Preterm births (PTBs), defined as births before 37 weeks of gestation account for the majority of deaths in the newborn period.
Prediction and prevention of PTB is challenging. A history of preterm labour or second trimester losses and accurate measurement of cervical length help to identify women who would benefit from progesterone and cerclage. Fibronectin estimation in the cervicovaginal secretions of a symptomatic woman with an undilated cervix can predict PTB within 10 days of testing.
Antibiotics should be given to women with preterm prelabour rupture of membranes but tocolysis has a limited role in the management of preterm labour. Antenatal corticosteroids to prevent complications in the neonate should be given only when gestational age assessment is accurate PTB is considered imminent, maternal infection and the preterm newborn can receive adequate care. Magnesium sulphate for fetal neuroprotection should be given when delivery is imminent.
After birth, most babies respond to simple interventions essential newborn care, basic care for feeding support, infections and breathing difficulties. Newborns weighing 2000 g or less, benefit from KMC. Babies, who are clinically unstable or cannot be given KMC may be nursed in an incubator or under a radiant warmer. Treatment modalities include oxygen therapy, CPAP, surfactant and assisted ventilation.
Highlights
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Preterm births are a major cause of neonatal mortality.
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Predictors include cervical length and cervicovaginal fibronectin levels.
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Kangaroo Mother Care (KMC) provides skin-to-skin contact between mother and baby, promotes bonding and breastfeeding.
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KMC is low cost, feasible and is suitable for stable infants, weighing <2500 g.
Introduction
Considerable success has been achieved in reducing deaths among children <5 years of age, but progress towards achievement of the fourth Millennium Development Goals (MDG) has been hampered by slow decline in neonatal mortality. If Sustainable Development Goals 3 (SDG 3) is to be attained, it is imperative that the determinants of neonatal mortality are addressed.
One of the most important predictors of an infant’s subsequent health and survival is the period of gestation at birth . Preterm birth (PTB), defined as birth before 37 weeks of gestation, is the leading cause of neonatal death and the second leading cause of deaths among children under the age of 5 years (2). Subcategories of PTB, based on gestational age (GA), are as follows: (1) extremely preterm (<28 weeks), (2) very preterm (28 to <32 weeks) and (3) moderate to late preterm (32 to <37 weeks). Outcomes are inversely related to GA. Globally, every year approximately 15 million babies, or one in ten, are born prematurely. More than a million babies die due to complications of PTB. Prematurity also renders these babies more prone to serious illness, lifelong disability and poor quality of life.
Countries in Africa and Asia account for >60% of global PTBs. Other major causes of neonatal mortality and morbidity in low- and middle-income countries (LMICs) are infections, birth asphyxia and low birth weight.
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Fifteen million preterm births are recorded every year and the number is still rising
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Nearly, 1.1 million babies die from preterm birth complications
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Preterm birth rates vary from 5% to 18% among the 184 countries where estimates are available
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More than 80% of preterm births occur between 32 and 37 weeks of gestation; most of these babies can survive with essential newborn care
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>75% of deaths following preterm births can be prevented without intensive care
Accurate estimation of GA is still a challenge in poor-resource settings where women do not avail antenatal care early in gestation. Unfortunately, optimal care of a preterm neonate, which is vital in preventing neonatal morbidity and mortality, may be expensive and unaffordable in under-resourced settings.
About 80% of preterm deliveries are the result of spontaneous labour or preterm rupture of membranes while the other 20% are ‘indicated’ PTBs where the fetus is delivered to prevent maternal or fetal morbidity and mortality.
Intrauterine inflammation associated with microbial infection, uterine vascular compromise or decidual haemorrhage brings about preterm labour. The complex processes involved in the pathogenesis of preterm labour with interlinked roles of the cervix, amnion, chorion, myometrium, placenta and the fetus have been called the preterm parturition syndrome . Despite good research spanning over many decades, a lucid understanding of the pathogenesis of preterm labour that could contribute to its prevention is still lacking . Table 1 has a comprehensive list of the environmental and epidemiological risk factors for preterm labour.
