European Journal of Obstetrics & Gynecology and Reproductive Biology 192 (2015) 79–85
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Risk factors for preterm delivery: do they add to fetal fibronectin testing and cervical length measurement in the prediction of preterm delivery in symptomatic women? Gert-Jan van Baaren a,*, Merel M.C. Bruijn a, Jolande Y. Vis b, Femke F. Wilms c, Martijn A. Oudijk d, Anneke Kwee d, Martina M. Porath e, Guid Oei f, Hubertina C.J. Scheepers f, Marc E.A. Spaanderman f, Kitty W.M. Bloemenkamp g, Monique C. Haak g, Antoinette C. Bolte h, Caroline J. Bax h, Je´roˆme M.J. Cornette i, Johannes J. Duvekot i, Bas W.A. Nij Bijvanck j, Jim van Eijck j, Maureen T.M. Franssen k, Krystyna M. Sollie k, Frank P.H.A. Vandenbussche l, Mallory Woiski l, Patrick M.M. Bossuyt m, Brent C. Opmeer n, Ben W.J. Mol o a
Department of Obstetrics and Gynaecology, Academic Medical Centre, Amsterdam, Netherlands Department of Clinical Chemistry and Haematology, University Medical Centre Utrecht, Utrecht, Netherlands c Department of Obstetrics and Gynaecology, Catharina Hospital, Eindhoven, Netherlands d Department of Obstetrics and Gynaecology, University Medical Centre Utrecht, Utrecht, Netherlands e Department of Obstetrics and Gynaecology, Ma´xima Medical Centre, Veldhoven, Netherlands f Department of Obstetrics and Gynaecology, University Hospital Maastricht, Maastricht, Netherlands g Department of Obstetrics, Leiden University Medical Centre, Leiden, Netherlands h Department of Obstetrics and Gynaecology, VU University Medical Centre, Amsterdam, Netherlands i Department of Obstetrics and Gynaecology, Erasmus Medical Centre, Rotterdam, Netherlands j Department of Obstetrics and Gynaecology, Isala Clinics, Zwolle, Netherlands k Department of Obstetrics and Gynaecology, University Medical Centre Groningen, Groningen, Netherlands l Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands m Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, Amsterdam, Netherlands n Clinical Research Unit, Academic Medical Centre, Amsterdam, Netherlands o Department of Obstetrics and Gynaecology, The Robinson Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Australia b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 31 August 2014 Received in revised form 22 April 2015 Accepted 19 May 2015
Objective: To assess whether patient characteristics add to the fetal fibronectin test and cervical length measurement in the prediction of preterm delivery in symptomatic women. Study design: A nationwide prospective cohort study was conducted in all ten perinatal centres in the Netherlands. Women with symptoms of preterm labour between 24 and 34 weeks gestation with intact membranes were invited. In all women qualitative fibronectin testing (0.050 mg/mL cut-off) and cervical length measurement were performed. Only singleton pregnancies were included in this analysis. Logistic regression was used to construct two multivariable models to predict spontaneously delivery within 7 days: a model including cervical length and fetal fibronectin as predictors, and an extended model including all potential predictors. The models were internally validated using bootstrapping techniques. Predictive performances were assessed as the area under the receiver operator characteristic curve (AUC) and calibration plots. We compared the models’ capability to identify women with a low risk to deliver within 7 days. A risk less than 5%, corresponding to the risk for women with a cervical length of at least 25 mm, was considered as low risk. Results: Seventy-three of 600 included women (12%) had delivered spontaneously within 7 days. The extended model included maternal age, parity, previous preterm delivery, vaginal bleeding, C-reactive
Keywords: Preterm labour Prediction Fetal fibronectin Cervical length Pregnancy
* Corresponding author at: Department of Obstetrics and Gynaecology, Academic Medical Centre, 1105 DE, Amsterdam, The Netherlands. Tel.: +31 205664256. E-mail address: [email protected] (G.-J. van Baaren). http://dx.doi.org/http://dx.doi.org/10.1016/j.ejogrb.2015.05.004 0301-2115/ß 2015 Elsevier Ireland Ltd. All rights reserved.
