- Email: [email protected]
724: A randomized trial of two dose regimens of nifedipine for management of preterm labor
SMFM Abstracts 723
USE OF PROGESTERONE TO PREVENT PRETERM BIRTHS: ATTITUDES AND PRACTICES OF U.S. OBSTETRICIAN-GYNECOLOGISTS ZSAKEBA HENDERSON1, MICHAEL POWER2, EVE LACKRITZ1, VINCENZO BERGHELLA3, JAY SCHULKIN2, 1Centers for Disease Control and Prevention, Division of Reproductive Health, Atlanta, Georgia, 2American College of Obstetricians and Gynecologists, Research Department, Washington, District of Columbia, 3Thomas Jefferson University, Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, Philadelphia, Pennsylvania OBJECTIVE: To determine current attitudes and practices regarding the use of progesterone to prevent preterm birth among members of the American College of Obstetricians and Gynecologists (ACOG). STUDY DESIGN: A self-administered mail survey was sent to members of the ACOG Collaborative Ambulatory Research Network in March-May 2007. Clinicians were eligible to complete the survey if they currently practiced obstetrics in the U.S. The survey consisted of 36 questions, including respondents= demographic characteristics, their preterm birth risk factor knowledge and screening practices, and their understanding and use of progesterone for the prevention of preterm birth. RESULTS: The overall response rate, adjusted for eligibility, was 52% (N⫽345). The primary specialty of 89% of respondents was general Ob/Gyn, followed by maternal-fetal medicine (8%). Seventy-four percent reported that they currently recommend or offer progesterone for prevention of preterm birth; of those (n⫽254), 42% reported recommending it to women with any prior preterm birth ⬍37 weeks, and 55% reported recommending progesterone to women without a prior preterm birth for other conditions in the current pregnancy (39% for prematurely dilated or effaced cervix, 35% for short cervix on ultrasound, and 27% for cerclage). Of all respondents, 55% considered prophylactic use of progesterone for high risk patients an effective treatment to reduce the incidence of preterm birth. However, some were very concerned that it was not easily available (36%), not covered by insurance (31%), that more data are needed (28%), and that there may be long-term fetal or neonatal effects (27%). CONCLUSION: Nearly three-fourths of responding physicians reported recommending or offering progesterone for the prevention of preterm birth, and over half of them reported offering it to women without a prior preterm birth. Despite this widespread use of progesterone, concerns still remain regarding long-term effects and the need for more data to support its use.
www.AJOG.org 725
Rate of preterm birth ⱕ32 weeks with progesterone supplementation by onset of therapy
0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.752
724
A RANDOMIZED TRIAL OF TWO DOSE REGIMENS OF NIFEDIPINE FOR MANAGEMENT OF PRETERM LABOR ANWAR NASSAR1, ALI KHALIL1, JOHNNY AWWAD1, ANTOINE ABU MUSA1, JAD TABBARA1, IHAB USTA1, 1American University of Beirut Medical Center, Department of Obstetrics and Gynecology, Beirut, Lebanon OBJECTIVE: To compare the efficacy of 2 doses of nifedipine for acute and maintenance tocolysis of preterm labor. STUDY DESIGN: Women with preterm labor (24-34 weeks’ gestation) were randomized to receive either high- (HD) or low-dose (LD) oral nifedipine. HD consisted of 20 mg SL nifedipine, repeated in 30 min, followed by 120-160 mg slowrelease nifedipine (nifedicor) daily for 48 hrs and 80-120 mg up to 36 weeks. In LD arm, 10 mg nifedipine was given, repeated every 15 min to a maximum of 4 doses, followed by 60-80 mg nifedicor daily for 48 hours and 60 mg up to 36 weeks. The primary outcome was to achieve uterine quiescence at 6 hrs of tocolysis. Analysis was performed with the intent to treat. RESULTS: 102 were enrolled (49 HD and 53 LD). More women