Journal of Obstetrics and Gynaecology, August 2014; 34: 457–461 © 2014 Informa UK, Ltd. ISSN 0144-3615 print/ISSN 1364-6893 online DOI: 10.3109/01443615.2014.896325
REVIEW
Prediction of spontaneous preterm delivery in singleton pregnancies: Where are we and where are we going? A review of literature N. Sananès1,2, B. Langer3, A. Gaudineau1, R. Kutnahorsky4, G. Aissi1, G. Fritz3, E. Boudier3, B. Viville3, I. Nisand3 & R. Favre1 1Department of Obstetrics and Gynecology, CMCO Hospital, Schiltigheim, 2INSERM, UMR-S 1121, Biomatériaux et Bioingénierie,
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Strasbourg, 3Department of Obstetrics and Gynecology, Hautepierre Hospital, Strasbourg and 4Department of Obstetrics and Gynecology, Le Parc Hospital, Colmar, France
Prematurity is the chief cause of neonatal morbidity and mortality. The objective of this study is to review the different methods for predicting preterm delivery in asymptomatic pregnant women and in situations of threatened preterm delivery. A search of the PubMed/Medline database was carried out for the years 1980–2012. We included studies for predicting preterm birth in asymptomatic and symptomatic patients. Models for predicting preterm delivery based on maternal factors, cervical length and obstetric history in first trimester of pregnancy is a valuable avenue of research. Nevertheless, prediction accuracy still needs to be improved. In the second and third trimesters, routine digital vaginal examination is of no value in asymptomatic women. Echography of the cervix is not useful except in patients with a history of late miscarriage or preterm delivery in order to offer them a preventive treatment. In symptomatic women, the combination of digital vaginal examination, cervical echography and fibronectin gives the best predictive results. Electromyography of the uterus and elastography of the cervix are interesting avenues for future research. Identifying patients at risk of preterm delivery should be considered differently at each stage of pregnancy. Keywords: General obstetrics, prediction, preterm delivery, score, screening
Introduction Prematurity is the chief cause of neonatal morbidity and mortality (Saigal and Doyle 2008). Morbidity is essentially a correlate of neurological (intraventricular haemorrhage and periventricular leukomalacia), pulmonary (hyaline membrane disease) and gastrointestinal complications (necrotising enterocolitis). The survival of preterm infants depends on their gestational age: it is rare below the age of 24 weeks, whereas it exceeds 90% for preterm infants of more than 29 weeks admitted living to a neonatology unit (Larroque et al. 2004; Costeloe et al. 2012). In France, antenatal care has been standardised since 1987, with seven prenatal consultations and three obstetric ultrasonographic investigations financed in full by the healthcare system. Since then, prenatal screening has increased sharply. Nevertheless, prematurity appears to be slightly on the rise; this is due to practices which tend to encourage the ever earlier birth of infants at risk in utero and because of the increasing proportion of
twin pregnancies (following the expansion of medically assisted reproduction services): 5.6% of births were preterm in 1981, as opposed to 7.4% in 2010 (INSERM-DREES-DGS 2011). This same rise in prematurity is seen in the rest of Europe as well as the USA (Goldenberg et al. 2008), probably to a large extent due to the increase in induced preterm deliveries. A distinction must be made between spontaneous preterm births (spontaneous onset of labour and premature rupture of the membranes) and induced preterm births (because of small for gestational age and/or pre-eclampsia) (Meis et al. 1995). Spontaneous preterm births account for approximately two-thirds of all cases of prematurity (Iams et al. 2008). Identifying patients at risk of preterm delivery is therefore a major challenge in several respects, in relation to the stage of gestational advancement when the prediction is made and in relation to the clinical situation. In the first trimester, as well as in asymptomatic patients in the second and third trimesters of pregnancy, identifying patients at risk of preterm delivery would enable an appropriate monitoring system to be set-up, and most importantly allow initiation of a preventive treatment such as progesterone (da Fonseca et al. 2003; Meis et al. 2003; Romero et al. 2012), cervical cerclage (Berghella et al. 2005; Simcox et al. 2009) or even cervical pessary (Abdel-Aleem et al. 2010; Goya et al. 2012). Furthermore, in patients with threatened preterm delivery, being able to identify those who are most likely to deliver early would assist in deciding whether to refer them to a higherlevel maternity unit, whether to modify tocolytic treatment and the length of hospital admission, and whether to administer a course of corticosteroids to allow fetal pulmonary maturation (ACOG 2011) or magnesium sulphate for neuroprotection (Bain et al. 2012). The objective of this article is to review the prediction of preterm delivery in asymptomatic pregnant women and in situations of threatened preterm delivery, based on the stage of gestational advancement.
