- Email: [email protected]
Oncofetal fibronectin in patients with false labor as a predictor of preterm delivery
Morrison et al.
pin, and estriol) to further refine the risk of Down's syndrome. I.
REFERENCES I. Lockwood C, Benacerraf BR, Krinsky A, et al. A sonographic screening method for Down syndrome. A'd J OBSTET GYNECOL 1987;157:803-8. 2. Benacerraf BR, Gelman F, Frigoletto FD Jr. Sonographic identification of second-trimester fetuses with Down's syndrome. N Engl ] Med 1987;317:1371-6. 3. Cuckle H, Wald N, Quinn J, Royston P, Butler L. Ultrasound fetal femur length measurement in the screening for Down's syndrome. Br J Obstet Gynaecol 1990;96: 13738. 4. Peters MT, Lockwood CJ, Miller WA. The efficacy of fetal sonographic biometry in Down syndrome screening. AM J OBSTET GVNECOL 1989; 161 :297-300. 5. Nyberg DA, Resta RG, Hickok DE, Hollenbach KA, Luthy DA, Mahony BS. Femur length shortening in the detection of Down syndrome: is prenatal screening feasible? AM J OBSTET GVNECOL 1990;162:1247-52. 6. FitzSimmons J, Droste S, Shepard TH, Pascoe-Mason J,
February 1993 Am J Obstet Gynecol
7.
8. 9.
10.
II.
12.
Chinn A, Mack LA. Long bone growth in fetuses with Down syndrome. AM J OBSTET GYNECOL 1989; 161: 1174-7. Benacerraf BR, Neuberg 0, Frigoletto FD Jr. Humeral shortening in second-trimester fetuses with Down syndrome. Obstet Gynecol 1991;77:223-7. Rodis JF, Vintzileos AM, Fleming AD, et al. Comparison of humerus length with femur length in fetuses with Down's syndrome. AM J OBSTET GYNECOL 1991;165: 1051-6. Dicke JM, Crane JP. Sonographic recognition of major malformations and aberrant fetal growth in trisomic fetuses. J Ultrasound Med 1991;10:433-8. Reynolds 'I'M, Penney MD, Hughes H. Ultrasonographic dating of pregnancy causes significant errors in Down syndrome risk assessment that may be minimized by use of biparietal diameter-based means. AM J OBSTET GVNECOL 1991;166:872-7. Perella R, Duerinckx AJ, Grant EG, er al. Second-trimester sonographic diagnosis of Down syndrome: Role of femurlength shortening and nuchal-fold thickening. Am J Roentgen 1988;151:981-5. Wald NJ, Cuckle HS, Densem JW, et al. Maternal serum screening for Down's syndrome in early pregnancy. BMJ 1988;297 :883-7.
Oncofetal fibronectin in patients with false labor as a predictor of preterm delivery John C. Morrison, MD, John R. AUbert, MD, Barbara N. McLaughlin, RN, MN, Neil S. Whitworth, PhD, William E. Roberts, MD, and Rick W. Martin, MD
Jackson, Mississippi OBJECTIVE: Our objective was to determine whether fetal fibronectin is a discriminator for preterm labor and early delivery in women who have intact membranes and uterine activity. STUDY DESIGN: In our prospective study 28 women between 24 and 34 weeks' gestation with regular, persistent uterine contractions (> 10/hr) and intact membranes were assessed for presence of fetal fibronectin. A Dacron swab was applied to the external os for 10 seconds. The cervix was :51 em, and all patients were diagnosed as having false labor. The assay was performed by using monoclonal antibody FDC-6 to bind fetal fibronectin. RESULTS: Of the 28 patients with false labor, 14 had a positive fetal fibronectin, and all had preterm labor (specificity and positive predictive value 100%). Of these, nine delivered preterm, yielding a specificity and positive predictive value of 72% and 64%, respectively. Among the 14 women with a negative fetal fibronectin, only four developed preterm labor (sensitivity 78%, negative predictive value 71%). One patient delivered preterm at 34 weeks (sensitivity 90% and negative predictive value 93%). CONCLUSIONS: A positive fetal fibronectin in women who have false labor indicates a significant risk for preterm labor and early delivery. A negative fetal fibronectin is a reassuring sign. (AM J OBSTET GVNECOL 1993;168:538-42.)