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G.-J. van Baaren et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 192 (2015) 79–85
protein, cervical length, dilatation and fibronectin status. Both models had high discriminative performances (AUC of 0.92 (95% CI 0.88–0.95) and 0.95 (95% CI 0.92–0.97) respectively). Compared to the model with fibronectin and cervical length, our extended model reclassified 38 women (6%) from low risk to high risk and 21 women (4%) from high risk to low risk. Preterm delivery within 7 days occurred once in both the reclassification groups. Conclusion: In women with symptoms of preterm labour before 34 weeks gestation, a model that integrates maternal characteristics, clinical signs and laboratory tests, did not predict delivery within 7 days better than a model with only fibronectin and cervical length. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Introduction Spontaneous preterm delivery occurs in 5–13% of all deliveries and remains the main cause of perinatal mortality and neonatal morbidity in the developed world [1]. Most women with symptoms of preterm labour before 32 weeks gestational age are transferred to a perinatal centre and receive treatment, such as tocolysis, magnesiumsulphate and corticosteroids. Yet, about 80– 95% will not deliver within 1 week after presentation, and half of these women deliver at term [2–5]. Consequently, many women are unnecessarily transferred and exposed to the potential side effects of tocolysis and corticosteroids in both mother and child [6–8]. To reduce overtreatment and costs of unnecessary referrals and treatment, accurate identification of those women who will not deliver on the short term – i.e. within 7 days – is of the utmost importance. On the other hand, knowledge about the short term risk to deliver helps to identify women with symptoms of preterm labour who need immediate treatment and referral to a perinatal centre in order to optimize circumstances if preterm delivery occurs. Despite many different predictors and risk factors of preterm delivery known in the literature, it remains difficult to assess this risk in individual women [1,9,10]. Several studies, including our nationwide cohort study, have reported promising results of the combination of cervical length and fetal fibronectin measurements to predict preterm delivery within 7 days in symptomatic women [2,11,12]. It is possible that predictions will improve even further when other prognostic features are added to these two measures. The aim of this study was to evaluate whether patient characteristics, when added to cervical length and fetal fibronectin, improve the prediction of delivery within 7 days in symptomatic women between 24 and 34 weeks of gestational age.
Methods Setting We used data collected in the APOSTEL-I study, a nationwide cohort study conducted in all ten perinatal centres in the Netherlands between December 2009 and August 2012. The objective of this study was to evaluate the predictive value of the fetal fibronectin test in addition to cervical length measurement in women with symptoms of preterm labour. The study design and main results are presented in detail elsewhere [13,12]. In short, we included women with symptoms of preterm labour between 24 and 34 weeks of gestational age with intact membranes. Exclusion criteria were cervical dilatation of more than three centimetres, previous treatment with tocolysis within 7 days before inclusion, and contra-indications for tocolysis, such as suspected intra-uterine infections, fetal distress or lethal congenital abnormalities. Women who had iatrogenic delivery within 7 days after inclusion were also excluded. All women provided written informed consent before entering the study.