assigned to HD achieved the primary outcome (79.6 vs 58.5%, P⫽0.037). There were no differences in delivery within 48 hrs (10.2% HD vs 13.2% LD, P⫽0.871), undelivered at 34 and 37 wks (79.6 vs 66.0%, P⫽0.190, and 38.8 vs 26.4%, P⫽0.262), time to achieve primary outcome (3.07 ⫾ 4.83 vs 4.43 ⫾ 4.94 hrs; P⫽0.163) and readmission for recurrent preterm labor (16.3 vs 20.7%, P⫽0.749); however, gestational age at delivery was significantly higher in HD (36.0 ⫾ 2.8 versus 34.7 ⫾ 3.7 wks, P⫽0.049). Violation of protocol was significantly higher in LD (38.8 vs 66.0%, P⫽0.011), the most common reason was the use of other tocolytics. In LD, nifedipine was increased to doses used in HD in 26.4% of cases. Maternal adverse effects were similar in both arms but were severe enough to stop tocolysis in 2 patients in HD. Birth weight, admission to intensive care nursery, and composite neonatal morbidity -IVH, RDS, NEC, and sepsis- were similar in both groups. However, need for mechanical ventilation (6.1 vs 20.8%, P⫽ 0.043) was significantly lower in HD. CONCLUSION: Patients who received high dose nifedipine achieved uterine quiescence at 6 hrs more frequently and delivered at a significantly higher gestational age. However, delay of delivery, recurrent preterm labor, maternal adverse effects and neonatal outcomes were similar between groups. 0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.753
DOES THE TIMING OF INITIAL PROGESTERONE DOSING ALTER THE UTILITY OF PROGESTERONE SUPPLEMENTATION? SECONDARY ANALYSIS FROM THE PROVAGGEL TRIAL. JOHN O’BRIEN1, DAVID ADAIR2, DAVID F. LEWIS3, EMILY DEFRANCO4, JAMES PHILLIPS5, GEORGE CREASY6, THE PROVAGGEL STUDY GROUP7, 1Central Baptist Hospital, Lexington, Kentucky, 2University of Tennessee College of Medicine, Chattanooga, Tennessee, 3Louisiana State University Health Sciences Center, Shreveport, Louisiana, 4Washington University in St. Louis, St. Louis, Missouri, 5Sage Statistical Solutions, Inc., Efland, North Carolina, 6Columbia Laboratories, Inc, Livingston, New Jersey, 7Columbia Laboratories, Inc, , New Jersey OBJECTIVE: Our goal was to determine whether the timing of risk screening and progesterone initiation in the second trimester alters the efficacy of treatment with vaginal progesterone. STUDY DESIGN: A secondary analysis was performed of women enrolled in a preterm prevention trial utilizing 90mg intravaginal, daily progesterone gel, Prochieve®. Patients were randomized 1:1 drug versus placebo. All patients had a transvaginal cervical length assessment at randomization between 18⫹0 and 22⫹6 weeks. A prior secondary analysis demonstrated women with a cervical length 30 mm at randomization had a treatment effect. Subpopulations from this efficacy group were identified and analyzed. Fisher=s exact, Cochran-Mantel-Haenszel (CMH), and Analysis of Covariance (ANCOVA) were utilized to compare outcomes. RESULTS: 668 women were randomized and 116 subjects had a cervical length 30 mm at randomization. The efficacy of progesterone to reduce the rate of preterm delivery ⱕ32 weeks is shown in the Table. Progesterone was associated with a reduction in early preterm birth even after adjusted for dosing interval (P⫽ .043). The early dosing interval group did not show a difference in early pretem birth rates with progesterone treatment (P⫽0.327), however, the later dosing interval demonstrated a trend (P⫽.059). Note for Table: P-value for treatment effect adjusting for dosing time using CMH was 0.056. CONCLUSION: The timing of progesterone initiation influences early preterm delivery among women with midtrimester cervical shortening. Based on the stratification of gestational age at first dose evaluated, a later gestational age (20⫹0 to 22⫹6) likely improves the utility of the therapy. Larger study populations may better define an optimal time for risk screening and initiation of progesterone prophylaxis.