Materials and methods A search of the PubMed/Medline database was carried out for the years 1980–2012. The terms were ‘preterm delivery’, ‘prediction’, ‘prevention’ and ‘screening’ in association with ‘score’, ‘cervical length’, ‘digital examination’, ‘tocometry’, ‘fibronectin’, ‘electromyography’ and ‘elastography’. We included studies for predicting
Correspondence: N. Sananès, INSERM, UMR-S 1121, Biomatériaux et Bioingénierie, 11 rue Humann, 67085 Strasbourg Cedex, France. E-mail: nicolas. [email protected]
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preterm birth in asymptomatic and symptomatic patients as well as randomised trials, cohorts, case–control studies and meta-analyses. Because of the extent of such a search, we only kept in this paper, studies that were the most recent and/or relevant. In this review, we will focus especially on spontaneous prematurity. We excluded studies whose language was not English or French.
Prediction of preterm delivery, based on maternal characteristics and obstetric history must be further improved. This kind of tool tends to perform better, however, in patients who have already delivered at least once. Last but not least, more studies are needed to evaluate the clinical utility of personally adapted monitoring and/or initiating a preventive treatment in patients who are identified as being high-risk on the basis of such a risk prediction tool.
Results Prediction in the first trimester
Prediction in the second and third trimesters in asymptomatic patients
A method for calculating the risk of spontaneous preterm delivery before 34 weeks based on various predictive factors already identifiable in the 1st trimester was proposed in a cohort study involving 34,025 patients, using maternal age, height, weight, racial origin, smoker status, spontaneous or assisted conception and obstetric history (Beta et al. 2011). This tool reportedly enabled between 18.4% and 38.2% of premature deliveries to be detected, depending on whether the target patient population was nulliparous or primiparous, for a 10% false-positive rate. Several authors have also examined the utility of 1st trimester cervical echography in detecting patients who are going to deliver before term (Antsaklis et al. 2011; Carvalho et al. 2003; Conoscenti et al. 2003; Greco et al. 2011; Ozdemir et al. 2007; Souka et al. 2011; Tsikouras et al. 2007; Berghella et al. 2003; Greco et al. 2012; Sananès et al. 2013; Naim et al. 2002; Zalar 1998). Their findings are divergent. The results of these studies are reported in Table I. We published recent data showing that isthmic length rather than the cervix itself could predict preterm delivery (Sananès et al. 2013). Only a single study has investigated cervical echography combined with analysis of maternal characteristics and obstetric history in the first trimester: maternal age and height, racial origin, smoker status, assisted conception and obstetric history (Greco et al. 2012). This study, in a cohort of 9,974 pregnancies, found that combining data derived from cervical echography with maternal characteristics enabled 54.8% of mothers who deliver prematurely to be detected, versus only 38.5% for maternal characteristics alone, for a 10% false-positive rate. Several other risk factors are identifiable in the first trimester, which could improve the prediction of early risk of preterm delivery. Maternal serum levels of PAPP-A have been reported to be reduced in the first trimester in patients who deliver prematurely (Huang et al. 2010). Numerous other biomarkers, including free β-hCG, have been evaluated but none to date has proved to be useful in the prediction of preterm delivery (Conde-Agudelo et al. 2011). Finally, the presence or absence of vaginosis in the 1st trimester would appear to be associated with the risk of preterm delivery (Donders et al. 2009).