Key words: Fetal fibronectin, preterm labor, early delivery From the Department of Obstetrics and Gynecology, University of Mississippi Medical Center. Supported in part by the Vicksburg Hospital Medical Foundation. Received for publication June 4, 1992; revised August It), 1992; acceptedAugust 13, 1992. Reprint requests: John C. Morrison, MD, Department of Obstetrics and Gynecology, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505. Copyright © 1993 Mosby-Year Book, Inc. 0002-9378/93 $1.00 + .20 6/1/41763
538
Distinguishing true from spurious labor is important, particularly when the gestation is remote from term. This distinction is critical because preterm delivery remains one of the major causes of neonatal mortality and morbidity. I Clinically, as many as 50% of women who have false labor eventually deliver preterrn." The differentiation of false from true labor is problematic because the only absolute differentiating factor is that
Volume 168, Number 2 Am J Obstet Gynecol
in true labor the contractions lead to irreversible progressive cervical change and, ultimately, delivery." Various reports have described the use of sedatives such as morphine, parenteral administration of fluids, periods of rest, or fetal breathing movements on ultrasonographic examination to distinguish false from true labor with little to moderate success. 1-7 More recently, oncofetal fibronectin in cervicovaginal fluid has been suggested as a sensitive and specific correlate of early delivery. This type of fibronectin has been identified in amniotic fluid, placental tissue, and malignant cell lines. It can be detected by the monoclonal antibody FDC-6, which specifically binds oncofetal fibronectin. S Clinically, this technique has been used to measure fetal fibronectin in the cervicovaginal secretions of women at risk for early delivery. In women admitted with a diagnosis of preterm labor, Lockwood et al. 9 reported that the presence of fetal fibronectin identified those patients who eventually delivered before term with a sensitivity of 81.7% and a specificity of 82.5%. What has not been studied are patients in false labor with contractions but no cervical change. The purpose of our study was to detail the effectiveness of oncofetal fibronectin obtained from cervicovaginal secretions in differentiating who would later have true preterm labor with subsequent early delivery in a population of women who had had an episode of false labor but were otherwise not at risk for preterm birth. The null hypothesis was that a positive fetal fibronectin would not discriminate the group of women who would deliver before term because of preterm labor from those who delivered at term. Material and methods
Women with singleton pregnancies between 24 and 36 weeks' gestation with documented episodes of false labor were eligible for this study. In each patient cervical dilatation was :5 I cm and :5 75% effaced, with regular uterine contractions (~ 10/hr). The fetal heart tones were in the normal range, and the membranes were intact according to speculum visualization and fern test. None of these women had historic indicators that would place them at high risk for preterm birth. Exclusion criteria included uterine or cervical abnormalities, placenta previa, suspected abruption, unknown gestational age, hypertension, diabetes, suspected rupture of the membranes, multifetal gestation, or maternal age of < 15 years. Also, women diagnosed and admitted with true preterm labor were not included. Each patient was observed in the Obstetric Receiving Unit for 2 to 6 hours with fetal heart rate and contraction frequency monitoring to assist in diagnosing false labor. During this period of time gestational age was documented by history and confirmed with ultrasonography by using current measurements and mensuration
Morrison et al.
539
earlier in pregnancy. Hydration with Ringer lactate or half-normal saline solution was used, but no tocolytics, analgesic agents, or sedative medications were administered. In no patient was vaginal bleeding present, and none of the patients had had intercourse or douched in the 12 hours before sampling. No patient had vaginal bleeding, although two reported spotting. The contractions abated during observation, and there was no cervical change in these patients. All women were diagnosed as having false labor and were discharged within 8 hours of registration in the Obstetric Receiving Unit. No subject was admitted to the hospital, and women were monitored routinely at 4-week intervals in our prenatal clinic. After the patients had been screened for inclusion and exclusion criteria and the diagnosis of false labor was made, they were offered entry. Women electing to participate were then asked to give informed consent and were placed into the study. At the time of speculum examination to confirm intact membranes, each subject had an oncofetal fibronectin sample taken by rolling a Dacron swab gently over the exocervix for 10 seconds. The swab was then extracted in 750 j.L1 of assay buffer (Tris buffer containing bovine serum albumin as a stabilizer and protease inhibitors), and the solution was immediately frozen at - 20° C. The samples were then stored I to 12 weeks until the time of assay. The stability of fetal fibronectin under these conditions is ~ 6 months (David Casal, PhD, unpublished data). The concentration of oncofetal fibronectin was measured by a solid-phase, enzyme-linked immunosorbent assay using the monoclonal antibody FDC-6 to specifically bind fetal fibronectin (Adeza Biomedical, Sunnyvale, Calif.). These assays were performed in batches. The absorbance of duplicate negative and positive controls and patient samples were determined at a wavelength of 550 nm with an automated microtiter-plate reader. Patient samples with an absorbance greater than or equal to the positive control (50 ng/ml fetal fibronectin) were deemed positive for the presence of fetal fibronectin. The interassay coefficient of variation was 8% to 12%. In no case was the result of the oncofetal fibronectin test available to the physician caring for the patient, and steroids were not given to enhance fetal lung maturity. Subsequently, patients who had an episode of documented preterm labor were noted. Preterm labor was defined as regular uterine contractions (usually > 10/hr) with confirmed change in cervical status from previous examinations (> I cm dilation and > 75% effacement). Women who were delivered at < 37 weeks and women with preterm labor were stratified as to the result of the fetal fibronectin test obtained when they had false labor. Other follow-up data included the time and date of delivery, the interval between discharge from the obstetric unit and delivery, gestational age at
540
Morrison at al.
February 1993 Am
J Obstet Gynecol
Table I. Patient characteristics Fetal fibronectin test result
14 14
Positive Negative
Age (yr)
Parity
22.0 :±: 5.8 22.9 :±: 4.9
0.8 :±: 1.2 1.5 :±: 1.1
Gestational age at sampling (wk)
Contractions/hr
31.8 :±: 2.9 32.6:±: 2.8
12.2 :±: 3.4 13.7 :±: 2.9
12/1/1 8/4/2
Values are mean:±: SD. *Blacklwhite/American Indian.
