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BRIEF REPORT |
Department of Pediatrics, Obstetrics, and Reproductive Medicine (P.F., M.T., E.F., F.M.R., A.I., G.C., E.P., F.P.), Section of Obstetrics and Gynecology, University of Siena, 53100 Siena, Italy; and Nuffield Department of Obstetrics and Gynecology (E.A.L.), John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, United Kingdom
Address all correspondence and requests for reprints to: Felice Petraglia, M.D., Department of Pediatrics, Obstetrics, and Reproductive Medicine, Section of Obstetrics and Gynecology, University of Siena, Policlinico "Le Scotte," viale Bracci, 53100 Siena, Italy. E-mail: petraglia{at}unisi.it.
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Abstract |
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Objective: We measured plasma levels of urocortin, a neuropeptide expressed by gestational tissues, in women with threatened preterm labor (TPTL) to evaluate whether the measurement may predict preterm delivery (PTD).
Design: We studied patients as part of an open observational study.
Setting: The study was conducted at a tertiary referral center for obstetric care.
Patients: Eighty-five women with singleton pregnancies between 28 and 34 completed gestational weeks with TPTL participated in the study.
Interventions: Interventions included clinical examination and urocortin measurement.
Main Outcome Measures: Pregnancy outcome and evaluation of sensitivity, specificity, and predictive values of urocortin as diagnostic test for PTD were measured.
Results: Thirty of 85 patients (35.3%) had PTD: 23 of 30 delivered within 7 d from admission (delivery time interval: 2.91 ± 1.62 d; gestational weeks at delivery: 32.12 ± 1.7); the remaining delivered later (delivery time interval: 11.71 ± 4.27 d; gestational weeks at delivery: 33.5 ± 2.18). Urocortin was significantly higher in women who delivered preterm (median 131.2 pg/ml, interquartile interval 115.1–139.4 pg/ml) than in those who progressed to term delivery [95.4 (69.9–101.3) pg/ml, P < 0.0001] and still higher in those delivering within 7 d from admission [137.7 (124.8–141.2) pg/ml]. Receiver operating characteristic curve analysis revealed that urocortin at the cutoff of 113.9 pg/ml had sensitivity of 80%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 90% as a marker for PTD.
Conclusions: Maternal plasma urocortin concentration is increased in patients with TPTL who have PTD, and its measurement may be a promising new biochemical marker of PTD.
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Introduction |
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Urocortin is a 40-amino acid neuropeptide belonging to the corticotropin-releasing factor (CRF) family, which binds both type 1 and type 2 CRF receptors with great affinity (reviewed in Ref. 2). Urocortin is expressed by gestational tissues such as amnion, chorion, decidua, trophoblast, and myometrium and is measurable in maternal and fetal circulation, showing stable concentrations in maternal plasma from the first to third trimesters of pregnancy. However, maternal plasma urocortin levels correlate to the status (quiescence or contractility) of the human myometrium because they are increased at preterm delivery (3) and decreased in postterm pregnancy when compared with term pregnancy (4). Moreover, urocortin directly enhances myometrial contractility by augmenting the myometrial contractile response to prostaglandins (5) and activating the MAPK signaling pathways that regulate myometrial contractility (6).
In the present study, we aimed to evaluate whether in women with threatened preterm labor maternal plasma urocortin concentrations differ between patients who deliver at term and those laboring and delivering preterm and whether the measurement of urocortin may be clinically useful as a diagnostic predictor of preterm delivery in women with threatened preterm labor.
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Patients and Methods |
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We evaluated 85 singleton pregnancies between 28 and 34 completed weeks of gestation that had threatened preterm labor, consecutively enrolled from November 2003 to June 2004 at the Department of Pediatrics, Obstetrics, and Reproductive Medicine, University of Siena, Siena, Italy. All patients had painful regular uterine contractions at less than 5-min intervals, dilatation or effacement of cervix, and/or ruptured membranes (Table 1
). Written informed consent was obtained from each pregnant woman, and the permission of the Local Human Investigation Committee was granted for the study.