We obtained fetal fibronectin and cervical length measurement in all participating women. Cervical length measurement in symptomatic women until 34 weeks is standard care in the Netherlands and is performed by clinically active physicians, who are trained in transvaginal sonography and perform cervical length measurements themselves. In order to standardize these measurements, all participating physicians were given a set of instructions and a pocket card with illustrated examples of accurate cervical length measurements. We used the qualitative Rapid fetal fibronectin TLIIQ analyser (Hologic) with a 0.050 mg/mL cut-off for the fetal fibronectin test. In addition, data collection included maternal characteristics, results from digital examination and laboratory tests, treatment related to preterm labour, and details of delivery and neonatal outcomes. Data analysis For current analyses we only included singleton pregnancies. The outcome of interest was spontaneous preterm delivery within 7 days. We developed two prediction models using logistic regression: the first model with cervical length and fibronectin as predictors and a second model with candidate predictors added to cervical length and fetal fibronectin. These candidate predictors were selected based on medical literature, and can be found in Table 1 [1,9,10]. The variables parity and previous preterm delivery were combined in a new categorical variable because nulliparous women cannot have had a previous preterm delivery; we used nulliparous women as the reference and multiparous with and without a history of previous preterm delivery as the other categories. Approximately 1600 data points (15%) for the predictors were missing, ranging from 0% missing values for maternal age to 41% for C-reactive protein. Missing data were interpreted as missing at random (MAR). Since it is well documented that exclusion of incomplete cases can yield biased results, we corrected the missing values using multiple imputation (10 times) [14–16]. The variables maternal age, BMI, number of contractions, C-reactive protein, cervical length and dilatation were analysed as continuous variables, whereas all other variables were dichotomous. Before developing the logistic models, linearity between these continuous variables and the outcome were checked using cubic spline analyses [17]. Variables were transformed in case of significant non-linearity. For the model including all candidate predictors univariable logistic regression analysis was used to evaluate the individual association between the candidate predictors and delivery within 7 days. Because of the low incidence of spontaneous preterm delivery within 7 days, we did a pre-selection of predictors for inclusion in the multivariable logistic regression analysis. We used the Akaike Information Criterion, meaning that predictors with a level of significance smaller than 0.157 were selected [18]. We used backwards elimination to arrive at a parsimonious model using the same Akaike Information Criterion [18]. We performed this selection in each imputation set separately to account for differences between imputation sets. Predictors for the final
G.-J. van Baaren et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 192 (2015) 79–85
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Table 1 Baseline demographic and clinical characteristics of the total study population. Missings (before imputation) n (%)
Delivery beyond 7 days N = 527 (88%)a
Total N = 600 (100%)a
30.9 5.4 40 (55) 22.4 (20.7–26.3) 52 (71) 13 (18) 9 (12)
29.2 5.3 303 (57) 22.3 (20.1–25.3) 250 (47) 130 (25) 79 (15)
29.4 5.4 443 (74) 22.3 (20.2–25.5) 302 (50) 144 (24) 88 (15)
478 (91) 42 (8) 6 (1) 6.0 (4.0–9.0)
513 (86) 66 (11) 20 (3) 6.0 (4.0–9.0)
Age, year (mean SD) Caucasian race (n (%)) Body-Mass Index, kg/m2 (median (IQR)) Nulliparous (n (%)) Previous preterm birth
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Risk factors for preterm delivery: do they add to fetal fibronectin testing and cervical length measurement in the prediction of preterm delivery in symptomatic women? Gert-Jan van Baaren a,*, Merel M.C. Bruijn a, Jolande Y. Vis b, Femke F. Wilms c, Martijn A. Oudijk d, Anneke Kwee d, Martina M. Porath e, Guid Oei f, Hubertina C.J. Scheepers f, Marc E.A. Spaanderman f, Kitty W.M. Bloemenkamp g, Monique C. Haak g, Antoinette C. Bolte h, Caroline J. Bax h, Je´roˆme M.J. Cornette i, Johannes J. Duvekot i, Bas W.A. Nij Bijvanck j, Jim van Eijck j, Maureen T.M. Franssen k, Krystyna M. Sollie k, Frank P.H.A. Vandenbussche l, Mallory Woiski l, Patrick M.M. Bossuyt m, Brent C. Opmeer n, Ben W.J. Mol o a