A multicentre randomised European trial pooling 5,836 pregnancies showed that performing routine digital vaginal examination during prenatal consultations did not bring about a reduction in preterm deliveries, as opposed to performing digital vaginal examination only when a presenting sign was present, such as uterine contractions (Buekens et al. 1994). In addition, the findings of a multicentre American study evaluating the prediction of preterm delivery using Bishop’s score at 24 weeks, suggested a poor sensitivity of 27.6% for a specificity of 90.6% (positive LR 3, negative LR 0.8) (Bishop 1964; Iams et al. 1996). Prediction in a high-risk subpopulation in an ancillary study was hardly any better (Iams et al. 2001). The Bishop’s score has the disadvantage of displaying very high between-observer variability (Phelps et al. 1995). Houlton et al. (1982) described a cervical score for twin pregnancies, which incorporated solely cervical length and dilatation, thus removing the more subjective criteria in the Bishop’s score (cervical consistency and position, fetal station). While Houlton’s cervical score appears slightly better at 28 weeks, the Bishop’s score is a better predictor of preterm delivery at 24 weeks (Newman et al. 2008). The same ancillary study in the American multicentre cohort compared cervical echography with the Bishop’s score (Iams et al. 2001). Prediction of preterm delivery remains mediocre if clearly better: a sensitivity of 39.1% for a specificity of 92.5% (positive LR 5.2, negative LR 5.7) with an echographic cervical length threshold at 25 mm vs 23.4% sensitivity and 92.6% specificity (positive LR 3.2, negative LR 0.8) with a Bishop’s score threshold at 5. However, a major recent meta-analysis concludes that there is no benefit in measuring the cervical length by echography in order to prevent the occurrence of preterm birth (Berghella et al. 2009). However, these findings should be qualified to some degree, particularly in asymptomatic patients with a history of late miscarriage or extremely preterm delivery: these patients may be able to benefit from a number of treatments based on the echographic length of the cervix (Berghella et al. 2005; Goya et al. 2012; Romero et al. 2012). Table II reports results of trials that studied prevention of preterm delivery
Table I. Prediction of preterm delivery by cervical length measurement in first trimester of pregnancy. Literature review. Author Greco et al. 2011 Souka et al. 2011 Antsaklis et al. 2011 Ozdemir et al. 2007 Tsikouras et al. 2007 Conoscenti et al. 2003 Carvalho et al. 2003 Berghella et al. 2003 Naim et al. 2002 Zalar et al. 1998
Gestational age for Cut-off Outcome Prediction of Patients (n) ultrasound (weeks) (mm) Population studied (weeks) preterm delivery 1,548 978 1113 152 500 2,469 529 183 154 373
11–13 11–14 11–14 10–14 9–12 13–15 ⫹ 6 11–14 11–14 ⬍ 16 11
25 27 27 27 30 20 25 30 30
Unselected Unselected Unselected Low risk High risk Unselected Unselected High risk Low risk Unselected
⬍ 34 ⬍ 37, ⬍ 34, ⬍ 32 ⬍ 37, ⬍ 35, ⬍ 32 ⬍ 35 ⬍ 37 ⬍ 37, ⬍ 34 ⬍ 37, ⬍ 33 ⬍ 35 ⬍ 37 ⬍ 37
Yes Yes No No Yes Yes No No Yes Yes
Prediction of preterm delivery 459 Table II. Prevention of preterm delivery using progesterone, among patients with a prior preterm birth. Literature review. Author
Patients (n)
Cetingoz et al. 2011
150
Rai et al. 2009
148
O’Brien et al. 2007
611
Da Fonseca et al. 2003
142
Meis et al. 2003
462
Progesterone (type and dose)
Outcome studied Rate of preterm birth (gestational age at delivery) (progesterone vs placebo)
Vaginal – micronised 100 mg/day Oral – micronised 100 mg ⫻ 2 per day Vaginal – natural 90 mg/day Vaginal – natural 100 mg/day Intramuscular – 17 OHP 250 mg/week
⬍ 37 weeks
40.0% vs 57.2%∗
⬍ 37 weeks
39.2% vs 59.5%∗
⬍ 32 weeks
10.0% vs 11.3%
⬍ 34 weeks
2.7% vs 18.5%∗
⬍ 37 weeks ⬍ 32 weeks
36.3% vs 54.9%∗ 11.4% vs 19.6%∗
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∗Means significant result.
using progesterone, among patients with a prior preterm birth (da Fonseca et al. 2003; Meis et al. 2003; O’Brien et al. 2007; Rai et al. 2009; Cetingoz et al. 2011). Recording contractions by external tocography is of no real value in asymptomatic patients (Main et al. 1988). It has been shown that there is no objective or subjective increase in uterine activity until the time of threatened preterm delivery (Iams et al. 2002). Many preterm delivery prediction scores which amalgamate various kinds of clinical and paraclinical data have been published, with very divergent outcomes. The score historically most used in France was the preterm delivery risk coefficient (coefficient de risque d’accouchement prématuré) (Papiernik 1982). Its drawback is that it conflated spontaneous and iatrogenic risk factors for preterm delivery, and it is now no longer used.
