Aetiology
Premature labour has a multifactorial aetiology, and it is now viewed as a syndrome. Its causal factors can be generally categorised into maternal or fetal.
Maternal factors
Spontaneous premature labour is often associated with infection and inflammation, particularly at early gestations. Once intrauterine infection occurs, it may not be desirable to prolong pregnancy, as infection can cause neurological damage to the fetus, as well as increased incidences of conditions such as necrotising enterocolitis and potentially bronchopulmonary dysplasia.[10][11][12] Urinary tract infections, including asymptomatic bacteriuria, have a strong association with preterm birth, and treatment may result in a significant reduction in the incidence of pyelonephritis and low birth weight.[13] Abnormal vaginal flora, particularly bacterial vaginosis found early in pregnancy, is associated with higher risk of spontaneous premature labour.[14] However, antimicrobial treatment does not have a significant impact on the likelihood of preterm delivery.[15] Furthermore, screening for bacterial vaginosis is not currently recommended as no interventions have been shown to improve outcome.[16] Systemic infections, such as malaria or listeriosis, may also cause premature labour.
Risks of premature labour are greater in women who have had a previous preterm delivery.[17] One previous preterm delivery increases the risk 4-fold, rising to 6.5-fold with two previous preterm deliveries. Gestational age at delivery also affects risk; the earlier the delivery, the higher the risk of recurrence.
Several factors associated with social disadvantage and with lifestyle have been related to spontaneous premature labour, including poor nutrition, cigarette smoking, single marital status, coffee consumption, and alcohol and recreational drug use.[18][19][20] Mechanism and causation are difficult to elucidate, as many of these factors are commonly associated. There is some evidence that smoking-cessation programmes may reduce preterm birth rates, but tackling other social factors has not proved to be effective.[21]
Domestic violence is associated with premature labour, and this association is prevalent across all social groups.[22]
Cervical trauma such as iatrogenic dilation of the cervix or previous treatment for cervical intra-epithelial neoplasia results in increased risk.[18] Laser conisation, radical diathermy, and large loop excisions may all be associated with higher risks of adverse events including perinatal mortality.[23] Cervical preparation or less invasive techniques (e.g., avoiding cone biopsies) could reduce future risks.[24]
Previous emergency caesarean section is associated with an increased risk of subsequent recurrent preterm delivery.[25][26]
Women with a history of induced abortion also have an increased risk of premature labour and delivery, particularly for deliveries before 28 weeks' gestation.[27]
A short cervical length (<2 cm) and a positive fetal fibronectin test place a woman at higher risk of preterm delivery. These tests have greater predictive value if performed in combination.[28]
Low maternal weight is associated with increased risk of early delivery. Higher rates of spontaneous premature labour are associated with low body mass index. However, iatrogenic causes of preterm birth are increased with obesity, possibly owing to the associated oxidative stress, particularly as a result of pre-eclampsia.[24]
Preterm prelabour rupture of membranes (PPROM): in more than one third of preterm women, rupture will occur prior to the onset of symptomatic contractions.[29] This is associated with a higher risk of maternal and fetal infection (both as a cause and a consequence of PPROM). Pooling of the liquor may be seen on speculum examination.
Dental caries, poor dentition, and peridontal disease may be associated with an increased risk for preterm birth.[30] However, treatment does not influence outcome.[31]
Fetal factors
Multiple (multi-fetal) pregnancies are associated with premature labour due to uterine stretch. This risk is further increased if other risk factors are present, including prior history of spontaneous preterm birth or the mother is found to have a short cervix on cervical length screening.[32] The raised risk of spontaneous preterm birth in a multiple pregnancy should be explained; and the risks, signs, and symptoms of premature labour should be discussed. Antenatal and intrapartum care should be provided by a multidisciplinary team of obstetricians and midwives, with experience in managing multiple pregnancies.[32] Evidence on the prediction and prevention of premature labour for multiple pregnancies is limited, and further research is required.[33][34] Limiting the number of embryo transfers to avoid higher-order multiple pregnancies could contribute substantially to reducing the rate of early preterm birth.
Fetal abnormalities and polyhydramnios can also result in spontaneous premature birth. Common fetal indications for premature labour include fetal growth restriction, fetal stress, and congenital abnormalities. Fetal abnormalities are associated with 8% of preterm deliveries (including iatrogenic preterm delivery).[35]
Pathophysiology
The endocrinology and biochemistry of premature labour are poorly understood, partly as the mechanisms of the onset of labour are different in animals, making extrapolations from animal studies to humans difficult.
For preterm delivery to occur, the cervix undergoes considerable change, related to collagen breakdown and altered proteoglycan and water content, allowing effacement and dilation. The hypertrophied upper uterine segment switches to fundally dominant contractions, which coordinate to expel the fetus. This is a gradual process, often over a number of weeks, allowing both biophysical (e.g., cervical ultrasound) and biochemical (e.g., fetal fibronectin) tests to predict delivery.[36][37] These tests have greater predictive value if performed in combination.[28] Clinically identified factors such as contractions or cervical dilation occur late in the process, partly explaining the poor performance of tocolysis in improving outcome.[38]
The lower uterine segment also stretches, and there is an increase in inflammatory mediators and prostaglandins. Cervical change is mediated by the influx of inflammatory cells releasing matrix metalloproteinases. Increased contractility of the upper segment is associated with expression of prostaglandin and oxytocin receptors and gap junction proteins and other signalling pathways. Progesterone withdrawal is not seen in humans prior to labour, but progesterone therapy may be anti-inflammatory, and thus has a plausible mechanism as a prophylactic treatment.[39]
Infection also causes inflammation, and ascending micro-organisms through a deficient cervix can stimulate an inflammatory response through the innate immune system. Other routes include haematogenous spread, iatrogenic introduction, and retrograde spread through the fallopian tubes. These activate prostaglandins, inflammatory cytokines, and phospholipase A2 and can result in ruptured membranes or contractions. This could also explain the increased risk of premature labour with genital tract infection.[14]
The aetiology of preterm birth is likely multifactorial and injury to the cervix may also be a contributing factor in some cases. Cervical surgery such as large loop excisions, cone biopsy, and emergency caesarean section are also thought to damage the cervix, which may contribute to premature delivery.[25][26][40]
Classification
Based on gestational age[3]
Moderate to late preterm: 32 weeks' to <37 weeks' gestation
Very preterm: 28 weeks' to <32 weeks’ gestation
Extremely preterm: <28 weeks' gestation.
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