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Maternal ethylenediaminetetra-acetic acid plasma samples (1 ml) were obtained at admission to hospital regardless of the time of day and before the administration of any medications, and kept at –80 C until assay. None of the patients had received any medications before blood sample collection, which was performed before antenatal corticosteroid and tocolytic therapies.
Urocortin assay
Urocortin was measured in a single RIA (3, 4) with the investigators blinded to the clinical condition of the subjects. To ensure removal of CRF binding protein, which competes with urocortin antibody for its ligand, urocortin was measured in methanol-extracted plasma samples using previously published methodology (8). The assay has a sensitivity of approximately 50 pg/ml with intraassay and interassay variations of 6 and 8%, respectively.
Statistical analysis
Urocortin levels were not normally distributed and therefore are reported as medians and interquartile intervals. The statistical significance was assessed by using the Mann-Whitney U test and the Spearman’s correlation coefficient, and the 
2 and Fisher exact tests were used to analyze differences between proportions. Statistical significance was assumed whenever P < 0.05.
The cutoff points for defining altered serum urocortin levels for prediction of preterm birth were evaluated by receiver operating characteristic (ROC) curve analysis (9). Using the best cutoff indicated by the ROC curve analysis, the sensitivity, specificity, and positive and negative likelihood ratios were calculated with their respective 95% confidence intervals. The posttest probability for a positive test result [i.e. the positive predictive value (PPV)] and the posttest probability for a negative test result (given by 100% – the negative predictive value) were calculated with their respective 95% confidence intervals and compared with the pretest probability, defined as the prevalence of preterm birth in the whole group of patients (10).
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Results |
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Thirty of 85 patients (35.3%) delivered preterm, and there were no statistically significant differences between the two groups of patients, with the exception of gestational age at delivery (P < 0.0001) and birth weight of newborns (P < 0.0001) (Table 1
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Patients who delivered preterm were subdivided, according to the time interval occurring between blood sampling (at hospitalization) and parturition, into those who delivered 7 d or sooner or longer than 7 d from the time of admission. We found that 23 of 30 patients delivered before 7 d from the time of admission (delivery time interval, 2.91 ± 1.62 d; gestational age at delivery, 32.12 ± 1.7 wk), whereas the remaining women delivered later (delivery time interval, 11.71 ± 4.27 d; gestational age at delivery, 33.5 ± 2.18 wk), with a statistically significant difference between groups (P < 0.0001, data not shown). No difference was found regarding the prevalence of ruptured membranes and histological chorioamnionitis between patients delivered before [ruptured membranes, five of 23 (27.7%); chorioamnionitis, 10 of 23; (43.5%)] and after [ruptured membranes, two of seven (28.6%); chorioamnionitis, three of seven (42.9%)] 7 d from the time of admission (data not shown).
Maternal plasma urocortin levels
Urocortin levels were measurable in all samples evaluated. As shown in Fig. 1A, maternal plasma urocortin concentrations were significantly (P < 0.0001) higher in women who delivered preterm (median 131.2 pg/ml, interquartile interval 115.1–139.4 pg/ml) than in those who progressed to term delivery [95.4 (69.9–101.3) pg/ml].
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). Prediction of preterm delivery in women with threatened preterm labor
Urocortin at the cutoff of 113.9 pg/ml achieved a sensitivity of 80.0% [95% confidence interval (C.I.95%) 61.4–92.2%] and a specificity of 100.0% (C.I.95% 93.4–100.0%) as single marker for prediction of preterm birth [area under the ROC curve 0.966 (C.I.95% 0.902–0.993), Fig. 1B]. The positive and negative likelihood ratios obtained with this criterion were 11.0 (C.I.95% 4.2–28.7) and 0.2 (C.I.95% 0.1–0.4), respectively.