| Maternal | Demographic |
| African-American/Aboriginal/Hispanic races | |
| Low BMI/poor weight gain/excess weight gain | |
| Young maternal age | |
| Obstetric | |
| Previous early pregnancy loss – induced/miscarriage | |
| Previous preterm birth – indicated or spontaneous labour | |
| Short inter-pregnancy interval (<12 months) | |
| Medical | |
| Procedures – LLETZ/amniocentesis | |
| Fetal | Male gender |
| Multifetal pregnancy | |
| Assisted conception | |
| Paternal | Older paternal age |
| Environmental | Infection |
| Bacterial vaginosis/sexually transmitted infection | |
| Periodontal infection | |
| Socioeconomic/psychosocial | |
| Social inequality/poverty/neighbourhood disadvantage | |
| Physical violence | |
| Marital status – single/cohabitation in the context of high marriage rates | |
| Stressful/traumatic life events/anxiety/depression | |
| Substance use/toxins | |
| Excess alcohol – ≥3 drinks per day/≥7 drinks per week | |
| Smoking – any but particularly moderate or heavy | |
| Cocaine – usually influenced by smoking | |
| Pollutants – sulphur dioxide, particulate matter | |
| Nutrition | |
| Elevated homocysteine/suboptimal vitamins B-12 and B-6 | |
| Unbalanced polyunsaturated fatty acids (PUFAs) | |
| Multivitamin (non-use) | |
| Genetic | TNF-α pro-inflammatory cytokine – polymorphisms |
| Factor VII/XIII – polymorphisms |
Currently, interventions to reduce PTB have been classified as primary, secondary and tertiary prevention . Preventing PTB in low-risk women is a primary intervention, while preventing PTB in high-risk women and early established preterm labour could be classified as secondary and tertiary interventions, respectively.
Prediction of preterm labour
The most useful and commonly recommended predictors other than history of PTB or second trimester loss are discussed below.
Transvaginal ultrasonographic cervical length
Transvaginal ultrasonographic cervical length (TVUCL) is currently the most accurate method for predicting PTB. An association between shortened cervical length by transvaginal ultrasound and preterm labour has been shown since 1992 and has been confirmed by Iams et al. . Receiver-operating characteristic curves of cervical length measured by transvaginal ultrasound in this study suggested 25 mm and 20 mm as potential threshold values for clinical use corresponding to 10th and 5th percentiles for cervical length. The sensitivity for a cut-off of 25 mm was 37% and the specificity was 92%. Similar studies showed that the longer the cervix, the less likely the chance of PTB.
Technique
TVUCL is best measured in the dorsal lithotomy position. After the bladder is emptied, a sagittal view of the cervix is obtained with a vaginal transducer (2.7–9.3 MHz). The distance between the triangular area of echodensity at the external os and V-shaped notch at the internal os is measured as the cervical length. The cervical canal is bordered by the endocervical mucosa, which is usually of decreased echogenicity but occasionally of increased echogenicity compared with surrounding tissues. Measurement is performed for at least >3 min avoiding undue pressure over the cervix . The image is enlarged to occupy two-thirds of the total image. Three images are recorded and the shortest value is taken as the cervical length. Transfundal pressure for 15 s is also recommended. The association between ultrasound-estimated cervical length and preterm labour in earlier studies was seen only at 20–24 weeks and not at 13–14 weeks. Inability to identify cervical incompetence until 20–24 weeks limits the use of both progesterone and cerclage earlier in gestation.
However, Greco and colleagues successfully showed an association between shortened cervical length in the 11–13-week scan and preterm labour when they modified the technique to ensure that the isthmus was not measured. They showed that it was important to distinguish between the endocervix and the isthmus. The endocervical length at 11–13 weeks was shorter in pregnancies resulting in spontaneous delivery before 34 weeks than in those delivering after 34 weeks. A systematic review looking at the accuracy of cervical transvaginal sonography in predicting PTB confirmed that a cut-off of <2.5 cm or funnelling whether used alone or as a combination were both effective in predicting PTB. This review showed a likelihood ratio (LR) of 6.29 (95% confidence interval (CI) 3.29–12.02) for PTB before 34 weeks in women with a cervical length of ≤25 mm at 20 weeks or earlier with a post-test probability of 15.8%. An LR of 27.92 (18.59–41.92) for PTB was seen when the cervical length was ≤15 mm at ≤24 weeks of GA at testing. Thus, accurate cervical length measurement may be a surrogate marker of cervical incompetence.
