Objective
To assess the accuracy of the cervical phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) test to predict preterm birth in women with and without symptoms of preterm labor through the use of formal methods for systematic reviews and metaanalytic techniques.
Data Sources
PubMed, Embase, Cinahl, Lilacs, and Medion (all from inception to June 30, 2015), reference lists, conference proceedings, and Google scholar.
Study Eligibility Criteria
Cohort or cross-sectional studies that reported on the predictive accuracy of the cervical phIGFBP-1 test for preterm birth.
Study Appraisal and Synthesis Methods
Two reviewers independently selected studies, assessed the risk of bias, and extracted the data. Summary receiver-operating characteristic curves, pooled sensitivities and specificities, and summary likelihood ratios were generated.
Results
Forty-three studies met the inclusion criteria, of which 15 provided data on asymptomatic women (n = 6583) and 34 on women with an episode of preterm labor (n = 3620). Among asymptomatic women, the predictive accuracy of the cervical phIGFBP-1 test for preterm birth at <37, <34, and <32 weeks of gestation was minimal, with pooled sensitivities and specificities and summary positive and negative likelihood ratios ranging from 14% to 47%, 76% to 93%, 1.5 to 4.4, and 0.6 to 1.0, respectively. Among women with an episode of preterm labor, the test had a low predictive performance for delivery within 7 and 14 days of testing, and preterm birth at <34 and <37 weeks of gestation with pooled sensitivities and specificities and summary positive and negative likelihood ratios that varied between 60% and 68%, 77% and 81%, 2.7 and 3.5, and 0.4 and 0.5, respectively. A negative test result in women with an episode of preterm labor had a low to moderate accuracy to identify women who are not at risk for delivering within the next 48 hours (summary negative likelihood ratio of 0.28 in all women and 0.23 in women with singleton gestations).
Conclusion
Cervical phIGFBP-1 has the potential utility to identify patients with an episode of preterm labor who will not deliver within 48 hours. However, its overall predictive ability for the identification of symptomatic and asymptomatic women at risk for preterm birth is limited.
Preterm birth and its complications constitute a major health problem in high- and low/middle-income countries. In 2010, it was estimated that 11.1% of all live births were preterm, a worldwide total of 14.9 million babies. The estimated preterm birth rate ranged from about 5% in several northern European countries to 18% in some African countries. Despite the fact that the preterm birth rate in the United States has declined for the seventh straight year to 11.39% in 2013, this country continues to be 1 of 10 with the highest numbers of preterm births (∼450,000). Preterm birth was the leading cause of both neonatal mortality (35% of 2.8 million deaths) and child mortality (17% of 6.3 million deaths) worldwide in 2013. In addition to its contribution to mortality, preterm birth is also associated with an increased risk of long-term neurodevelopmental impairment among surviving babies.
About two-thirds of preterm births are spontaneous, following spontaneous onset of labor or premature rupture of the membranes, whereas the remaining third is medically indicated because of maternal or fetal complications. Spontaneous preterm labor is a syndrome caused by multiple pathological processes whose prediction has been a long-standing challenge. The accurate prediction of preterm birth in asymptomatic women in early pregnancy could allow the use of prophylactic interventions and more intensive antenatal surveillance. In addition, being able to identify women at low risk of preterm birth would avoid the use of unnecessary and sometimes costly interventions. On the other hand, the prediction of preterm birth in patients with symptoms and signs of preterm labor could allow interventions to prevent or delay birth and to avoid or reduce adverse neonatal outcomes associated to prematurity.
Several tests have been proposed to predict preterm birth in both asymptomatic and symptomatic women including cervical phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1). The insulin-like growth factors and their binding proteins are important for placental and fetal growth and development. PhIGFBP-1 is a major protein synthesized in decidualized endometrium cells during pregnancy. Tissue disruption at the choriodecidual interface because of uterine contractions can result in leakage of phIGFBP-1 into cervical secretions. In 2001, Kekki et al and Kurkinen-Räty et al reported that high levels of phIGFBP-1 in cervical secretions could identify symptomatic women at risk of preterm birth. Since then, several authors have reported that cervical phIGFBP-1 can accurately predict preterm birth in women with an episode of preterm labor and intact membranes and that, compared with cervicovaginal fetal fibronectin, it has several advantages. Specifically, results are not affected by recent sexual intercourse or contamination with urine, lower costs, and faster testing. Nevertheless, the predictive ability of this test for preterm birth has also been challenged in some reports.