Table II. Outcome statistics Fetal fibronectin test result
Positive Negative
14 14
Interval (diagnosis to delivery) (day)
Gestational age at delivery (wk)
Birth weight
21.6 :±: 20.2 37.4 :±: 20.8
34.3 :±: 2.9 37.9:±: 1.6
2199 :±: 774 2957 :±: 348
Significant neonatal morbidity
(gm)
9 1
5
o
Values are mean:±: SD. *Sensitivity 90%, specificity 72%, negative predictive value 93%.
assessment for false labor and at delivery, and birth weight and infant status at discharge. Statistical analysis was carried out with the Fisher exact test and X2 testing where appropriate. A p value of < 0.05 was considered significant. Results
A shown in Table I the age, parity, and race of patients who had false labor and whose test results were positive for fetal fibronectin were not significantly different from those with negative oncofetal fibronectin test results. In addition, the gestational age at the time of sampling for patients with positive test results (31.8 ± 2.9 weeks) was not dissimilar from women with negative oncofetal fibronectin test results (32.6 ± 2.9 weeks; p = 0.90). Similarly, the dilatation and effacement of the cervix in women who had positive test results for fetal fibronectin was not different from those with negative results (p == 0.72 and 0.29, respectively). Finally, the maximum number of contractions per hour was approximately the same in women whether they had positive or negative oncofetal fibronectin tests. All women whose test results for fetal fibronectin were positive had early labor (n == 14), and only 4 with negative test results subsequently had preterm labor (p == 0.04). Table II shows a significant increase in the interval from diagnosis to delivery in women who had negative test results for oncofetal fibronectin (37.4 ± 20.8 days) when compared with those women with positive test results (21.6 ± 20.2 days; p < 0.05). This increase resulted in a significant reduction in the gestational age at delivery and birth weight in women with positive fetal fibronectin test results (34.3 ± 2.9 weeks, 2199 ± 744 gm) when compared with those with neg-
ative test results (37.9 ± 1.6 weeks, 2957 ± 348 gm); this difference was statistically different (p == 0.002 and 0.003, respectively). Fig. 1 offers a scatter plot of gestational age and delivery stratified by the result of the fetal fibronectin tests. It shows good correlation between a positive test result and early delivery and a negative fetal fibronectin test result and delivery at term. There were a greater number of preterm deliveries in women with positive test results (nine) when compared with women with negative test results (one), and this was likewise a significant difference (p == 0.002). Among those women with positive fetal fibronectin test results, five babies with significant neonatal complications were admitted to the newborn intensive care unit compared with none in women with negative test results (p == 0.06). There were no cases of neonatal morbidity in pregnancies with negative test results. Four infants had respiratory distress syndrome (29, 31, 31, and 32 weeks' gestation), and one had a patent ductus arteriosus that was surgically ligated. All infants survived, but three had extended hospital stays (> 28 days). Comment
The accurate determination of whether a patient is in true preterm labor is important but difficult. The level of discomfort and the intensity and frequency of contractions does not allow distinction of uterine activity that results in false labor and therefore does not single out those who are destined to deliver early." 4. 10 Although some investigators have revealed that a decreased interval between contractions is more often associated with true labor, the mean and SD of these measurements were too wide to make this a clinically
Volume 168, Number 2 Am J Obstet Gynecol
Morrison et al. 541
-
42
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40
~ Q)
e-
38
Q)
.~
CD
36 0 1;i Q) C)
34
«S
c
32
~
30
<
x= 37.9
••
••
•
•• • •
x= 34.3
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:
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C!' 28
FFN Positive
FFN Negative
Fig. 1. Scatter plot of gestational ages at delivery stratified by result of fetal fibronectin (FFN) test obtained at diagnosis of false labor.
valuable tool. 3. 4 Likewise, cervical dilatation at the time of observation for false labor has been noted to be less in those with false labor, but the large SD often results in data that are not clinically useful if dilatation is < I em." \I Various tests, such as analgesic administration, observation, hydration, and administration of subcutaneous tocolytic agents are also frequently not predictive of women who have false labor but who are at risk of preterm delivery. ,,·7. 12 Therefore because clinicians do not have a good discriminator of false versus true labor, and because as many as 50% of women with "false labor" deliver early, the need for an accurate test is evident. 3. II The study by Lockwood et al." reveals that of 117 women with uterine contractions and intact membranes, 51.3% delivered preterm. In that study women who had positive fetal fibronectin test results were far more likely to deliver before term (83.1 %) than were patients with negative test results (19%). Our results are similar: 9 (64%) of 14 patients delivered early with positive oncofetal fibronectin, whereas of patients with negative test results only one (7%) patient delivered early. The correlation of a positive fetal fibronectin test result with preterm delivery revealed a sensitivity of 90% and specificity of 82.5%.9 These figures correspond well with our values (sensitivity 90%, specificity 72%). In our estimation the most important feature of oncofetal fibronectin was the 93% negative predictive value in women with false labor. Our findings also imply other clinically relevant information. For example, iffetal fibronectin was present the positive predictive value was 64% for preterm delivery. However, in women with positive test results,
100% had true labor at < 37 weeks, and the interval between the assessment tor false labor and delivery was significantly shorter than in patients with negative oncofetal fibronectin concentrations (p < 0.05). Likewise, this translated into more patients eventually delivering before term, a lower birth weight, and a trend toward more neonatal complications in women who had false labor but positive fetal fibronectin test results. We conclude that positive fetal fibronectin test results in women between 24 and 34 weeks' gestation who have false labor indicates a significant risk for the subsequent development of true preterm labor and a high risk for early delivery. These early births portend increased morbidity for the neonate. On the other hand, a negative fetal fibronectin test result is a good indication that subsequent preterm labor and early delivery are unlikely to occur. Further work in this area is indicated on the basis of these preliminary results.