(Schmitz et al. 2008). The Bishop’s score alone, with a threshold of 4, was reported to detect 97% of preterm deliveries for a specificity of 45%, while cervical echography, with a threshold of 30 mm, had a sensitivity of 94% for 42% specificity. Combining both methods would allow specificity to be boosted (60%), while retaining good sensitivity (94%). These results are reported in Table III. It should be noted that a recent meta-analysis suggests performing cervical echography in cases of threatened preterm labour would enable the rate of premature deliveries to be reduced, although the difference was not significant: 22.3% vs 34.7%; risk ratio 0.59, 95% CI 0.26–1.32 (Berghella et al. 2009). With regard to evaluation of the cervix, elastography appears to be an interesting field to explore. This method has been shown to be objective and reproducible but has yet to be evaluated in situations of threatened preterm labour (Molina et al. 2012). Few studies have examined the issue of the predictive value of the number of recorded contractions on the occurrence or non-occurrence of preterm delivery in a situation of threatened preterm labour. A recent paper investigated the utility of electromyography and reported very encouraging results with an area under the ROC curve for prediction of preterm delivery within 7 days of 0.96 vs 0.72, 0.67 and 0.54 for the Bishop’s score, number of contractions and cervical echographic length, respectively (Lucovnik et al. 2011). Fetal fibronectin ought to find its place in cases of threatened preterm delivery with an intermediate cervix of between 15 and 30 mm, in order to improve the specificity of echographic prediction in this medium-risk population without loss of sensitivity. Results of studies evaluating a sequential use of fibronectin are reported in Table IV (Audibert et al. 2010; Deplagne et al. 2010; Sénéclauze-Seguin 2013). In any case, fibronectin test has an accurate negative predictive value. It allows no overtreating cases of threatened preterm delivery and avoids unnecessary hospitalisation.
Prediction in the second and third trimesters in symptomatic patients Only 20–40% of pregnant women hospitalised for threatened preterm labour actually go on to have a preterm delivery (Goffinet et al. 1997; McPheeters et al. 2005). This cannot be ascribed solely to the efficacy of tocolysis and suggests the difficulties of predicting preterm deliveries under circumstances of threatened preterm labour. A cohort study in 3,496 cases of threatened preterm labour showed that the higher the degree of cervical dilatation and higher the threat of preterm delivery, the greater the probability that labour would indeed be preterm (Herbst and Nilsson 2006). However, the higher the degree of cervical dilatation, the lower the level of sensitivity, when having more precise clinical criteria, such as the Bishop’s score, but also of combining these clinical criteria with echographic criteria. Only a single study has looked at the combination of the Bishop’s score and cervical echography in the prediction of preterm delivery
Table III. Prediction of preterm delivery within 7 days according to Bishop’s score, sonographic cervical length and combination of both. Technique
Cut-off
Bishop’s score Bishop’s score Cervical length ⫹: B ⱖ 8 or 4–7 and CL ⱕ 30 mm ⫺: B ⬍ 3 or 4–7 and CL ⬎ 30 mm
ⱖ4 ⱖ8 ⱕ 30 mm
Sensitivity
Specificity
97 34 94 94
45 98 42 60∗
PPV 13 58 12 17
NPV 99 94 99 99
LR⫹ 1.76 3.3 1.63 2.35∗
LR⫺ 0.05 0.67 0.15 0.10
PPV, predictive positive value; NPV, negative predictive value; LR⫹, positive likelihood ratio; LR⫺, negative likelihood ratio. ∗Significant difference between cervical length alone vs combination with digital examination. Source: Schmitz et al. (2008).
460
N. Sananès et al. Table IV. Results of studies evaluating a sequential use of fetal fibronectin after cervical length measurement for prediction of preterm delivery. Review of literature. Outcome Preterm delivery before 37 weeks Preterm delivery within 14 days
Authors
Sensitivity
Specificity
PPV
NPV
LR⫹
LR⫺
Sénéclauze et al. 2013 Deplagne et al. 2010 Audibert et al. 2010 Sénéclauze et al. 2013 Deplagne et al. 2010 Audibert et al. 2010
68 75.9 56 86.7 71.4 50
60.9 69.6 74 56.6 59.4 64
38.6 47.8 56 14.8 10.9 13
84.0 88.7 74 98.0 96.8 92
1.74 2.49 2.2 2.0 1.76 1.4
0.53 0.35 0.4 0.23 0.48 0.8
PPV, predictive positive value; NPV, negative predictive value; LR⫹, positive likelihood ratio; LR⫺, negative likelihood ratio.
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Finally, some preterm delivery risk scores have been described in cases of threatened preterm labour but are primarily intended to allow emergency care physicians to arrange the most appropriate type of transfer.