Cervical assessment using transabdominal, translabial and transperineal ultrasound
Transabdominal ultrasound (TAU) is said to be less reliable than transvaginal ultrasound. Over distention of the bladder can compress the walls of the lower uterine segment creating a normal appearance, and an under-distended bladder can allow acoustic shadowing from the symphysis pubis. The internal os is normally at the level where the cervical canal meets the amniotic sac but the demarcation of the external os is more difficult because of the rectal gas shadow. However, scanning the patient in the lateral decubitus position or elevating the hip with a pillow has been used to improve cervical canal visibility . Abdominal ultrasound has a definite advantage as it may be quicker to perform, more feasible and more acceptable to women. However, there is very little research assessing its accuracy . Fundal pressure for a few moments while performing abdominal estimation of cervical length has been tried to improve accuracy . TAU has been shown to be superior to digital evaluation as about 50% of the cervix is supravaginal .
Translabial and transperineal measurements of cervical length have also been used . Ziliante and coworkers have described an alphabetical progression of cervical effacement from the internal os to the external os by the letters ‘T’, ‘Y’, ‘V’ and then ‘U’. Although ‘T’ is a closed, uneffaced cervix ‘U’ is an open cervix suggesting high risk for PTB.
Role of universal screening of cervical length
Universal cervical length screening using transvaginal ultrasound has a limited role in resource-limited countries. Challenges in implementing such a strategy include the need for a good ultrasound scanner and rigorous training of sonologists, and acceptability of vaginal route for screening. Three large randomized controlled trials (RCTs) that used universal screening have been published. The RCT that used universal screening of cervical length for placement of cerclage screened 47,123 women to identify 1% of women with cervical length <1.5 cm and found no benefits with use of cerclage. The other two studies with universal screening, screened 24,600 women and 32,091 women and identified 1.7% and 2.3% of women with short cervix, respectively. These two studies that assessed the use of progesterone showed a definite benefit but needed to screen 400 women or 588 women to prevent one PTB. Thus, universal screening for preterm labour may not be cost-effective . Currently, there is insufficient evidence to recommend universal screening for PTB .
Cervicovaginal fetal fibronectin screening
Fetal fibronectin is a glycoprotein produced by amniocytes and cytotrophoblasts that has an adhesive-like action and is localized in the maternal–fetal interface between the decidua and the trophoblast. Very low levels of glycoprotein are normally present (<50 ng/ml is seen after 22 weeks) . The level of ≥50 ng/ml fibronectin in the cervicovaginal secretions collected with a swab after 22 weeks is associated with increased risk of spontaneous PTB. As a predictor for preterm delivery fibronectin has a sensitivity of 60%, specificity of 85% and a negative predictive value of 96%. However, there is still a paucity of evidence for its use in clinical practice . In symptomatic women, a positive test is able to predict PTB within 7–10 days of testing among women without advanced cervical dilatation . Seventeen symptomatic women with increased fibronectin levels at 31 weeks of gestation would need to be treated with antenatal steroids to prevent one case of respiratory distress syndrome (RDS). The role of this test would be to ensure in utero transfer, administration of antenatal steroids to prevent RDS and magnesium sulphate infusion for neuroprotection.
Risk scoring
A systematic review that evaluated the accuracy of different risk-scoring systems showed a wide range of accuracy with a lack of clinically relevant reference standards . A positive history leads to a post-test probability of 16.5% for spontaneous PTB before 34 weeks and a negative history leads to a post-test probability of 2.8% .
Some researchers have looked at predictions of PTB using a combination of the above modalities . However, the last word on the ideal method of prediction is not yet known.
Screening for asymptomatic bacteriuria
Screening for asymptomatic bacteriuria may play an important role in preventing PTB with the use of appropriate antibiotics. A meta-analysis of 14 randomized trials comparing placebo with antibiotic treatment demonstrated a significant reduction in preterm delivery with antibiotic use (odds ratio (OR) 0.60, 95% CI 0.45–0.80) .
Bacterial vaginosis
An association between bacterial vaginosis (BV) and PTB has been shown . However, screening and treating of asymptomatic BV have not been shown to be useful .
Prediction of preterm labour
The most useful and commonly recommended predictors other than history of PTB or second trimester loss are discussed below.
Transvaginal ultrasonographic cervical length
Transvaginal ultrasonographic cervical length (TVUCL) is currently the most accurate method for predicting PTB. An association between shortened cervical length by transvaginal ultrasound and preterm labour has been shown since 1992 and has been confirmed by Iams et al. . Receiver-operating characteristic curves of cervical length measured by transvaginal ultrasound in this study suggested 25 mm and 20 mm as potential threshold values for clinical use corresponding to 10th and 5th percentiles for cervical length. The sensitivity for a cut-off of 25 mm was 37% and the specificity was 92%. Similar studies showed that the longer the cervix, the less likely the chance of PTB.