REFERENCES I. Vital statistics of the United States. Natality. Rockville,
2. 3. 4. 5. 6.
Maryland: United States Department of Health and Human Services, 1987:255-8. Arulkumaran S, Michelsen], Ingermarsson I, Ratnam SS. Obstetric outcome of patients with a previous episode of spurious labor. A\I] OllSTFT GY"n:COL 1987;157:17-20. Eganhouse DJ. A comparative study of variables differentiating false labor from early labor. ] Perinatol 1991; 11: 249-57. Friedman E. Labor: clinical evaluation and management. 2nd ed. New York: Appleton-Century-Crofts, 1978. Valenzuela G, Cline S, Hayashgi RH. Follow-up of hydration and sedation in the pretherapy of premature labor. Asr ] OBSTET GYNECOL 1983;147:396-8. Scrimshaw S, Souza R. Recognizing active labor: a test of a decision-making guide for pregnant women. Soc Sci Med 1982;16: 1473-82.
Finan et al.
7. Schreyer P, Caspi E, Bar Natan N, Tal E, Weinraub Z. The predictive value of fetal breathing movement and Bishop score in the diagnosis of "true" preterm labor. AM] OBSTET GYNECOL 1989;161:886-9. 8. Matsuura H, Takio K, Titani K, et al. The oncofetal structure of human fibronectin defined by monoclonal antibody FDC-6.] BioI Chern 1988;263:3314-22. 9. Lockwood C], Senyei AE, Dische MR, et al. Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery. N Engl] Med 1991;325:669-74.
February 1993 Am J Obstet Gynecol
10. Caldeyro-Barcia R, Poserio ]]. Physiology of the uterine contraction. Clin Obstet Gynecol 1960;3:386. 11. Schauberger CWo False labor. Obstet Gynecol 1986;68: 770-2. 12. American College of Obstetricians and Gynecologists. Preterm labor. Washington, D.C.: American College of Obstetricians and Gynecologists, 1989, ACOG technical bulletin no 133.
The effects of cold therapy on postoperative pain in gynecologic patients: A prospective, randomized study Michael A. Finan, MD, William S. Roberts, MD, Mitchel S. Hoffman, MD, James V. Fiorica, MD, Denis Cavanagh, MD, and B.J. Dudney, RN Tampa, Florida OBJECTIVE: The purpose of the study was to determine the effect of cold therapy on the subjective assessment of pain, analgesic requirements, and wound complications in female patients undergoing major abdominal surgery. STUDY DESIGN: Twenty-seven patients were entered in the study in a prospective, randomized fashion. The Hot/Ice Thermal Blanket was applied to 13 patients, and 12 patients were in the control group. All patients underwent exploratory laparotomy and received postoperative pain relief with intravenously self-administered morphine sulfate through a patient-controlled analgesic pump. RESULTS: Compared with the control group (0.363 ± 0.118 mg/kg/day), the cold pack group used more morphine sulfate on the first postoperative day (0.529 ± 0.236 mg/kg/day, p < 0.05). The mean amount of morphine sulfate used by both groups was similar on postoperative day 2. CONCLUSION: We conclude that the cold pack does not improve postoperative pain control in gynecologic patients undergoing exploratory laparotomy. (AM J OBSTET GVNECOL 1993;168:542-4.)
Key words: Cold therapy, postoperative pain
The topical application of cold substances after minor injuries has long been known to reduce swelling and discomfort. The use of cold therapy for postoperative pain control after exploratory laparotomy has not been extensively studied. Shaubel' noted in 1946 that ice applied to orthopedic surgical sites resulted in reduced postoperative pain and fewer postoperative complications. Cold baths are more effective than warm baths in relieving postpartum perineal pain." Cohn et
al. 3 evaluated the Hot/Ice Thermal Blanket cooling machine (Hollister, Tampa) prospectively in patients undergoing arthroscopic procedures. They noted a reduction in postoperative narcotic use and a more rapid conversion to oral pain medication in patients with cold therapy. The current study was undertaken to determine the effect of cold therapy on the subjective assessment of pain, analgesic requirements, and wound complications in female patients undergoing major abdominal surgery.
From the Division of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida. Received for publication February 26, 1992; revised July 21, 1992; accepted August 24, 1992. Reprint requests: Michael A. Finan, MD, Division of Gynecologic Oncology, Ochsner Clinic, 1514 Jefferson Highwav. New Orleans, LA 70121. Copyright © 1993 Mosby-Year Book, Inc. 0002-9378/93 $1.00 + .20 6/1/42024
Material and methods Between April 1, 1989, and Sept. 30, 1989, 27 patients were entered in the study. Informed consent was obtained, and the protocol was approved by the investigational review board. The patients all underwent exploratory laparotomy performed by members of the Division of Gynecologic Oncology at the H. Lee Moffitt
542
pin, and estriol) to further refine the risk of Down's syndrome. I.