Department of Obstetrics and Gynaecology, Academic Medical Centre, Amsterdam, Netherlands Department of Clinical Chemistry and Haematology, University Medical Centre Utrecht, Utrecht, Netherlands c Department of Obstetrics and Gynaecology, Catharina Hospital, Eindhoven, Netherlands d Department of Obstetrics and Gynaecology, University Medical Centre Utrecht, Utrecht, Netherlands e Department of Obstetrics and Gynaecology, Ma´xima Medical Centre, Veldhoven, Netherlands f Department of Obstetrics and Gynaecology, University Hospital Maastricht, Maastricht, Netherlands g Department of Obstetrics, Leiden University Medical Centre, Leiden, Netherlands h Department of Obstetrics and Gynaecology, VU University Medical Centre, Amsterdam, Netherlands i Department of Obstetrics and Gynaecology, Erasmus Medical Centre, Rotterdam, Netherlands j Department of Obstetrics and Gynaecology, Isala Clinics, Zwolle, Netherlands k Department of Obstetrics and Gynaecology, University Medical Centre Groningen, Groningen, Netherlands l Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands m Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, Amsterdam, Netherlands n Clinical Research Unit, Academic Medical Centre, Amsterdam, Netherlands o Department of Obstetrics and Gynaecology, The Robinson Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Australia b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 31 August 2014 Received in revised form 22 April 2015 Accepted 19 May 2015
Objective: To assess whether patient characteristics add to the fetal fibronectin test and cervical length measurement in the prediction of preterm delivery in symptomatic women. Study design: A nationwide prospective cohort study was conducted in all ten perinatal centres in the Netherlands. Women with symptoms of preterm labour between 24 and 34 weeks gestation with intact membranes were invited. In all women qualitative fibronectin testing (0.050 mg/mL cut-off) and cervical length measurement were performed. Only singleton pregnancies were included in this analysis. Logistic regression was used to construct two multivariable models to predict spontaneously delivery within 7 days: a model including cervical length and fetal fibronectin as predictors, and an extended model including all potential predictors. The models were internally validated using bootstrapping techniques. Predictive performances were assessed as the area under the receiver operator characteristic curve (AUC) and calibration plots. We compared the models’ capability to identify women with a low risk to deliver within 7 days. A risk less than 5%, corresponding to the risk for women with a cervical length of at least 25 mm, was considered as low risk. Results: Seventy-three of 600 included women (12%) had delivered spontaneously within 7 days. The extended model included maternal age, parity, previous preterm delivery, vaginal bleeding, C-reactive
Keywords: Preterm labour Prediction Fetal fibronectin Cervical length Pregnancy
* Corresponding author at: Department of Obstetrics and Gynaecology, Academic Medical Centre, 1105 DE, Amsterdam, The Netherlands. Tel.: +31 205664256. E-mail address: [email protected] (G.-J. van Baaren). http://dx.doi.org/http://dx.doi.org/10.1016/j.ejogrb.2015.05.004 0301-2115/ß 2015 Elsevier Ireland Ltd. All rights reserved.
80
G.-J. van Baaren et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 192 (2015) 79–85
protein, cervical length, dilatation and fibronectin status. Both models had high discriminative performances (AUC of 0.92 (95% CI 0.88–0.95) and 0.95 (95% CI 0.92–0.97) respectively). Compared to the model with fibronectin and cervical length, our extended model reclassified 38 women (6%) from low risk to high risk and 21 women (4%) from high risk to low risk. Preterm delivery within 7 days occurred once in both the reclassification groups. Conclusion: In women with symptoms of preterm labour before 34 weeks gestation, a model that integrates maternal characteristics, clinical signs and laboratory tests, did not predict delivery within 7 days better than a model with only fibronectin and cervical length. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Introduction Spontaneous preterm delivery occurs in 5–13% of all deliveries and remains the main cause of perinatal mortality and neonatal morbidity in the developed world [1]. Most women with symptoms of preterm labour before 32 weeks gestational age are transferred to a perinatal centre and receive treatment, such as tocolysis, magnesiumsulphate and corticosteroids. Yet, about 80– 95% will not deliver within 1 week after presentation, and half of these women deliver at term [2–5]. Consequently, many women are unnecessarily transferred and exposed to the potential side effects of tocolysis and corticosteroids in both mother and child [6–8]. To reduce overtreatment and costs of unnecessary referrals and treatment, accurate identification of those women who will not deliver on the short term – i.e. within 7 days – is of the utmost importance. On the other hand, knowledge about the short term risk to deliver helps to identify women with symptoms of preterm labour who need immediate treatment and referral to a perinatal centre in order to optimize circumstances if preterm delivery occurs. Despite many different predictors and risk factors of preterm delivery known in the literature, it remains difficult to assess this risk in individual women [1,9,10]. Several studies, including our nationwide cohort study, have reported promising results of the combination of cervical length and fetal fibronectin measurements to predict preterm delivery within 7 days in symptomatic women [2,11,12]. It is possible that predictions will improve even further when other prognostic features are added to these two measures. The aim of this study was to evaluate whether patient characteristics, when added to cervical length and fetal fibronectin, improve the prediction of delivery within 7 days in symptomatic women between 24 and 34 weeks of gestational age.