Currently, the cervical phIGFBP-1 test is used in many countries around the world such as the United Kingdom, Canada, Germany, Italy, France, Japan, Australia, New Zealand, India, and Israel among others. Therefore, a critical appraisal of its predictive performance is timely and necessary. We carried out a systematic review and metaanalysis to assess the accuracy of cervical phIGFBP-1 to predict preterm birth in women with and without symptoms of preterm labor.
Materials and methods
This study was conducted according to a prospective protocol and in accordance with recommended methods for systematic reviews of diagnostic test accuracy.
Literature search
We undertook a search in PubMed, Embase, Cinahl, Lilacs, and Medion (all from inception to June 30, 2015) and Google Scholar using an existing search strategy for systematic reviews of accuracy studies evaluating tests for predicting preterm birth. Proceedings of several meetings on preterm birth and maternal-fetal medicine, bibliographies of the retrieved articles, and review articles were also searched. In addition, we contacted investigators involved in the field to locate unpublished studies. There were no language restrictions.
Study selection
We included cohort or cross-sectional studies that reported on the accuracy of the cervical phIGFBP-1 test to predict preterm birth in asymptomatic and/or symptomatic women with a singleton or twin gestation, and that allowed the construction of 2×2 contingency tables. Studies were excluded if they were case-control studies because there is consistent evidence that they are associated with higher diagnostic or predictive accuracy compared with cohort studies ; were reviews, case series or reports, editorials, or letters without original data; assessed cervical phIGFBP-1 in women with suspected or established preterm premature rupture of membranes; assessed phIGFBP-1 only in vaginal secretions, amniotic fluid, or blood; reported data for cervical phIGFBP-1 only as mean or median values; or did not publish accuracy test estimates and sufficient information to calculate them could not be retrieved. In cases of duplicate publication, we included only the most recent or complete version.
All of the potentially relevant studies were retrieved and reviewed independently by the 2 authors to determine the inclusion. Disagreements were resolved through consensus.
Reference standard outcomes
In asymptomatic women, the reference standard outcomes were preterm birth (both spontaneous and indicated) and spontaneous preterm birth at <32, <34, and <37 weeks of gestation; in women with an episode of preterm labor, the reference standard outcomes were delivery within 48 hours and 7 and 14 days of testing and preterm birth at <34 and <37 weeks of gestation.
Methodological quality assessment
Study quality was assessed using a modified version of the QUADAS (Quality Assessment of Diagnostic Accuracy Studies)-2 tool. The assessments were judged as low risk, high risk, or unclear risk of bias. The items evaluated and how they were interpreted were as follows:
- 1.
Patient selection . Low risk of bias: pregnant women consecutively or randomly selected; high risk of bias: convenience sampling (arbitrary recruitment or nonconsecutive recruitment).
- 2.
Selection of test cutoff value . Low risk of bias: prespecified; high risk of bias: determined by a data-driven approach.
- 3.
Reference standard . Low risk of bias: spontaneous preterm birth, defined as a preterm delivery after the spontaneous onset of contractions or the preterm premature rupture of membranes, regardless of whether the delivery was vaginal, by cesarean delivery, or, in the case of rupture of membranes, induced; high risk of bias: inclusion of both spontaneous and indicated preterm birth in the reference standard.
- 4.
Blinding . Low risk of bias: the study clearly stated that clinicians managing the patient did not have knowledge of the phIGFBP-1 test results; high risk of bias: unmasking of clinicians to test results.
- 5.
Inclusion of women in the analysis . Low risk of bias: if at least 90% of women recruited into the study were included in the analysis; high risk of bias: if <90% of women recruited into the study were included in the analysis.
- 6.