REFERENCES I. Lockwood C, Benacerraf BR, Krinsky A, et al. A sonographic screening method for Down syndrome. A'd J OBSTET GYNECOL 1987;157:803-8. 2. Benacerraf BR, Gelman F, Frigoletto FD Jr. Sonographic identification of second-trimester fetuses with Down's syndrome. N Engl ] Med 1987;317:1371-6. 3. Cuckle H, Wald N, Quinn J, Royston P, Butler L. Ultrasound fetal femur length measurement in the screening for Down's syndrome. Br J Obstet Gynaecol 1990;96: 13738. 4. Peters MT, Lockwood CJ, Miller WA. The efficacy of fetal sonographic biometry in Down syndrome screening. AM J OBSTET GVNECOL 1989; 161 :297-300. 5. Nyberg DA, Resta RG, Hickok DE, Hollenbach KA, Luthy DA, Mahony BS. Femur length shortening in the detection of Down syndrome: is prenatal screening feasible? AM J OBSTET GVNECOL 1990;162:1247-52. 6. FitzSimmons J, Droste S, Shepard TH, Pascoe-Mason J,
February 1993 Am J Obstet Gynecol
7.
8. 9.
10.
II.
12.
Chinn A, Mack LA. Long bone growth in fetuses with Down syndrome. AM J OBSTET GYNECOL 1989; 161: 1174-7. Benacerraf BR, Neuberg 0, Frigoletto FD Jr. Humeral shortening in second-trimester fetuses with Down syndrome. Obstet Gynecol 1991;77:223-7. Rodis JF, Vintzileos AM, Fleming AD, et al. Comparison of humerus length with femur length in fetuses with Down's syndrome. AM J OBSTET GYNECOL 1991;165: 1051-6. Dicke JM, Crane JP. Sonographic recognition of major malformations and aberrant fetal growth in trisomic fetuses. J Ultrasound Med 1991;10:433-8. Reynolds 'I'M, Penney MD, Hughes H. Ultrasonographic dating of pregnancy causes significant errors in Down syndrome risk assessment that may be minimized by use of biparietal diameter-based means. AM J OBSTET GVNECOL 1991;166:872-7. Perella R, Duerinckx AJ, Grant EG, er al. Second-trimester sonographic diagnosis of Down syndrome: Role of femurlength shortening and nuchal-fold thickening. Am J Roentgen 1988;151:981-5. Wald NJ, Cuckle HS, Densem JW, et al. Maternal serum screening for Down's syndrome in early pregnancy. BMJ 1988;297 :883-7.
Oncofetal fibronectin in patients with false labor as a predictor of preterm delivery John C. Morrison, MD, John R. AUbert, MD, Barbara N. McLaughlin, RN, MN, Neil S. Whitworth, PhD, William E. Roberts, MD, and Rick W. Martin, MD
Jackson, Mississippi OBJECTIVE: Our objective was to determine whether fetal fibronectin is a discriminator for preterm labor and early delivery in women who have intact membranes and uterine activity. STUDY DESIGN: In our prospective study 28 women between 24 and 34 weeks' gestation with regular, persistent uterine contractions (> 10/hr) and intact membranes were assessed for presence of fetal fibronectin. A Dacron swab was applied to the external os for 10 seconds. The cervix was :51 em, and all patients were diagnosed as having false labor. The assay was performed by using monoclonal antibody FDC-6 to bind fetal fibronectin. RESULTS: Of the 28 patients with false labor, 14 had a positive fetal fibronectin, and all had preterm labor (specificity and positive predictive value 100%). Of these, nine delivered preterm, yielding a specificity and positive predictive value of 72% and 64%, respectively. Among the 14 women with a negative fetal fibronectin, only four developed preterm labor (sensitivity 78%, negative predictive value 71%). One patient delivered preterm at 34 weeks (sensitivity 90% and negative predictive value 93%). CONCLUSIONS: A positive fetal fibronectin in women who have false labor indicates a significant risk for preterm labor and early delivery. A negative fetal fibronectin is a reassuring sign. (AM J OBSTET GVNECOL 1993;168:538-42.)