Technique
TVUCL is best measured in the dorsal lithotomy position. After the bladder is emptied, a sagittal view of the cervix is obtained with a vaginal transducer (2.7–9.3 MHz). The distance between the triangular area of echodensity at the external os and V-shaped notch at the internal os is measured as the cervical length. The cervical canal is bordered by the endocervical mucosa, which is usually of decreased echogenicity but occasionally of increased echogenicity compared with surrounding tissues. Measurement is performed for at least >3 min avoiding undue pressure over the cervix . The image is enlarged to occupy two-thirds of the total image. Three images are recorded and the shortest value is taken as the cervical length. Transfundal pressure for 15 s is also recommended. The association between ultrasound-estimated cervical length and preterm labour in earlier studies was seen only at 20–24 weeks and not at 13–14 weeks. Inability to identify cervical incompetence until 20–24 weeks limits the use of both progesterone and cerclage earlier in gestation.
However, Greco and colleagues successfully showed an association between shortened cervical length in the 11–13-week scan and preterm labour when they modified the technique to ensure that the isthmus was not measured. They showed that it was important to distinguish between the endocervix and the isthmus. The endocervical length at 11–13 weeks was shorter in pregnancies resulting in spontaneous delivery before 34 weeks than in those delivering after 34 weeks. A systematic review looking at the accuracy of cervical transvaginal sonography in predicting PTB confirmed that a cut-off of <2.5 cm or funnelling whether used alone or as a combination were both effective in predicting PTB. This review showed a likelihood ratio (LR) of 6.29 (95% confidence interval (CI) 3.29–12.02) for PTB before 34 weeks in women with a cervical length of ≤25 mm at 20 weeks or earlier with a post-test probability of 15.8%. An LR of 27.92 (18.59–41.92) for PTB was seen when the cervical length was ≤15 mm at ≤24 weeks of GA at testing. Thus, accurate cervical length measurement may be a surrogate marker of cervical incompetence.
Cervical assessment using transabdominal, translabial and transperineal ultrasound
Transabdominal ultrasound (TAU) is said to be less reliable than transvaginal ultrasound. Over distention of the bladder can compress the walls of the lower uterine segment creating a normal appearance, and an under-distended bladder can allow acoustic shadowing from the symphysis pubis. The internal os is normally at the level where the cervical canal meets the amniotic sac but the demarcation of the external os is more difficult because of the rectal gas shadow. However, scanning the patient in the lateral decubitus position or elevating the hip with a pillow has been used to improve cervical canal visibility . Abdominal ultrasound has a definite advantage as it may be quicker to perform, more feasible and more acceptable to women. However, there is very little research assessing its accuracy . Fundal pressure for a few moments while performing abdominal estimation of cervical length has been tried to improve accuracy . TAU has been shown to be superior to digital evaluation as about 50% of the cervix is supravaginal .
Translabial and transperineal measurements of cervical length have also been used . Ziliante and coworkers have described an alphabetical progression of cervical effacement from the internal os to the external os by the letters ‘T’, ‘Y’, ‘V’ and then ‘U’. Although ‘T’ is a closed, uneffaced cervix ‘U’ is an open cervix suggesting high risk for PTB.
Role of universal screening of cervical length
Universal cervical length screening using transvaginal ultrasound has a limited role in resource-limited countries. Challenges in implementing such a strategy include the need for a good ultrasound scanner and rigorous training of sonologists, and acceptability of vaginal route for screening. Three large randomized controlled trials (RCTs) that used universal screening have been published. The RCT that used universal screening of cervical length for placement of cerclage screened 47,123 women to identify 1% of women with cervical length <1.5 cm and found no benefits with use of cerclage. The other two studies with universal screening, screened 24,600 women and 32,091 women and identified 1.7% and 2.3% of women with short cervix, respectively. These two studies that assessed the use of progesterone showed a definite benefit but needed to screen 400 women or 588 women to prevent one PTB. Thus, universal screening for preterm labour may not be cost-effective . Currently, there is insufficient evidence to recommend universal screening for PTB .