Methods Setting We used data collected in the APOSTEL-I study, a nationwide cohort study conducted in all ten perinatal centres in the Netherlands between December 2009 and August 2012. The objective of this study was to evaluate the predictive value of the fetal fibronectin test in addition to cervical length measurement in women with symptoms of preterm labour. The study design and main results are presented in detail elsewhere [13,12]. In short, we included women with symptoms of preterm labour between 24 and 34 weeks of gestational age with intact membranes. Exclusion criteria were cervical dilatation of more than three centimetres, previous treatment with tocolysis within 7 days before inclusion, and contra-indications for tocolysis, such as suspected intra-uterine infections, fetal distress or lethal congenital abnormalities. Women who had iatrogenic delivery within 7 days after inclusion were also excluded. All women provided written informed consent before entering the study.
We obtained fetal fibronectin and cervical length measurement in all participating women. Cervical length measurement in symptomatic women until 34 weeks is standard care in the Netherlands and is performed by clinically active physicians, who are trained in transvaginal sonography and perform cervical length measurements themselves. In order to standardize these measurements, all participating physicians were given a set of instructions and a pocket card with illustrated examples of accurate cervical length measurements. We used the qualitative Rapid fetal fibronectin TLIIQ analyser (Hologic) with a 0.050 mg/mL cut-off for the fetal fibronectin test. In addition, data collection included maternal characteristics, results from digital examination and laboratory tests, treatment related to preterm labour, and details of delivery and neonatal outcomes. Data analysis For current analyses we only included singleton pregnancies. The outcome of interest was spontaneous preterm delivery within 7 days. We developed two prediction models using logistic regression: the first model with cervical length and fibronectin as predictors and a second model with candidate predictors added to cervical length and fetal fibronectin. These candidate predictors were selected based on medical literature, and can be found in Table 1 [1,9,10]. The variables parity and previous preterm delivery were combined in a new categorical variable because nulliparous women cannot have had a previous preterm delivery; we used nulliparous women as the reference and multiparous with and without a history of previous preterm delivery as the other categories. Approximately 1600 data points (15%) for the predictors were missing, ranging from 0% missing values for maternal age to 41% for C-reactive protein. Missing data were interpreted as missing at random (MAR). Since it is well documented that exclusion of incomplete cases can yield biased results, we corrected the missing values using multiple imputation (10 times) [14–16]. The variables maternal age, BMI, number of contractions, C-reactive protein, cervical length and dilatation were analysed as continuous variables, whereas all other variables were dichotomous. Before developing the logistic models, linearity between these continuous variables and the outcome were checked using cubic spline analyses [17]. Variables were transformed in case of significant non-linearity. For the model including all candidate predictors univariable logistic regression analysis was used to evaluate the individual association between the candidate predictors and delivery within 7 days. Because of the low incidence of spontaneous preterm delivery within 7 days, we did a pre-selection of predictors for inclusion in the multivariable logistic regression analysis. We used the Akaike Information Criterion, meaning that predictors with a level of significance smaller than 0.157 were selected [18]. We used backwards elimination to arrive at a parsimonious model using the same Akaike Information Criterion [18]. We performed this selection in each imputation set separately to account for differences between imputation sets. Predictors for the final
G.-J. van Baaren et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 192 (2015) 79–85
81
Table 1 Baseline demographic and clinical characteristics of the total study population. Missings (before imputation) n (%)
Delivery beyond 7 days N = 527 (88%)a
Total N = 600 (100%)a
30.9 5.4 40 (55) 22.4 (20.7–26.3) 52 (71) 13 (18) 9 (12)
29.2 5.3 303 (57) 22.3 (20.1–25.3) 250 (47) 130 (25) 79 (15)
29.4 5.4 443 (74) 22.3 (20.2–25.5) 302 (50) 144 (24) 88 (15)
478 (91) 42 (8) 6 (1) 6.0 (4.0–9.0)
513 (86) 66 (11) 20 (3) 6.0 (4.0–9.0)
Age, year (mean SD) Caucasian race (n (%)) Body-Mass Index, kg/m2 (median (IQR)) Nulliparous (n (%)) Previous preterm birth