Key words: Fetal fibronectin, preterm labor, early delivery From the Department of Obstetrics and Gynecology, University of Mississippi Medical Center. Supported in part by the Vicksburg Hospital Medical Foundation. Received for publication June 4, 1992; revised August It), 1992; acceptedAugust 13, 1992. Reprint requests: John C. Morrison, MD, Department of Obstetrics and Gynecology, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505. Copyright © 1993 Mosby-Year Book, Inc. 0002-9378/93 $1.00 + .20 6/1/41763
538
Distinguishing true from spurious labor is important, particularly when the gestation is remote from term. This distinction is critical because preterm delivery remains one of the major causes of neonatal mortality and morbidity. I Clinically, as many as 50% of women who have false labor eventually deliver preterrn." The differentiation of false from true labor is problematic because the only absolute differentiating factor is that
Volume 168, Number 2 Am J Obstet Gynecol
in true labor the contractions lead to irreversible progressive cervical change and, ultimately, delivery." Various reports have described the use of sedatives such as morphine, parenteral administration of fluids, periods of rest, or fetal breathing movements on ultrasonographic examination to distinguish false from true labor with little to moderate success. 1-7 More recently, oncofetal fibronectin in cervicovaginal fluid has been suggested as a sensitive and specific correlate of early delivery. This type of fibronectin has been identified in amniotic fluid, placental tissue, and malignant cell lines. It can be detected by the monoclonal antibody FDC-6, which specifically binds oncofetal fibronectin. S Clinically, this technique has been used to measure fetal fibronectin in the cervicovaginal secretions of women at risk for early delivery. In women admitted with a diagnosis of preterm labor, Lockwood et al. 9 reported that the presence of fetal fibronectin identified those patients who eventually delivered before term with a sensitivity of 81.7% and a specificity of 82.5%. What has not been studied are patients in false labor with contractions but no cervical change. The purpose of our study was to detail the effectiveness of oncofetal fibronectin obtained from cervicovaginal secretions in differentiating who would later have true preterm labor with subsequent early delivery in a population of women who had had an episode of false labor but were otherwise not at risk for preterm birth. The null hypothesis was that a positive fetal fibronectin would not discriminate the group of women who would deliver before term because of preterm labor from those who delivered at term. Material and methods
Women with singleton pregnancies between 24 and 36 weeks' gestation with documented episodes of false labor were eligible for this study. In each patient cervical dilatation was :5 I cm and :5 75% effaced, with regular uterine contractions (~ 10/hr). The fetal heart tones were in the normal range, and the membranes were intact according to speculum visualization and fern test. None of these women had historic indicators that would place them at high risk for preterm birth. Exclusion criteria included uterine or cervical abnormalities, placenta previa, suspected abruption, unknown gestational age, hypertension, diabetes, suspected rupture of the membranes, multifetal gestation, or maternal age of < 15 years. Also, women diagnosed and admitted with true preterm labor were not included. Each patient was observed in the Obstetric Receiving Unit for 2 to 6 hours with fetal heart rate and contraction frequency monitoring to assist in diagnosing false labor. During this period of time gestational age was documented by history and confirmed with ultrasonography by using current measurements and mensuration
Morrison et al.
539
earlier in pregnancy. Hydration with Ringer lactate or half-normal saline solution was used, but no tocolytics, analgesic agents, or sedative medications were administered. In no patient was vaginal bleeding present, and none of the patients had had intercourse or douched in the 12 hours before sampling. No patient had vaginal bleeding, although two reported spotting. The contractions abated during observation, and there was no cervical change in these patients. All women were diagnosed as having false labor and were discharged within 8 hours of registration in the Obstetric Receiving Unit. No subject was admitted to the hospital, and women were monitored routinely at 4-week intervals in our prenatal clinic. After the patients had been screened for inclusion and exclusion criteria and the diagnosis of false labor was made, they were offered entry. Women electing to participate were then asked to give informed consent and were placed into the study. At the time of speculum examination to confirm intact membranes, each subject had an oncofetal fibronectin sample taken by rolling a Dacron swab gently over the exocervix for 10 seconds. The swab was then extracted in 750 j.L1 of assay buffer (Tris buffer containing bovine serum albumin as a stabilizer and protease inhibitors), and the solution was immediately frozen at - 20° C. The samples were then stored I to 12 weeks until the time of assay. The stability of fetal fibronectin under these conditions is ~ 6 months (David Casal, PhD, unpublished data). The concentration of oncofetal fibronectin was measured by a solid-phase, enzyme-linked immunosorbent assay using the monoclonal antibody FDC-6 to specifically bind fetal fibronectin (Adeza Biomedical, Sunnyvale, Calif.). These assays were performed in batches. The absorbance of duplicate negative and positive controls and patient samples were determined at a wavelength of 550 nm with an automated microtiter-plate reader. Patient samples with an absorbance greater than or equal to the positive control (50 ng/ml fetal fibronectin) were deemed positive for the presence of fetal fibronectin. The interassay coefficient of variation was 8% to 12%. In no case was the result of the oncofetal fibronectin test available to the physician caring for the patient, and steroids were not given to enhance fetal lung maturity. Subsequently, patients who had an episode of documented preterm labor were noted. Preterm labor was defined as regular uterine contractions (usually > 10/hr) with confirmed change in cervical status from previous examinations (> I cm dilation and > 75% effacement). Women who were delivered at < 37 weeks and women with preterm labor were stratified as to the result of the fetal fibronectin test obtained when they had false labor. Other follow-up data included the time and date of delivery, the interval between discharge from the obstetric unit and delivery, gestational age at
540
Morrison at al.
February 1993 Am
J Obstet Gynecol
Table I. Patient characteristics Fetal fibronectin test result
14 14
Positive Negative
Age (yr)
Parity
22.0 :±: 5.8 22.9 :±: 4.9
0.8 :±: 1.2 1.5 :±: 1.1
Gestational age at sampling (wk)
Contractions/hr
31.8 :±: 2.9 32.6:±: 2.8
12.2 :±: 3.4 13.7 :±: 2.9
12/1/1 8/4/2
Values are mean:±: SD. *Blacklwhite/American Indian.