Use of interventions aimed to prevent preterm birth based on the results of the test . Low risk of bias: clinicians did not use interventions based on the results of the cervical phIGFBP-1 test; high risk of bias: clinicians used interventions based on the results of the test (eg, tocolytics, vaginal progesterone, 17-alphahydroxyprogesterone caproate).
If there was insufficient information available to make a judgment about these items, then they were scored as unclear risk of bias. Summary quality score for each study was not calculated because of the well-known problems associated with such scores. The risk of bias in each included study was assessed independently by the 2 investigators. Any differences of opinion regarding assessment of risk of bias were resolved by discussion.
Data extraction
The 2 reviewers independently extracted data on characteristics of the study (authors, setting, year of publication, method of recruiting women, prospective or retrospective data collection, blinding of test results, flow diagram, percentage of women recruited into the study that were included in the analysis, and use of interventions to prevent preterm birth); patient characteristics (inclusion and exclusion criteria, risk classification for preterm birth, sample size, plurality of pregnancy, and demographic characteristics); how the test was carried out (gestational age at sampling, laboratory methods used, and cutoff value used); reference standard outcomes assessed and their prevalences; and numbers of true-positive, false-positive, true-negative, and false-negative test results. When predictive accuracy data were not available, we recalculated them from the reported results. The corresponding authors of primary studies were contacted to obtain additional information on methods used and/or unpublished relevant data. Only 2 authors supplied additional data. Interreviewer disagreements were resolved by discussion.
Data were extracted separately for asymptomatic and symptomatic women, singleton and twin gestations, and for each reference standard outcome assessed. Studies that reported preterm birth at <36 weeks of gestation were grouped with those that reported preterm birth at <37 weeks of gestation, and those reporting preterm birth at <35 weeks of gestation were considered alongside studies reporting preterm birth at <34 weeks of gestation.
Data synthesis
Data from individual studies were synthesized separately for asymptomatic and symptomatic women and stratified according to the predefined reference standard outcomes, plurality of pregnancy, and risk status of women for preterm birth. For asymptomatic women, we synthesized data for all women, those with singleton and twin gestations, those with a singleton gestation and previous spontaneous preterm birth, and those at high risk for preterm birth. For patients with an episode of preterm labor, we synthesized data for all women, those with a singleton gestation, and those with a singleton gestation and a sonographic cervical length ≤30 mm.
Data extracted from each study were arranged in 2×2 contingency tables. Where 2×2 tables contained zero cells, we added 0.5 to each cell to enable calculations. Sensitivity and specificity with 95% confidence intervals (CIs) were calculated separately for each study and reference standard outcome reported. Then we constructed summary receiver-operating characteristic (ROC) curves for each predefined reference standard outcome and derived pooled estimates and 95% CIs of sensitivity and specificity using random-effects bivariate metaregression models. Thereafter we calculated summary likelihood ratios with 95% CIs from the pooled sensitivities and specificities. Likelihood ratios for a positive test result above 10 and likelihood ratios for a negative test result below 0.1 are considered to provide strong predictive evidence in most circumstances. Moderate prediction can be achieved with likelihood ratios of 5–10 and 0.1–0.2, whereas those <5 and >0.2 give only minimal prediction. Finally, we planned to calculate the posttest probabilities of the most important reference standard outcomes by combining likelihood ratios obtained from metaanalyses for positive and negative test results and a global prevalence (pretest probability) of these reference standard outcomes across the studies.
Heterogeneity of the results among studies was assessed through visual examination of both forest plots of sensitivities and specificities and ROC plots and by means of the quantity I 2 . A substantial level of heterogeneity was defined as an I 2 of ≥50%. We explored potential sources of heterogeneity by performing a metaregression analysis of subgroups defined a priori (study setting, sample size, study’s year of publication, prevalence of the reference standard outcome, and study quality). If there were at least 10 studies included in a metaanalysis, we assessed publication and related biases by examining the symmetry of the funnel plots with the Deeks’ test. A value of P < .10 for the slope coefficient indicated significant asymmetry of the funnel plot.
Bivariate random-effects models were fitted using the NLMIXED procedure of SAS version 9.2 (SAS Institute Inc, Cary, NC). Review Manager 5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark) was used to construct forest plots of sensitivity and specificity and summary ROC curves.