Timing of cervical scan (Weeks)
Progesterone (n⫽58)
Placebo (n⫽58)
P-value
18⫹0- 19⫹6 (n⫽ 59) 20⫹0 to 22⫹6 (n⫽ 57)
3 of 28 (10.7%) 1 of 30 (3.3%)
5 of 31 (16.1%) 6 of 27 (22.2%)
0.710 0.045
0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.754
726
FUNISITIS AND FETAL INFLAMMATORY RESPONSE SYNDROME (FIRS) DANIEL SURBEK1, SILKE JOHANN1, MARKUS BERGER2, ANTONELLA CROMI3, FABIO GHEZZI3, LUIGI RAIO1, 1University of Berne, Dept. of Obstetrics and Gynecology, Berne, Switzerland, 2University of Berne, Dept. of Pediatrics, Berne, Switzerland, 3University Hospital Varese, Dept. of Obstetrics and Gynecology, Varese, Italy OBJECTIVE: Intrauterine infection is associated with premature rupture of membranes (PROM) and preterm delivery (PD). The identification of a fetal infection is of major relevance regarding short- and longterm morbidity. Funisitis (inflammation of the umbilical cord with leucocytal invasion of the Wharton=s jelly and/or vessels) is –in contrast to acute chorioamnitis – a histological marker for a purely fetal inflammatory response, the “Fetal Inflammatory Response Syndrome” (FIRS). STUDY DESIGN: Preterm neonates (24⫹0 - 36⫹6 weeks of gestation) with histological evidence of funisitis were retrospectively compared to a control group of neonates without funisitis matched for gestational age, sex and year of birth. All children were inborn and taken care at the neonatal intensive care unit of our hospital and followed up in the postnatal development center. Respiratory, inflammatory and neurological parameters were compared. RESULTS: 66 neonates with funisitis and 66 control children were included into the study. There were no significant differences regarding gestational age at delivery (30.8⫾3.8 vs. 30.9⫾3.5 weeks), birthweight (1595⫾677 vs. 1578⫾707g), incidence of SGA (7.6% vs. 9.1%), Apgar ⬍4 at 5= (15.2% vs. 7.6%), higher grade intracranial hemorrhage (1.6% vs. 1.5%), periventricular leucomalacia (0% vs. 4.6%), cerebral palsy (1.6% vs. 1.5%), sepsis (3.9% s. 4.8%), neonatal respiratory distress syndrome (39.3% vs. 26.2%) or neonatal death (13.6% vs. 6.1%). A higher incidence of hypertensive disorders (31.3% vs. 3.2%; p⬍0.05), in particular preeclampsia (21.9% vs. 1.6%; p⬍0.001) was found in the control group whereas PROM (58.7% vs. 28.1%;p⬍0.001) or preterm labor (81% vs. 60.9%; p⬍0.05) occured more often in the funisitis group. CONCLUSION: No significant difference in short and longterm outcome could be demonstrated between the groups. We suppose that both, infectious and noninfectious cause of PD induces the same inflammatory processes. Therefore, it should be discussed, if the defintion of FIRS may only be restricted to infectious events. 0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.755
S206
American Journal of Obstetrics & Gynecology Supplement to DECEMBER 2007
USE OF PROGESTERONE TO PREVENT PRETERM BIRTHS: ATTITUDES AND PRACTICES OF U.S. OBSTETRICIAN-GYNECOLOGISTS ZSAKEBA HENDERSON1, MICHAEL POWER2, EVE LACKRITZ1, VINCENZO BERGHELLA3, JAY SCHULKIN2, 1Centers for Disease Control and Prevention, Division of Reproductive Health, Atlanta, Georgia, 2American College of Obstetricians and Gynecologists, Research Department, Washington, District of Columbia, 3Thomas Jefferson University, Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, Philadelphia, Pennsylvania OBJECTIVE: To determine current attitudes and practices regarding the use of progesterone to prevent preterm birth among members of the American College of Obstetricians and Gynecologists (ACOG). STUDY DESIGN: A self-administered mail survey was sent to members of the ACOG Collaborative Ambulatory Research Network in March-May 2007. Clinicians were eligible to complete the survey if they currently practiced obstetrics in the U.S. The survey consisted of 36 questions, including respondents= demographic characteristics, their preterm birth risk factor knowledge and screening practices, and their understanding and use of progesterone for the prevention of preterm birth. RESULTS: The overall response rate, adjusted for eligibility, was 52% (N⫽345). The primary specialty of 89% of respondents was general Ob/Gyn, followed by maternal-fetal medicine (8%). Seventy-four percent reported that they currently recommend or offer progesterone for prevention of preterm birth; of those (n⫽254), 42% reported recommending it to women with any prior preterm birth ⬍37 weeks, and 55% reported recommending progesterone to women without a prior preterm birth for other conditions in the current pregnancy (39% for prematurely dilated or effaced cervix, 35% for short cervix on ultrasound, and 27% for cerclage). Of all respondents, 55% considered prophylactic use of progesterone for high risk patients an effective treatment to reduce the incidence of preterm birth. However, some were very concerned that it was not easily available (36%), not covered by insurance (31%), that more data are needed (28%), and that there may be long-term fetal or neonatal effects (27%). CONCLUSION: Nearly three-fourths of responding physicians reported recommending or offering progesterone for the prevention of preterm birth, and over half of them reported offering it to women without a prior preterm birth. Despite this widespread use of progesterone, concerns still remain regarding long-term effects and the need for more data to support its use.