Conclusion Prediction of preterm delivery in the 1st trimester ought to be further improved. It is of potential benefit, since it would allow early introduction of appropriate monitoring and even treatment. In the second or third trimesters, routine digital vaginal examination is of no value, whether for calculating the Bishop’s score or Houlton’s cervical score. Echography of the cervix is not useful, except in patients with a history of late miscarriage or preterm delivery, in order to offer them a preventive treatment. The prediction of preterm delivery remains modest, even in situations of threatened preterm labour. The combination of digital vaginal examination, cervical echography and fibronectin in cases of intermediate risk, gives the best predictive results. Electromyography of the uterus and elastography of the cervix are interesting avenues for future research. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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REVIEW
Prediction of spontaneous preterm delivery in singleton pregnancies: Where are we and where are we going? A review of literature N. Sananès1,2, B. Langer3, A. Gaudineau1, R. Kutnahorsky4, G. Aissi1, G. Fritz3, E. Boudier3, B. Viville3, I. Nisand3 & R. Favre1 1Department of Obstetrics and Gynecology, CMCO Hospital, Schiltigheim, 2INSERM, UMR-S 1121, Biomatériaux et Bioingénierie,
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Strasbourg, 3Department of Obstetrics and Gynecology, Hautepierre Hospital, Strasbourg and 4Department of Obstetrics and Gynecology, Le Parc Hospital, Colmar, France
Prematurity is the chief cause of neonatal morbidity and mortality. The objective of this study is to review the different methods for predicting preterm delivery in asymptomatic pregnant women and in situations of threatened preterm delivery. A search of the PubMed/Medline database was carried out for the years 1980–2012. We included studies for predicting preterm birth in asymptomatic and symptomatic patients. Models for predicting preterm delivery based on maternal factors, cervical length and obstetric history in first trimester of pregnancy is a valuable avenue of research. Nevertheless, prediction accuracy still needs to be improved. In the second and third trimesters, routine digital vaginal examination is of no value in asymptomatic women. Echography of the cervix is not useful except in patients with a history of late miscarriage or preterm delivery in order to offer them a preventive treatment. In symptomatic women, the combination of digital vaginal examination, cervical echography and fibronectin gives the best predictive results. Electromyography of the uterus and elastography of the cervix are interesting avenues for future research. Identifying patients at risk of preterm delivery should be considered differently at each stage of pregnancy. Keywords: General obstetrics, prediction, preterm delivery, score, screening
Introduction Prematurity is the chief cause of neonatal morbidity and mortality (Saigal and Doyle 2008). Morbidity is essentially a correlate of neurological (intraventricular haemorrhage and periventricular leukomalacia), pulmonary (hyaline membrane disease) and gastrointestinal complications (necrotising enterocolitis). The survival of preterm infants depends on their gestational age: it is rare below the age of 24 weeks, whereas it exceeds 90% for preterm infants of more than 29 weeks admitted living to a neonatology unit (Larroque et al. 2004; Costeloe et al. 2012). In France, antenatal care has been standardised since 1987, with seven prenatal consultations and three obstetric ultrasonographic investigations financed in full by the healthcare system. Since then, prenatal screening has increased sharply. Nevertheless, prematurity appears to be slightly on the rise; this is due to practices which tend to encourage the ever earlier birth of infants at risk in utero and because of the increasing proportion of
twin pregnancies (following the expansion of medically assisted reproduction services): 5.6% of births were preterm in 1981, as opposed to 7.4% in 2010 (INSERM-DREES-DGS 2011). This same rise in prematurity is seen in the rest of Europe as well as the USA (Goldenberg et al. 2008), probably to a large extent due to the increase in induced preterm deliveries. A distinction must be made between spontaneous preterm births (spontaneous onset of labour and premature rupture of the membranes) and induced preterm births (because of small for gestational age and/or pre-eclampsia) (Meis et al. 1995). Spontaneous preterm births account for approximately two-thirds of all cases of prematurity (Iams et al. 2008). Identifying patients at risk of preterm delivery is therefore a major challenge in several respects, in relation to the stage of gestational advancement when the prediction is made and in relation to the clinical situation. In the first trimester, as well as in asymptomatic patients in the second and third trimesters of pregnancy, identifying patients at risk of preterm delivery would enable an appropriate monitoring system to be set-up, and most importantly allow initiation of a preventive treatment such as progesterone (da Fonseca et al. 2003; Meis et al. 2003; Romero et al. 2012), cervical cerclage (Berghella et al. 2005; Simcox et al. 2009) or even cervical pessary (Abdel-Aleem et al. 2010; Goya et al. 2012). Furthermore, in patients with threatened preterm delivery, being able to identify those who are most likely to deliver early would assist in deciding whether to refer them to a higherlevel maternity unit, whether to modify tocolytic treatment and the length of hospital admission, and whether to administer a course of corticosteroids to allow fetal pulmonary maturation (ACOG 2011) or magnesium sulphate for neuroprotection (Bain et al. 2012). The objective of this article is to review the prediction of preterm delivery in asymptomatic pregnant women and in situations of threatened preterm delivery, based on the stage of gestational advancement.