Results
Selection, characteristics, and quality of studies
Figure 1 summarizes the process of identification and selection of studies. The searches produced 417 citations, of which 65 were considered relevant. Of these, 22 were excluded, mainly because they were not a test accuracy study, were duplicate publications, or did not report original data. A total of 43 studies, including 10,203 women, met the inclusion criteria, of which 9 provided data on asymptomatic women (n = 6131), 28 on symptomatic women (n = 3212), and 6 on both asymptomatic (n = 452) and symptomatic (n = 408) women.
The main characteristics of included studies are displayed in Table 1 . Twenty studies (47%) were performed in European countries, 16 (37%) in Asia, 3 (7%) in South America, and 4 (9%) in Canada. The sample size ranged from 18 to 4984 (median, 88) in asymptomatic women and from 30 to 350 (median, 70) in symptomatic women. Among the 34 studies performed in symptomatic women, only 7 (21%) defined preterm labor as the presence of uterine contractions with evidence of cervical changes. Twelve studies (35%) did not include cervical changes in the diagnosis of preterm labor ; 1 study included women with or without cervical changes ; and 14 studies did not report clearly on the definition of preterm labor. All the studies were limited to women with intact membranes. Two studies included exclusively twin gestations, both in asymptomatic women.
Study, year | Country | Number of women | Inclusion criteria | Exclusion criteria | Gestational age at testing, wks | Cutoff value, μg/L | Reference standard outcome |
|---|---|---|---|---|---|---|---|
| Asymptomatic women | |||||||
| Paternoster et al, 2000 | Italy | 88 | Gestation at high risk for preterm birth: multiple gestation, previous preterm birth or second-trimester miscarriage, prophylactic cerclage, placenta previa, uterine malformations, chronic gestational hypertension, IUGR, polyhydramnios, and/or uteroplacental insufficiency | Not reported | 24–34 | 10 | Spontaneous preterm birth <37 wks |
| Bittar et al, 2007 | Brazil | 105 | Singleton gestation and at least 1 previous spontaneous preterm birth <37 wks’ gestation | Multiple gestation, history of cervical incompetence, previous cervical surgery, or previous preterm labor in the current pregnancy | 24–34 serial | 10 | Spontaneous preterm birth <34 and <37 wks |
| Balić et al, 2008 | Bosnia and Herzegovina | 80 | Singleton gestation | Uncertain gestational age, previous preterm delivery, history of pregnancy loss, urinary infection, uterine anomalies, or previous cesarean section | 24–34 | 10 | Preterm birth <37 wks |
| Adeyemi and Osoba, 2010 | United Kingdom | 40 | Twin gestation | Not reported | 26 | 10 | Preterm birth <34 and <37 wks |
| Rakhonen et al, 2010 | Finland | 4984 | Singleton (99.4%) or multiple (0.6%) gestation | Not reported | 12–13 and 18–20 | 10 | Spontaneous preterm birth <2 and <37 wks |
| Khambay et al, 2012 | United Kingdom | 45 | Gestation at high risk for preterm birth: history of previous preterm birth, second-trimester miscarriage, cervical surgery, and/or uterine malformations | PROM or vaginal bleeding | 23–24 | 10 | Preterm birth <34 and <37 wks |
| Riboni et al, 2012 | Italy | 491 | Singleton gestation | Uterine contractions, vaginal bleeding, placenta previa, multiple gestation, fetal abnormalities, or uterine anomalies | 24 | 33 | Preterm birth <37 wks |
| Rolnik et al, 2013 | Brazil | 101 | Singleton gestation and previous spontaneous preterm birth | Fetal malformations, use of progesterone, use of tocolytic agents followed by term birth | 24–34 serial | 10 | Spontaneous preterm birth <37 wks |
| Fichera et al, 2014 | Italy | 197 | Twin gestation | Active vaginal bleeding, PROM, death of 1 fetus, or use of cerclage or pessary | 16–25 | 10 | Spontaneous preterm birth <34, <32, <30, and <28 wks |