Table II. Outcome statistics Fetal fibronectin test result
Positive Negative
14 14
Interval (diagnosis to delivery) (day)
Gestational age at delivery (wk)
Birth weight
21.6 :±: 20.2 37.4 :±: 20.8
34.3 :±: 2.9 37.9:±: 1.6
2199 :±: 774 2957 :±: 348
Significant neonatal morbidity
(gm)
9 1
5
o
Values are mean:±: SD. *Sensitivity 90%, specificity 72%, negative predictive value 93%.
assessment for false labor and at delivery, and birth weight and infant status at discharge. Statistical analysis was carried out with the Fisher exact test and X2 testing where appropriate. A p value of < 0.05 was considered significant. Results
A shown in Table I the age, parity, and race of patients who had false labor and whose test results were positive for fetal fibronectin were not significantly different from those with negative oncofetal fibronectin test results. In addition, the gestational age at the time of sampling for patients with positive test results (31.8 ± 2.9 weeks) was not dissimilar from women with negative oncofetal fibronectin test results (32.6 ± 2.9 weeks; p = 0.90). Similarly, the dilatation and effacement of the cervix in women who had positive test results for fetal fibronectin was not different from those with negative results (p == 0.72 and 0.29, respectively). Finally, the maximum number of contractions per hour was approximately the same in women whether they had positive or negative oncofetal fibronectin tests. All women whose test results for fetal fibronectin were positive had early labor (n == 14), and only 4 with negative test results subsequently had preterm labor (p == 0.04). Table II shows a significant increase in the interval from diagnosis to delivery in women who had negative test results for oncofetal fibronectin (37.4 ± 20.8 days) when compared with those women with positive test results (21.6 ± 20.2 days; p < 0.05). This increase resulted in a significant reduction in the gestational age at delivery and birth weight in women with positive fetal fibronectin test results (34.3 ± 2.9 weeks, 2199 ± 744 gm) when compared with those with neg-
ative test results (37.9 ± 1.6 weeks, 2957 ± 348 gm); this difference was statistically different (p == 0.002 and 0.003, respectively). Fig. 1 offers a scatter plot of gestational age and delivery stratified by the result of the fetal fibronectin tests. It shows good correlation between a positive test result and early delivery and a negative fetal fibronectin test result and delivery at term. There were a greater number of preterm deliveries in women with positive test results (nine) when compared with women with negative test results (one), and this was likewise a significant difference (p == 0.002). Among those women with positive fetal fibronectin test results, five babies with significant neonatal complications were admitted to the newborn intensive care unit compared with none in women with negative test results (p == 0.06). There were no cases of neonatal morbidity in pregnancies with negative test results. Four infants had respiratory distress syndrome (29, 31, 31, and 32 weeks' gestation), and one had a patent ductus arteriosus that was surgically ligated. All infants survived, but three had extended hospital stays (> 28 days). Comment
The accurate determination of whether a patient is in true preterm labor is important but difficult. The level of discomfort and the intensity and frequency of contractions does not allow distinction of uterine activity that results in false labor and therefore does not single out those who are destined to deliver early." 4. 10 Although some investigators have revealed that a decreased interval between contractions is more often associated with true labor, the mean and SD of these measurements were too wide to make this a clinically
Volume 168, Number 2 Am J Obstet Gynecol
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Fig. 1. Scatter plot of gestational ages at delivery stratified by result of fetal fibronectin (FFN) test obtained at diagnosis of false labor.
valuable tool. 3. 4 Likewise, cervical dilatation at the time of observation for false labor has been noted to be less in those with false labor, but the large SD often results in data that are not clinically useful if dilatation is < I em." \I Various tests, such as analgesic administration, observation, hydration, and administration of subcutaneous tocolytic agents are also frequently not predictive of women who have false labor but who are at risk of preterm delivery. ,,·7. 12 Therefore because clinicians do not have a good discriminator of false versus true labor, and because as many as 50% of women with "false labor" deliver early, the need for an accurate test is evident. 3. II The study by Lockwood et al." reveals that of 117 women with uterine contractions and intact membranes, 51.3% delivered preterm. In that study women who had positive fetal fibronectin test results were far more likely to deliver before term (83.1 %) than were patients with negative test results (19%). Our results are similar: 9 (64%) of 14 patients delivered early with positive oncofetal fibronectin, whereas of patients with negative test results only one (7%) patient delivered early. The correlation of a positive fetal fibronectin test result with preterm delivery revealed a sensitivity of 90% and specificity of 82.5%.9 These figures correspond well with our values (sensitivity 90%, specificity 72%). In our estimation the most important feature of oncofetal fibronectin was the 93% negative predictive value in women with false labor. Our findings also imply other clinically relevant information. For example, iffetal fibronectin was present the positive predictive value was 64% for preterm delivery. However, in women with positive test results,
100% had true labor at < 37 weeks, and the interval between the assessment tor false labor and delivery was significantly shorter than in patients with negative oncofetal fibronectin concentrations (p < 0.05). Likewise, this translated into more patients eventually delivering before term, a lower birth weight, and a trend toward more neonatal complications in women who had false labor but positive fetal fibronectin test results. We conclude that positive fetal fibronectin test results in women between 24 and 34 weeks' gestation who have false labor indicates a significant risk for the subsequent development of true preterm labor and a high risk for early delivery. These early births portend increased morbidity for the neonate. On the other hand, a negative fetal fibronectin test result is a good indication that subsequent preterm labor and early delivery are unlikely to occur. Further work in this area is indicated on the basis of these preliminary results.