Materials and methods A search of the PubMed/Medline database was carried out for the years 1980–2012. The terms were ‘preterm delivery’, ‘prediction’, ‘prevention’ and ‘screening’ in association with ‘score’, ‘cervical length’, ‘digital examination’, ‘tocometry’, ‘fibronectin’, ‘electromyography’ and ‘elastography’. We included studies for predicting
Correspondence: N. Sananès, INSERM, UMR-S 1121, Biomatériaux et Bioingénierie, 11 rue Humann, 67085 Strasbourg Cedex, France. E-mail: nicolas. [email protected]
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preterm birth in asymptomatic and symptomatic patients as well as randomised trials, cohorts, case–control studies and meta-analyses. Because of the extent of such a search, we only kept in this paper, studies that were the most recent and/or relevant. In this review, we will focus especially on spontaneous prematurity. We excluded studies whose language was not English or French.
Prediction of preterm delivery, based on maternal characteristics and obstetric history must be further improved. This kind of tool tends to perform better, however, in patients who have already delivered at least once. Last but not least, more studies are needed to evaluate the clinical utility of personally adapted monitoring and/or initiating a preventive treatment in patients who are identified as being high-risk on the basis of such a risk prediction tool.
Results Prediction in the first trimester
Prediction in the second and third trimesters in asymptomatic patients
A method for calculating the risk of spontaneous preterm delivery before 34 weeks based on various predictive factors already identifiable in the 1st trimester was proposed in a cohort study involving 34,025 patients, using maternal age, height, weight, racial origin, smoker status, spontaneous or assisted conception and obstetric history (Beta et al. 2011). This tool reportedly enabled between 18.4% and 38.2% of premature deliveries to be detected, depending on whether the target patient population was nulliparous or primiparous, for a 10% false-positive rate. Several authors have also examined the utility of 1st trimester cervical echography in detecting patients who are going to deliver before term (Antsaklis et al. 2011; Carvalho et al. 2003; Conoscenti et al. 2003; Greco et al. 2011; Ozdemir et al. 2007; Souka et al. 2011; Tsikouras et al. 2007; Berghella et al. 2003; Greco et al. 2012; Sananès et al. 2013; Naim et al. 2002; Zalar 1998). Their findings are divergent. The results of these studies are reported in Table I. We published recent data showing that isthmic length rather than the cervix itself could predict preterm delivery (Sananès et al. 2013). Only a single study has investigated cervical echography combined with analysis of maternal characteristics and obstetric history in the first trimester: maternal age and height, racial origin, smoker status, assisted conception and obstetric history (Greco et al. 2012). This study, in a cohort of 9,974 pregnancies, found that combining data derived from cervical echography with maternal characteristics enabled 54.8% of mothers who deliver prematurely to be detected, versus only 38.5% for maternal characteristics alone, for a 10% false-positive rate. Several other risk factors are identifiable in the first trimester, which could improve the prediction of early risk of preterm delivery. Maternal serum levels of PAPP-A have been reported to be reduced in the first trimester in patients who deliver prematurely (Huang et al. 2010). Numerous other biomarkers, including free β-hCG, have been evaluated but none to date has proved to be useful in the prediction of preterm delivery (Conde-Agudelo et al. 2011). Finally, the presence or absence of vaginosis in the 1st trimester would appear to be associated with the risk of preterm delivery (Donders et al. 2009).