| Women with symptoms of preterm labor | |||||||
| Kurkinen-Räty et al, 2001 | Finland | 77 | Singleton gestation, preterm labor (uterine contractions or cervical shortening, opening or softening), and intact membranes | PROM or ongoing preterm delivery | 22–32 serial | 6.4 | Spontaneous preterm birth <37 wks |
| Shine et al, 2001 | Korea | 32 | Preterm labor (uterine contractions with cervical dilatation <2 cm) and intact membranes | Not reported | 24–36 | 10 | Preterm birth <34 and <37 wks |
| Choi et al, 2003 | Korea | 42 | Singleton gestation and preterm labor (2-3 uterine contractions/min for 30 min) | Not reported | 20–36 | 10 | Preterm birth <37 wks |
| Heraud et al, 2003 | France | 93 | Singleton or twin gestation, preterm labor (not defined), and intact membranes | PROM or indicated preterm delivery | 23–35 | 10 | Spontaneous preterm birth <37 wks |
| Park et al, 2003 | Korea | 50 | Preterm labor, cervical dilatation <3 cm, intact membranes, and no prior tocolysis | Not reported | 24–34 | 10 | Delivery within 7 d of testing, and preterm birth <34 and <37 wks |
| Winograd et al, 2003 | Argentina | 85 | Singleton gestation, preterm labor (not defined), and intact membranes | Multiple gestation or PROM | 24–35 | 10 | Delivery within 7 d of testing |
| Kwek et al, 2004 | Singapore | 42 | Preterm labor (≥1 uterine contractions in 10 min) and intact membranes | Antepartum hemorrhage, PROM, cervical dilatation >3 cm, contraindications to tocolysis, or cerclage | 23–33 | 10 | Delivery within 48 hrs and 7 d of testing, and preterm birth <36 wks |
| Elizur et al, 2005 | Israel | 64 | Singleton (67%) or twin (33%) gestation, preterm labor (≥2 uterine contractions in 10 min), and intact membranes | Heavy vaginal bleeding, PROM, placenta previa, previous preterm induction of labor, or nonreassuring fetal condition | 24–35 | 10 | Spontaneous preterm birth <35 and <37 wks |
| Halle et al, 2005 | Germany | 93 | Singleton gestation, preterm labor (not defined), and intact membranes | Not reported | 23–32 | 10 | Preterm birth <37 wks |
| Turnell et al, 2005 | Canada | 100 | Singleton or multiple gestation, idiopathic preterm labor (not defined), cervical dilatation <3 cm, and intact membranes | PROM, history of digital examination or sexual intercourse within the previous 24 hrs, vaginal bleeding, suspected IUGR, or nonreassuring maternal or fetal status | 24–35 | 10 | Delivery within 14 d of testing |
| Sanchez Martinez et al, 2006 | Spain | 149 | Singleton gestation, preterm labor (not defined) requiring admission, and no parturition within 24-48 hrs after admission | Clinical chorioamnionitis, nonreassuring fetal status, or PROM | 24–35 | 10 | Delivery within 7 d of testing and spontaneous preterm birth <36 wks |
| Larouche and Simard, 2007 | Canada | 55 | Singleton gestation, preterm labor (cervical dilatation ≤2 cm and effacement <80%), intact membranes, and reassuring fetal well-being | History of sexual intercourse or use a speculum or lubricant in the previous 24 hrs, moderate or heavy vaginal bleeding, or PROM | 24–34 | 10 | Delivery within 14 d of testing and preterm birth <37 wks |
| Ting et al, 2007 | Singapore | 94 | Singleton gestation, preterm labor (not defined), and intact membranes | Multiple gestation, PROM, cerclage, cervical dilatation ≥3 cm, preeclampsia, IUGR, placenta previa, suspected fetal asphyxia, chorioamnionitis, or major fetal anomaly | 24–34 | 10 | Delivery within 48 hrs, and 7 and 14 d of testing |
| Latifagić et al, 2008 | Bosnia and Herzegovina | 30 | Singleton gestation, preterm labor (not defined), and intact membranes | Chronic diseases, maternal genital tract anomalies, fetal genetic/anatomical defects, or previous preterm delivery | 24–34 | 10 | Preterm birth <37 wks |