REFERENCES I. Vital statistics of the United States. Natality. Rockville,
2. 3. 4. 5. 6.
Maryland: United States Department of Health and Human Services, 1987:255-8. Arulkumaran S, Michelsen], Ingermarsson I, Ratnam SS. Obstetric outcome of patients with a previous episode of spurious labor. A\I] OllSTFT GY"n:COL 1987;157:17-20. Eganhouse DJ. A comparative study of variables differentiating false labor from early labor. ] Perinatol 1991; 11: 249-57. Friedman E. Labor: clinical evaluation and management. 2nd ed. New York: Appleton-Century-Crofts, 1978. Valenzuela G, Cline S, Hayashgi RH. Follow-up of hydration and sedation in the pretherapy of premature labor. Asr ] OBSTET GYNECOL 1983;147:396-8. Scrimshaw S, Souza R. Recognizing active labor: a test of a decision-making guide for pregnant women. Soc Sci Med 1982;16: 1473-82.
Finan et al.
7. Schreyer P, Caspi E, Bar Natan N, Tal E, Weinraub Z. The predictive value of fetal breathing movement and Bishop score in the diagnosis of "true" preterm labor. AM] OBSTET GYNECOL 1989;161:886-9. 8. Matsuura H, Takio K, Titani K, et al. The oncofetal structure of human fibronectin defined by monoclonal antibody FDC-6.] BioI Chern 1988;263:3314-22. 9. Lockwood C], Senyei AE, Dische MR, et al. Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery. N Engl] Med 1991;325:669-74.
February 1993 Am J Obstet Gynecol
10. Caldeyro-Barcia R, Poserio ]]. Physiology of the uterine contraction. Clin Obstet Gynecol 1960;3:386. 11. Schauberger CWo False labor. Obstet Gynecol 1986;68: 770-2. 12. American College of Obstetricians and Gynecologists. Preterm labor. Washington, D.C.: American College of Obstetricians and Gynecologists, 1989, ACOG technical bulletin no 133.
The effects of cold therapy on postoperative pain in gynecologic patients: A prospective, randomized study Michael A. Finan, MD, William S. Roberts, MD, Mitchel S. Hoffman, MD, James V. Fiorica, MD, Denis Cavanagh, MD, and B.J. Dudney, RN Tampa, Florida OBJECTIVE: The purpose of the study was to determine the effect of cold therapy on the subjective assessment of pain, analgesic requirements, and wound complications in female patients undergoing major abdominal surgery. STUDY DESIGN: Twenty-seven patients were entered in the study in a prospective, randomized fashion. The Hot/Ice Thermal Blanket was applied to 13 patients, and 12 patients were in the control group. All patients underwent exploratory laparotomy and received postoperative pain relief with intravenously self-administered morphine sulfate through a patient-controlled analgesic pump. RESULTS: Compared with the control group (0.363 ± 0.118 mg/kg/day), the cold pack group used more morphine sulfate on the first postoperative day (0.529 ± 0.236 mg/kg/day, p < 0.05). The mean amount of morphine sulfate used by both groups was similar on postoperative day 2. CONCLUSION: We conclude that the cold pack does not improve postoperative pain control in gynecologic patients undergoing exploratory laparotomy. (AM J OBSTET GVNECOL 1993;168:542-4.)
Key words: Cold therapy, postoperative pain
The topical application of cold substances after minor injuries has long been known to reduce swelling and discomfort. The use of cold therapy for postoperative pain control after exploratory laparotomy has not been extensively studied. Shaubel' noted in 1946 that ice applied to orthopedic surgical sites resulted in reduced postoperative pain and fewer postoperative complications. Cold baths are more effective than warm baths in relieving postpartum perineal pain." Cohn et
al. 3 evaluated the Hot/Ice Thermal Blanket cooling machine (Hollister, Tampa) prospectively in patients undergoing arthroscopic procedures. They noted a reduction in postoperative narcotic use and a more rapid conversion to oral pain medication in patients with cold therapy. The current study was undertaken to determine the effect of cold therapy on the subjective assessment of pain, analgesic requirements, and wound complications in female patients undergoing major abdominal surgery.
From the Division of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida. Received for publication February 26, 1992; revised July 21, 1992; accepted August 24, 1992. Reprint requests: Michael A. Finan, MD, Division of Gynecologic Oncology, Ochsner Clinic, 1514 Jefferson Highwav. New Orleans, LA 70121. Copyright © 1993 Mosby-Year Book, Inc. 0002-9378/93 $1.00 + .20 6/1/42024
Material and methods Between April 1, 1989, and Sept. 30, 1989, 27 patients were entered in the study. Informed consent was obtained, and the protocol was approved by the investigational review board. The patients all underwent exploratory laparotomy performed by members of the Division of Gynecologic Oncology at the H. Lee Moffitt
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