A multicentre randomised European trial pooling 5,836 pregnancies showed that performing routine digital vaginal examination during prenatal consultations did not bring about a reduction in preterm deliveries, as opposed to performing digital vaginal examination only when a presenting sign was present, such as uterine contractions (Buekens et al. 1994). In addition, the findings of a multicentre American study evaluating the prediction of preterm delivery using Bishop’s score at 24 weeks, suggested a poor sensitivity of 27.6% for a specificity of 90.6% (positive LR 3, negative LR 0.8) (Bishop 1964; Iams et al. 1996). Prediction in a high-risk subpopulation in an ancillary study was hardly any better (Iams et al. 2001). The Bishop’s score has the disadvantage of displaying very high between-observer variability (Phelps et al. 1995). Houlton et al. (1982) described a cervical score for twin pregnancies, which incorporated solely cervical length and dilatation, thus removing the more subjective criteria in the Bishop’s score (cervical consistency and position, fetal station). While Houlton’s cervical score appears slightly better at 28 weeks, the Bishop’s score is a better predictor of preterm delivery at 24 weeks (Newman et al. 2008). The same ancillary study in the American multicentre cohort compared cervical echography with the Bishop’s score (Iams et al. 2001). Prediction of preterm delivery remains mediocre if clearly better: a sensitivity of 39.1% for a specificity of 92.5% (positive LR 5.2, negative LR 5.7) with an echographic cervical length threshold at 25 mm vs 23.4% sensitivity and 92.6% specificity (positive LR 3.2, negative LR 0.8) with a Bishop’s score threshold at 5. However, a major recent meta-analysis concludes that there is no benefit in measuring the cervical length by echography in order to prevent the occurrence of preterm birth (Berghella et al. 2009). However, these findings should be qualified to some degree, particularly in asymptomatic patients with a history of late miscarriage or extremely preterm delivery: these patients may be able to benefit from a number of treatments based on the echographic length of the cervix (Berghella et al. 2005; Goya et al. 2012; Romero et al. 2012). Table II reports results of trials that studied prevention of preterm delivery
Table I. Prediction of preterm delivery by cervical length measurement in first trimester of pregnancy. Literature review. Author Greco et al. 2011 Souka et al. 2011 Antsaklis et al. 2011 Ozdemir et al. 2007 Tsikouras et al. 2007 Conoscenti et al. 2003 Carvalho et al. 2003 Berghella et al. 2003 Naim et al. 2002 Zalar et al. 1998
Gestational age for Cut-off Outcome Prediction of Patients (n) ultrasound (weeks) (mm) Population studied (weeks) preterm delivery 1,548 978 1113 152 500 2,469 529 183 154 373
11–13 11–14 11–14 10–14 9–12 13–15 ⫹ 6 11–14 11–14 ⬍ 16 11
25 27 27 27 30 20 25 30 30
Unselected Unselected Unselected Low risk High risk Unselected Unselected High risk Low risk Unselected
⬍ 34 ⬍ 37, ⬍ 34, ⬍ 32 ⬍ 37, ⬍ 35, ⬍ 32 ⬍ 35 ⬍ 37 ⬍ 37, ⬍ 34 ⬍ 37, ⬍ 33 ⬍ 35 ⬍ 37 ⬍ 37
Yes Yes No No Yes Yes No No Yes Yes
Prediction of preterm delivery 459 Table II. Prevention of preterm delivery using progesterone, among patients with a prior preterm birth. Literature review. Author
Patients (n)
Cetingoz et al. 2011
150
Rai et al. 2009
148
O’Brien et al. 2007
611
Da Fonseca et al. 2003
142
Meis et al. 2003
462
Progesterone (type and dose)
Outcome studied Rate of preterm birth (gestational age at delivery) (progesterone vs placebo)
Vaginal – micronised 100 mg/day Oral – micronised 100 mg ⫻ 2 per day Vaginal – natural 90 mg/day Vaginal – natural 100 mg/day Intramuscular – 17 OHP 250 mg/week
⬍ 37 weeks
40.0% vs 57.2%∗
⬍ 37 weeks
39.2% vs 59.5%∗
⬍ 32 weeks
10.0% vs 11.3%
⬍ 34 weeks
2.7% vs 18.5%∗
⬍ 37 weeks ⬍ 32 weeks
36.3% vs 54.9%∗ 11.4% vs 19.6%∗
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∗Means significant result.
using progesterone, among patients with a prior preterm birth (da Fonseca et al. 2003; Meis et al. 2003; O’Brien et al. 2007; Rai et al. 2009; Cetingoz et al. 2011). Recording contractions by external tocography is of no real value in asymptomatic patients (Main et al. 1988). It has been shown that there is no objective or subjective increase in uterine activity until the time of threatened preterm delivery (Iams et al. 2002). Many preterm delivery prediction scores which amalgamate various kinds of clinical and paraclinical data have been published, with very divergent outcomes. The score historically most used in France was the preterm delivery risk coefficient (coefficient de risque d’accouchement prématuré) (Papiernik 1982). Its drawback is that it conflated spontaneous and iatrogenic risk factors for preterm delivery, and it is now no longer used.