| Sunagawa et al, 2008 | Japan | 76 | Singleton gestation, preterm labor (≥6 uterine contractions in 60 min documented by external tocography or any uterine activity associated with cervical changes), and intact membranes | Multiple gestation, rupture of membranes, herniation of membranes protruding beyond the external cervical os, indicated preterm delivery, fetal congenital anomalies, or contraindications to tocolysis | 22–34 | 10 | Delivery within 72 hrs and 7 d of testing |
| Rahkonen et al, 2009 | Finland | 246 | Singleton gestation, preterm labor (uterine contractions confirmed with external tocography), and intact membranes | Major fetal anomalies, vaginal bleeding, or placenta previa | 22–34 | 10 | Delivery within 14 d of testing and spontaneous preterm birth ≤34 wks |
| Tanir et al, 2009 | Turkey | 68 | Singleton gestation, preterm labor (≥4 uterine contractions lasting at least 30 sec in 20 min and cervical changes), cervical dilatation <3 cm, and intact membranes | Cerclage, massive vaginal bleeding, use of tocolytics at admission, history of vaginal douche, intercourse or digital examination within the previous 24 hrs, preeclampsia, multiple gestation, diabetes mellitus, hyperthyroidism, or asthma | 24–36 | 10 | Delivery within 7 and 14 d of testing and preterm birth <34 wks |
| Audibert et al, 2010 | Canada | 62 | Singleton (89%) or multiple (11%) gestation, preterm labor (≥4 uterine contractions in 30 min and lasting at least 30 sec with significant cervical changes), and intact membranes | PROM, cervical dilatation >3 cm, cerclage, vaginal bleeding, placenta previa, placental abruption, severe IUGR, preeclampsia, or medically indicated preterm delivery <34 wks | 24–34 | 10 | Delivery within 14 d of testing and preterm birth <34 and <37 wks |
| Azlin et al, 2010 | Malaysia | 51 | Singleton gestation, preterm labor (not defined), and intact membranes | Multiple gestation, PROM, cervical incompetence, cerclage, placenta previa, placental abruption, or cervical dilatation >3 cm | 24–36 | 10 | Delivery within 7 d of testing |
| Brik et al, 2010 | Spain | 276 | Singleton gestation, preterm labor (not defined), and intact membranes | PROM, vaginal bleeding, placental abruption, fetal distress, cord prolapse, cervical dilatation >3 cm or cervical effacement of 100%, cerclage, or fetal anomalies | 24–34 | 10 | Delivery within 48 hrs and 7 d of testing, and spontaneous preterm birth <32 and <34 wks |
| Randhawa and Kwek, 2010 | Singapore | 293 | Preterm labor (not defined) and intact membranes | Not reported | 22–36 | 10 | Delivery within 48 hrs of testing |
| Danti et al, 2011 | Italy | 60 | Singleton gestation, preterm labor (≥4 uterine contractions in 20 min), cervical length ≤30 mm, and intact membranes | Multiple gestation, vaginal bleeding, PROM, cervical dilatation >3 cm, cerclage, uterine or fetal abnormalities, and other pregnancy complications | 24–32 | 10 | Delivery within 7 d of testing and preterm birth <34 and <37 wks |
| Riboni et al, 2011 | Italy | 210 | Singleton gestation, preterm labor (≥10 uterine contractions/h), and intact membranes | Cervical dilatation >2 cm, cervical examination or sexual intercourse within the last 24 hrs, vaginal bleeding, placenta previa, multiple gestations, fetal abnormalities, or uterine anomalies | 24–34 | 10 | Delivery within 7 d of testing and preterm birth <34 and <37 wks |
| Cooper et al, 2012 | Canada | 349 | Singleton (94%) or multiple (6%) gestation, preterm labor (not defined), and intact membranes | PROM, antepartum hemorrhage, active labor, or suspected chorioamnionitis | 24–34 | 10 | Delivery within 7 and 14 d of testing and preterm birth <37 wks |
| Singh et al, 2013 | India | 50 | Preterm labor (regular uterine contractions), cervical dilatation of 1 to <3 cm, and intact membranes | PROM, vaginal bleeding, heart disease, or diabetes | 28–36 | 10 | Delivery within 48 hrs and 7 d of testing and preterm birth <34 and <37 wks |