Cervicovaginal fetal fibronectin screening
Fetal fibronectin is a glycoprotein produced by amniocytes and cytotrophoblasts that has an adhesive-like action and is localized in the maternal–fetal interface between the decidua and the trophoblast. Very low levels of glycoprotein are normally present (<50 ng/ml is seen after 22 weeks) . The level of ≥50 ng/ml fibronectin in the cervicovaginal secretions collected with a swab after 22 weeks is associated with increased risk of spontaneous PTB. As a predictor for preterm delivery fibronectin has a sensitivity of 60%, specificity of 85% and a negative predictive value of 96%. However, there is still a paucity of evidence for its use in clinical practice . In symptomatic women, a positive test is able to predict PTB within 7–10 days of testing among women without advanced cervical dilatation . Seventeen symptomatic women with increased fibronectin levels at 31 weeks of gestation would need to be treated with antenatal steroids to prevent one case of respiratory distress syndrome (RDS). The role of this test would be to ensure in utero transfer, administration of antenatal steroids to prevent RDS and magnesium sulphate infusion for neuroprotection.
Risk scoring
A systematic review that evaluated the accuracy of different risk-scoring systems showed a wide range of accuracy with a lack of clinically relevant reference standards . A positive history leads to a post-test probability of 16.5% for spontaneous PTB before 34 weeks and a negative history leads to a post-test probability of 2.8% .
Some researchers have looked at predictions of PTB using a combination of the above modalities . However, the last word on the ideal method of prediction is not yet known.
Screening for asymptomatic bacteriuria
Screening for asymptomatic bacteriuria may play an important role in preventing PTB with the use of appropriate antibiotics. A meta-analysis of 14 randomized trials comparing placebo with antibiotic treatment demonstrated a significant reduction in preterm delivery with antibiotic use (odds ratio (OR) 0.60, 95% CI 0.45–0.80) .
Bacterial vaginosis
An association between bacterial vaginosis (BV) and PTB has been shown . However, screening and treating of asymptomatic BV have not been shown to be useful .
Interventions for prevention
Cerclage
Currently, cerclage is performed for three indications: history-indicated cerclage or prophylactic cerclage, ultrasound-indicated cerclage (UIC) or therapeutic cerclage and physical examination-indicated cerclage (PEIC) or emergency cerclage. In 1993, the Medical Research Council/Royal College of Obstetricians (MRC/RCOG) study , which randomized women for cerclage, when the physician was uncertain of the indication, found that it was useful only when there were three or more previous spontaneous losses. In 2000, Althuisius and colleagues published the CIPRACT trial that used cerclage based on history and cervical length, and found a definite decrease in PTB rate. However, in 2004, To et al. screened women for short cervix in the general population and placed a cerclage when the cervical length was ≤15 mm and found no benefits with the use of cerclage. Another multicentre randomized trial among high-risk women with cervical length ≤2.5 cm found no difference in births before 35 weeks. However, this study found that cerclage reduced previable births. A meta-analysis published in 2011 has also shown that cerclage prevents PTB. Evidence does not support the use of cerclage in multiple pregnancy. A meta-analysis showed an increased risk of PTB if cerclage is used in multiple pregnancy .
Progesterone
Progesterone is known to cause uterine quiescence by direct effect on the myometrium, and it is also shown to block the effect of prostaglandin F2α and alpha-adrenergic stimulation . However, significant evidence is available to support its use to prevent preterm labour in high-risk women, especially when the cervix is short. Both synthetic progesterone , administered intramuscularly, and natural progesterone have shown a significant decrease in the incidence in PTB. Several meta-analyses have confirmed these findings. Vaginal administration of natural progesterone prevents first-pass metabolism through the liver, thereby increasing bioavailability. Progesterone has no role in women with arrested PTB . Similarly, there is no evidence to support the use of progesterone in multiple pregnancies .
Tocolysis
The current role of tocolysis in tertiary prevention is to delay PTB for at least 48 h after the onset of therapy in order to facilitate the effect of antenatal steroids. Tocolysis is contraindicated when continuation of pregnancy is detrimental to the fetus, as in chorioamnionitis and abruptio placentae. In addition, it is not used in heart disease and preeclampsia as it could precipitate heart failure and jeopardize the mother. There is no role for chronic tocolysis . The main groups of tocolytic agents that have been used and assessed are calcium channel blockers (nifedipine) , betamimetics , prostaglandin synthetase inhibitors and magnesium sulphate . Nifedipine, which is an oral tocolytic agent, is the most commonly used modality, that is, also user-friendly and has the least number of complications .
Cervical pessary
Transvaginal placement of a silicon pessary around the cervix could support the cervix and change its direction towards the sacrum. This could prevent direct pressure of the uterine contents on to the cervix. Two studies have shown contradictory results . The pessary has not shown reduction in PTBs in twins in two RCTs .
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