(Schmitz et al. 2008). The Bishop’s score alone, with a threshold of 4, was reported to detect 97% of preterm deliveries for a specificity of 45%, while cervical echography, with a threshold of 30 mm, had a sensitivity of 94% for 42% specificity. Combining both methods would allow specificity to be boosted (60%), while retaining good sensitivity (94%). These results are reported in Table III. It should be noted that a recent meta-analysis suggests performing cervical echography in cases of threatened preterm labour would enable the rate of premature deliveries to be reduced, although the difference was not significant: 22.3% vs 34.7%; risk ratio 0.59, 95% CI 0.26–1.32 (Berghella et al. 2009). With regard to evaluation of the cervix, elastography appears to be an interesting field to explore. This method has been shown to be objective and reproducible but has yet to be evaluated in situations of threatened preterm labour (Molina et al. 2012). Few studies have examined the issue of the predictive value of the number of recorded contractions on the occurrence or non-occurrence of preterm delivery in a situation of threatened preterm labour. A recent paper investigated the utility of electromyography and reported very encouraging results with an area under the ROC curve for prediction of preterm delivery within 7 days of 0.96 vs 0.72, 0.67 and 0.54 for the Bishop’s score, number of contractions and cervical echographic length, respectively (Lucovnik et al. 2011). Fetal fibronectin ought to find its place in cases of threatened preterm delivery with an intermediate cervix of between 15 and 30 mm, in order to improve the specificity of echographic prediction in this medium-risk population without loss of sensitivity. Results of studies evaluating a sequential use of fibronectin are reported in Table IV (Audibert et al. 2010; Deplagne et al. 2010; Sénéclauze-Seguin 2013). In any case, fibronectin test has an accurate negative predictive value. It allows no overtreating cases of threatened preterm delivery and avoids unnecessary hospitalisation.
Prediction in the second and third trimesters in symptomatic patients Only 20–40% of pregnant women hospitalised for threatened preterm labour actually go on to have a preterm delivery (Goffinet et al. 1997; McPheeters et al. 2005). This cannot be ascribed solely to the efficacy of tocolysis and suggests the difficulties of predicting preterm deliveries under circumstances of threatened preterm labour. A cohort study in 3,496 cases of threatened preterm labour showed that the higher the degree of cervical dilatation and higher the threat of preterm delivery, the greater the probability that labour would indeed be preterm (Herbst and Nilsson 2006). However, the higher the degree of cervical dilatation, the lower the level of sensitivity, when having more precise clinical criteria, such as the Bishop’s score, but also of combining these clinical criteria with echographic criteria. Only a single study has looked at the combination of the Bishop’s score and cervical echography in the prediction of preterm delivery
Table III. Prediction of preterm delivery within 7 days according to Bishop’s score, sonographic cervical length and combination of both. Technique
Cut-off
Bishop’s score Bishop’s score Cervical length ⫹: B ⱖ 8 or 4–7 and CL ⱕ 30 mm ⫺: B ⬍ 3 or 4–7 and CL ⬎ 30 mm
ⱖ4 ⱖ8 ⱕ 30 mm
Sensitivity
Specificity
97 34 94 94
45 98 42 60∗
PPV 13 58 12 17
NPV 99 94 99 99
LR⫹ 1.76 3.3 1.63 2.35∗
LR⫺ 0.05 0.67 0.15 0.10
PPV, predictive positive value; NPV, negative predictive value; LR⫹, positive likelihood ratio; LR⫺, negative likelihood ratio. ∗Significant difference between cervical length alone vs combination with digital examination. Source: Schmitz et al. (2008).
460
N. Sananès et al. Table IV. Results of studies evaluating a sequential use of fetal fibronectin after cervical length measurement for prediction of preterm delivery. Review of literature. Outcome Preterm delivery before 37 weeks Preterm delivery within 14 days
Authors
Sensitivity
Specificity
PPV
NPV
LR⫹
LR⫺
Sénéclauze et al. 2013 Deplagne et al. 2010 Audibert et al. 2010 Sénéclauze et al. 2013 Deplagne et al. 2010 Audibert et al. 2010
68 75.9 56 86.7 71.4 50
60.9 69.6 74 56.6 59.4 64
38.6 47.8 56 14.8 10.9 13
84.0 88.7 74 98.0 96.8 92
1.74 2.49 2.2 2.0 1.76 1.4
0.53 0.35 0.4 0.23 0.48 0.8
PPV, predictive positive value; NPV, negative predictive value; LR⫹, positive likelihood ratio; LR⫺, negative likelihood ratio.
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Finally, some preterm delivery risk scores have been described in cases of threatened preterm labour but are primarily intended to allow emergency care physicians to arrange the most appropriate type of transfer.
Conclusion Prediction of preterm delivery in the 1st trimester ought to be further improved. It is of potential benefit, since it would allow early introduction of appropriate monitoring and even treatment. In the second or third trimesters, routine digital vaginal examination is of no value, whether for calculating the Bishop’s score or Houlton’s cervical score. Echography of the cervix is not useful, except in patients with a history of late miscarriage or preterm delivery, in order to offer them a preventive treatment. The prediction of preterm delivery remains modest, even in situations of threatened preterm labour. The combination of digital vaginal examination, cervical echography and fibronectin in cases of intermediate risk, gives the best predictive results. Electromyography of the uterus and elastography of the cervix are interesting avenues for future research. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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