| Bruijn et al, 2014 | The Netherlands | 350 | Singleton gestation, preterm labor (not defined), cervical length <30 mm, and intact membranes | Multiple gestation or PROM | 24–34 | 10 | Delivery within 7 d of testing |
| Abo El-Ezz et al, 2014 | Kuwait | 57 | Singleton gestation, preterm labor (≥1 uterine contractions in 10 min), and intact membranes | PROM, multiple gestation, or vaginal bleeding | 24–34 | 10 | Delivery within 7 d of testing |
| Hadži-Lega et al, 2014 | Macedonia | 58 | Singleton gestation, preterm labor (not defined), cervical dilatation ≤3 cm, and intact membranes | Multiple gestation, PROM, antepartum hemorrhage, active labor, cerclage, or suspected chorioamnionitis | 22–33 | 10 | Delivery within 14 d of testing |
| Both asymptomatic and symptomatic women | |||||||
| Kekki et al, 2001 | Finland | 121 | Singleton or twin gestation without (n = 58) and with (n = 63) symptoms of preterm labor (uterine contractions) and intact membranes | PROM | 22–36 | 10 | Spontaneous preterm birth <32, <34, and <37 wks |
| Lembet et al, 2002 | Turkey | 54 | Singleton gestation without (n = 18) and with (n = 36) symptoms of preterm labor (>10 uterine contractions per hr, regardless of the cervical dilatation) and intact membranes | Multiple gestation, vaginal bleeding, IUGR, uterine anomaly, congenital fetal abnormality, or preeclampsia | 20–36 | 10 | Delivery within 48 hrs and 7 d of testing and preterm birth <37 wks |
| Akercan et al, 2004 | Turkey | 65 | Singleton gestation without (n = 20) and with (n = 45) symptoms of preterm labor (>4 contractions in 20 min) and intact membranes | Multiple gestation, PROM, cervical dilatation >2 cm, IUGR, vaginal bleeding, preeclampsia, or congenital fetal or uterine anomaly | 24–36 | 10 | Preterm birth <37 wks |
| Eroglu et al, 2007 | Turkey | 141 | Singleton gestation without (n = 90) and with (n = 51) symptoms of preterm labor (≥10 uterine contractions per hr) and intact membranes | Vaginal bleeding, cervical dilatation ≥3 cm, PROM, sexual intercourse within the past 24 hrs, multiple pregnancy, uterine anomalies, congenital fetal abnormality, placenta previa, placental abruption, IUGR, or preeclampsia | 24–35 | 10 | Delivery within 7 d of testing and preterm birth <35 wks |
| Paternoster et al, 2007 | Italy | 301 | Singleton gestation without (n = 193) and with (n = 108) symptoms of preterm labor (>10 uterine contractions per hr) and intact membranes | Vaginal bleeding, PROM, uterine abnormalities, IUGR, or medical complications of pregnancy | 22–34 | 10 | Preterm birth <37 wks |
| Altinkaya et al, 2009 | Turkey | 178 | Singleton gestation without (n = 73) and with (n = 105) symptoms of preterm labor (uterine contractions confirmed by external tocography) and intact membranes | Multiple gestation, PROM, cervical dilatation ≥2 cm, preeclampsia, vaginal bleeding, IUGR, fetal or uterine anomalies, history of preterm birth, or smoking | 24–34 | 10 | Delivery within 7 d of testing and preterm birth <37 wks |
Of the 15 studies in asymptomatic women, 10 performed the test from 20 to 36 weeks of gestation, 3 from 23 to 26 weeks, and one at 16–25 weeks. The remaining study measured the concentration of cervical phIGFBP-1 at 12–13 and 18–20 weeks of gestation. Most studies in symptomatic women assessed the test between 22 and 24 and between 34 and 36 weeks of gestation. In all studies, the concentration of phIGFBP-1 in cervical secretions was measured by an immunoenzymometric assay involving monoclonal antibodies specific for the phosphorylated form of IGFBP-1. All studies except two used a concentration ≥10 μg/L to indicate an abnormal test result. Most studies in both asymptomatic and symptomatic women reported on the predictive accuracy of cervical phIGFBP-1 for preterm birth at <37 weeks of gestation. Twenty-five studies (58%) reported data for more than one reference standard outcome.