Thirty of 85 patients delivered preterm, with an overall prevalence of 35.3% (C.I.95% 25.1–45.4%). This was the predicted probability of preterm birth before having performed maternal plasma urocortin measurement (pretest probability). When urocortin levels were found to be high (i.e. above the threshold defined by the ROC curve analysis), the posttest probability (i.e. the PPV) was 100.0% (C.I.95% 87.0–100.0%), whereas if they were found unaltered, the posttest probability was 9.8% (C.I.95% 4.6–19.8%), which corresponds to a negative predictive value of 90.2% (C.I.95% 80.2–95.4%).
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Discussion |
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The evidence that urocortin in maternal circulation is mainly derived from fetal sources (3, 11) raises new questions on the role played by the cross talk between the fetus and the maternal environment in maintaining uterine quiescence as well as in the onset and maintenance of preterm parturition. The ability of the hypothalamus-pituitary-adrenal axis to develop a response is essential for fetal life and also for survival during parturition, when compression of the umbilical cord may reduce the transfer of oxygen from the mother to the fetus (12). The findings that preterm parturition may be associated with a decrease in vascular resistance to blood flow in the fetal cerebral circulation (13), that fetal urocortin secretion correlates with uteroplacental blood perfusion (11), and that urocortin has profound and sustained hemodynamic effects and protective compensatory actions against hypoxia in animals (14, 15) lead us to hypothesize that the secretion of urocortin may also serve to protect the fetus from the consequences of hypoxic insults.
Whatever the role of the elevated levels of circulating urocortin, the clinical usefulness of urocortin measurement for predicting the occurrence of preterm delivery in an at-risk pregnant woman merits further consideration. In the present study, we found that measuring urocortin yields posttest probabilities that differ materially from the overall prevalence of preterm delivery in our population. However, the PPV of any test is directly related to the prevalence of the disease, which in our study was high (35.3%) because we evaluated only symptomatic women. The PPV found here (100%) thus cannot be extrapolated to populations with different prevalence rates of preterm birth, but this limitation is overcome by the use of likelihood ratios combined with the pretest probability (16). For instance, if the prevalence of preterm birth were 12% (1), then we would have a PPV of 60.0% and a negative predictive value (100 – posttest probability after a negative result) of 97.3%.
These predictive values are of great interest, particularly when comparing them with those of CRF, a peptide sharing substantial sequence homology with urocortin and whose maternal plasma levels rise before preterm delivery (2). Indeed, when evaluated in symptomatic pregnancies, a raised CRF level predicted delivery at less than 37 wk gestation with sensitivity, specificity, and positive and negative predictive values of 39, 90, 67, and 75%, respectively (17), that differ from those reported for urocortin in the present study.
In the present study, patients with threatened preterm labor with and without ruptured membranes were evaluated together because the putative mechanisms involving increased urocortin levels close to labor apply to both cases (3). It is important to note, however, that patients with any clinical sign of infection and/or histological diagnosis of chorioamnionitis were excluded from the study, minimizing the interference of infectious mechanisms on the timing of birth. Whereas in this study all women received corticosteroid therapy and attempted tocolysis regardless of whether they had intact or ruptured membranes, patients with ruptured membranes are often managed differently from those with intact membranes, so the accuracy indexes that we obtained in the pooled group might not be extrapolated to particular subgroups if they are managed in a different way.
In conclusion, maternal plasma urocortin levels are increased in patients with threatened preterm labor who delivered before 34 completed weeks of pregnancy, and this measurement provides a promising new biochemical marker to add significant prognostic information for predicting preterm delivery among at-risk women.
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Footnotes |
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Disclosure Statement: P.F., E.A.L., M.T., E.F., F.M.R., A.I., G.C., E.P., and F.P. have nothing to declare.
First Published Online November 6, 2007
Abbreviations: C.I.95%, 95% confidence interval; CRF, corticotropin-releasing factor; PPV, positive predictive value; ROC, receiver operating characteristic.
Received September 18, 2006.
Accepted February 27, 2007.
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References |
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