hours and 7 days with moderately useful positive and negative likelihood ratios [7].
Biomarker Testing
There are three commonly used biomarkers to assist triage in symptomatic women presenting with threatened preterm labour. They are all bedside tests on a vaginal swab and are outlined in Table 39.1.
Table 39.1 Commercial biomarkers available for clinical use
| Actim® Partus | PartoSureTM | Rapid fFN® | |
|---|---|---|---|
| Biomarker | Phosphorylated insulin-like growth factor binding protein-1 | Placental alpha microglobulin-1 | Fetal fibronectin |
| Gestation for use (weeks) | From 22+0 | 22+0–36+6 | 22+0–35+6 |
| Result | Positive or negative | Positive or negative | Concentration (0–500 ng/mL) |
| Contraindications | Vaginal bleeding, amniotic fluid | Vaginal bleeding, previous vaginal medication within the Past 6 hours | Cervix ≥3 cm, vaginal bleeding, amniotic fluid, cervical cerclage, recent internal examination |
Actim® Partus and PartoSureTM are qualitative tests. Rapid fFN® gives a numerical result which then allows the clinician to make a judgement on the absolute value. Common thresholds employed are >10, >50, >200 and >500 ng/mL.
The strength of all these tests lies in their ability to rule out preterm birth within 48 hours and 7 days. All three tests have a high negative predictive value (with Rapid fFN® this is dependent on the threshold used by the clinician to denote ‘at risk’). The positive predictive values for all these tests are poor.
There is limited evidence comparing these tests head to head. A recent Health Technology Authority systematic review and economic evaluation attempted to elicit which of these tests was superior [8]. It concluded there was too much uncertainty in the results to draw any clear conclusions on the relative accuracies of the tests when compared.
Combination of Cervical Length Ultrasound and Biomarkers
There is a freely available app, QUiPP (https://quipp.org/), that allows clinicians to use a combination of history (previous cervical surgery, previous preterm birth, previous PPROM), gestation (18+0–36+6), shortest cervical length (mm) and fFN result (ng/mL). It will give a result as the percentage risk of delivering within 1 week, 2 weeks, 4 weeks, <30 weeks, <34 weeks and <37 weeks. There are validation data published using fFN but not cervical length. The area under the curve ranged between 0.77 and 0.88 for the time points listed above, implying this is an effective test [9]. The challenge for the clinician is to determine what percentage risk as a cut-off is high enough to prompt intervention.
Gestational Age–Dependent Testing
The concept of assessment based on gestational age was controversially introduced following the publication of NICE guidance in 2015 [7]. The recommendation was that women with signs and symptoms of preterm labour <30 weeks should not undergo a diagnostic test and instead be managed as if they are in confirmed preterm labour, that is, corticosteroids, tocolysis and transfer to a site with adequate neonatal care. Those women ≥30 weeks should be offered a diagnostic test in the form of transvaginal cervical length (positive if <15 mm) or fetal fibronectin (positive if >50 ng/mL). The justification for this approach was based on a ‘what-if’ analysis (‘if’ a diagnostic strategy had this particular diagnostic accuracy, then ‘what’ would the cost-effective strategy be?). This involved calculating the cost–utility for all combinations of sensitivity and specificity between 0% and 100% and determining what the cost-effective strategy would be for a diagnostic strategy with a certain cost at each of these different combinations. It was determined that the diagnostic tests on offer lacked the appropriate sensitivity and specificity to be deemed cost effective below 30 weeks. This approach has not been adopted by the majority of units in the United Kingdom due to some problematic assumptions made by the NICE model, no harm from unnecessary interventions and assuming all false negatives came to harm. This approach suggested by NICE does not tally with experience from clinical practice, as women with false-negative results who are sent home may be re-admitted with symptoms and signs of preterm labour and then be prescribed corticosteroids at this point (arguably receiving this intervention at a more relevant time point). Given the improvement in diagnostic tests since the publication of NICE guidance the recent Health Technology Authority systematic review and economic evaluation suggests that treating all women <30 weeks without testing may not be cost effective [8]. A prospective observational secondary analysis using the QUiPP app with a risk threshold of 5% demonstrated that 89% of women presenting with signs and symptoms of preterm labour <30 weeks would screen negative (avoiding admission/intervention), with a negative predictive value of 100% [10]. There are two large studies enrolling >1000 women, PETRA (Threatened Preterm Labour: a prospective cohort study of risk assessment tool and a qualitative exploration of women’s experiences of risk assessment and management) and QUIDS, (Qualitative fibronectin to help decision-making in women with symptoms of preterm labour) to looking at the utility of diagnostic tests in women with signs and symptoms of preterm labour due to publish soon and we await the results.
Management of Established Spontaneous Preterm Labour
Once an accurate diagnosis of spontaneous preterm labour (s-PTL) has been made, a cascade of interventions including antenatal corticosteroids (ACS), magnesium sulphate (MgSO4), emergency cerclage or referral to a tertiary centre should be instigated where appropriate.
Corticosteroid Treatment
Maternally administrated antenatal corticosteroids speed the development of both type 1 and type 2 pneumocyte cells in the fetal lung, leading to an increased production of surfactant and increased pulmonary gas exchange. The pioneering clinical trial by Liggins and Howie in 1972 established that administration of two doses of betamethasone corticosteroid in mothers with symptoms of preterm labour significantly reduced neonatal deaths, respiratory distress syndrome and intraventricular haemorrhage compared to placebo controls [11]. Such findings have been further clarified by Cochrane review leading to the following recommendations of management [12]:
A single course of antenatal corticosteroids may be offered for all patients in established preterm labour or PPROM between 34 and 35+6 weeks of gestation following discussion with parents regarding possible benefits and risks of treatment.
A single course of antenatal corticosteroids should be offered to all patients in established preterm labour or PPROM between 26 and 33+6 weeks of gestation following explanation of the benefits of reduced neonatal deaths, respiratory distress syndrome and intraventicular haemorrhage.
A single course of antenatal corticosteroids should be considered for all patients in established preterm labour or PPROM between 24 and 25+6 weeks of gestation.
For patients in established preterm labour or PPROM between 22+5 and 23+6 weeks of gestation antenatal steroids may be considered following multidisciplinary team discussion with the senior obstetric and neonatal teams, involving the parents in the discussion. Decision making at the extremes of prematurity should take a holistic approach and give reference to the complex ethical and practical dilemmas that exist in such a situation [13].
Timing of Steroid Use and Use of Repeated Doses of Steroids
A reduction in neonatal death of 28% (relative risk [RR] 0.72; 95% confidence interval [CI] 0.58–0.99) and a decrease in RDS of 34% (RR 0.66 95%; CI 0.56–0.77) has been demonstrated at 24 hours and 7 days following steroid administration; however, any benefits beyond this timeframe remain uncertain [12]. For women who do not deliver within 7 days following steroid administration and who remain at risk of preterm birth, a further course of corticosteroid treatment can reduce the risk of neonatal respiratory distress syndrome by 17% (RR 0.83; 95% CI 0.75–0.91). However, repeat or multiple courses of steroids have been associated with low birth weight and smaller head size in infants born at near term, and animal studies have suggested a link between delayed brain development and multiple courses of steroid treatment [14]. Therefore, consideration of further steroid treatment should be made only by a senior clinician with a clear knowledge of previous treatments received during the pregnancy.
There is an association with lower birthweight in infants born at or near term who have received antenatal corticosteroid therapy, compared with infants who have not [15]. This makes an accurate predictive diagnosis of preterm labour leading to preterm birth vital to avoid unnecessary treatment.
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