Figure 2 summarizes the quality assessment of included studies. Ten studies (23%), 9 among symptomatic and 1 among asymptomatic women, fulfilled ≥5 criteria. Twenty-five studies (58%) had ≥3 methodological flaws. The most common shortcomings were the lack of information regarding blinding of clinicians to the test results, follow-up of women and the reference standard outcome assessed. Only 14 studies reported clearly that the reference standard outcome assessed was spontaneous preterm birth.
Cervical phIGFBP-1 in asymptomatic women
Figure 3 , A shows the sensitivity and specificity of the cervical phIGFBP-1 test in the individual studies to predict preterm birth in asymptomatic women. The summary ROC curves showed that the cervical phIGFBP-1 test had a similar predictive ability for preterm birth at <37 and at <34 weeks of gestation ( Figure 4 , A). Overall, regardless of the risk status of women, plurality of pregnancy and reference standard outcome assessed, the predictive accuracy of this test for preterm birth at <37, <34, and <32 weeks of gestation was minimal with pooled sensitivities and specificities, and summary positive and negative likelihood ratios ranging from 14% to 47%, 76% to 93%, 1.5 to 4.4, and 0.6 to 1.0, respectively ( Table 2 ).
| Outcome | Studies, n | Number of women | Pooled sensitivity, % (95% CI) | Pooled specificity, % (95% CI) | Positive likelihood ratio (95% CI) | Negative likelihood ratio (95% CI) | I 2 , % |
|---|---|---|---|---|---|---|---|
| All women | |||||||
| Preterm birth <37 wks | 13 | 6287 | 38 (33–43) | 77 (76–78) | 1.7 (1.4–2.0) | 0.8 (0.7–0.9) | 65 |
| Spontaneous preterm birth <37 wks | 5 | 5327 | 38 (32–44) | 77 (76–78) | 1.6 (1.3–2.0) | 0.8 (0.7–0.9) | 0 |
| Preterm birth <34 wks | 5 | 476 | 34 (20–51) | 90 (86–93) | 3.4 (1.2–10.6) | 0.7 (0.5–0.9) | 85 |
| Spontaneous preterm birth <34 wks | 2 | 301 | 39 (23–58) | 90 (86–94) | 3.9 (1.6–9.7) | 0.7 (0.4–0.9) | 94 |
| Spontaneous preterm birth <32 wks | 2 | 5181 | 40 (24–58) | 76 (75–77) | 1.7 (1.0–2.5) | 0.8 (0.5–1.0) | 14 |
| Unselected women with a singleton gestation | |||||||
| Preterm birth <37 wks | 7 | 5828 | 41 (34–47) | 77 (75–78) | 1.8 (1.3–2.2) | 0.8 (0.7–0.9) | 70 |
| Women with a twin gestation | |||||||
| Preterm birth <34 wks | 2 | 237 | 16 (5–36) | 93 (89–96) | 2.3 (0.5–9.2) | 0.9 (0.7–1.1) | 0 |
| Women with a singleton gestation and previous spontaneous preterm birth | |||||||
| Preterm birth <37 wks | 2 | 197 | 47 (32–62) | 89 (83–94) | 4.4 (1.9–10.4) | 0.6 (0.4–0.8) | 0 |
| All women at high risk for preterm birth | |||||||
| Preterm birth <37 wks | 5 | 370 | 31 (22–40) | 90 (86–93) | 3.1 (1.6–5.9) | 0.8 (0.6–0.9) | 69 |
| Preterm birth <34 wks | 3 | 272 | 14 (4–32) | 91 (86–94) | 1.5 (0.4–4.3) | 1.0 (0.8–1.1) | 0 |
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