www.AJOG.org 725
Rate of preterm birth ⱕ32 weeks with progesterone supplementation by onset of therapy
0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.752
724
A RANDOMIZED TRIAL OF TWO DOSE REGIMENS OF NIFEDIPINE FOR MANAGEMENT OF PRETERM LABOR ANWAR NASSAR1, ALI KHALIL1, JOHNNY AWWAD1, ANTOINE ABU MUSA1, JAD TABBARA1, IHAB USTA1, 1American University of Beirut Medical Center, Department of Obstetrics and Gynecology, Beirut, Lebanon OBJECTIVE: To compare the efficacy of 2 doses of nifedipine for acute and maintenance tocolysis of preterm labor. STUDY DESIGN: Women with preterm labor (24-34 weeks’ gestation) were randomized to receive either high- (HD) or low-dose (LD) oral nifedipine. HD consisted of 20 mg SL nifedipine, repeated in 30 min, followed by 120-160 mg slowrelease nifedipine (nifedicor) daily for 48 hrs and 80-120 mg up to 36 weeks. In LD arm, 10 mg nifedipine was given, repeated every 15 min to a maximum of 4 doses, followed by 60-80 mg nifedicor daily for 48 hours and 60 mg up to 36 weeks. The primary outcome was to achieve uterine quiescence at 6 hrs of tocolysis. Analysis was performed with the intent to treat. RESULTS: 102 were enrolled (49 HD and 53 LD). More women assigned to HD achieved the primary outcome (79.6 vs 58.5%, P⫽0.037). There were no differences in delivery within 48 hrs (10.2% HD vs 13.2% LD, P⫽0.871), undelivered at 34 and 37 wks (79.6 vs 66.0%, P⫽0.190, and 38.8 vs 26.4%, P⫽0.262), time to achieve primary outcome (3.07 ⫾ 4.83 vs 4.43 ⫾ 4.94 hrs; P⫽0.163) and readmission for recurrent preterm labor (16.3 vs 20.7%, P⫽0.749); however, gestational age at delivery was significantly higher in HD (36.0 ⫾ 2.8 versus 34.7 ⫾ 3.7 wks, P⫽0.049). Violation of protocol was significantly higher in LD (38.8 vs 66.0%, P⫽0.011), the most common reason was the use of other tocolytics. In LD, nifedipine was increased to doses used in HD in 26.4% of cases. Maternal adverse effects were similar in both arms but were severe enough to stop tocolysis in 2 patients in HD. Birth weight, admission to intensive care nursery, and composite neonatal morbidity -IVH, RDS, NEC, and sepsis- were similar in both groups. However, need for mechanical ventilation (6.1 vs 20.8%, P⫽ 0.043) was significantly lower in HD. CONCLUSION: Patients who received high dose nifedipine achieved uterine quiescence at 6 hrs more frequently and delivered at a significantly higher gestational age. However, delay of delivery, recurrent preterm labor, maternal adverse effects and neonatal outcomes were similar between groups. 0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.753
DOES THE TIMING OF INITIAL PROGESTERONE DOSING ALTER THE UTILITY OF PROGESTERONE SUPPLEMENTATION? SECONDARY ANALYSIS FROM THE PROVAGGEL TRIAL. JOHN O’BRIEN1, DAVID ADAIR2, DAVID F. LEWIS3, EMILY DEFRANCO4, JAMES PHILLIPS5, GEORGE CREASY6, THE PROVAGGEL STUDY GROUP7, 1Central Baptist Hospital, Lexington, Kentucky, 2University of Tennessee College of Medicine, Chattanooga, Tennessee, 3Louisiana State University Health Sciences Center, Shreveport, Louisiana, 4Washington University in St. Louis, St. Louis, Missouri, 5Sage Statistical Solutions, Inc., Efland, North Carolina, 6Columbia Laboratories, Inc, Livingston, New Jersey, 7Columbia Laboratories, Inc, , New Jersey OBJECTIVE: Our goal was to determine whether the timing of risk screening and progesterone initiation in the second trimester alters the efficacy of treatment with vaginal progesterone. STUDY DESIGN: A secondary analysis was performed of women enrolled in a preterm prevention trial utilizing 90mg intravaginal, daily progesterone gel, Prochieve®. Patients were randomized 1:1 drug versus placebo. All patients had a transvaginal cervical length assessment at randomization between 18⫹0 and 22⫹6 weeks. A prior secondary analysis demonstrated women with a cervical length 30 mm at randomization had a treatment effect. Subpopulations from this efficacy group were identified and analyzed. Fisher=s exact, Cochran-Mantel-Haenszel (CMH), and Analysis of Covariance (ANCOVA) were utilized to compare outcomes. RESULTS: 668 women were randomized and 116 subjects had a cervical length 30 mm at randomization. The efficacy of progesterone to reduce the rate of preterm delivery ⱕ32 weeks is shown in the Table. Progesterone was associated with a reduction in early preterm birth even after adjusted for dosing interval (P⫽ .043). The early dosing interval group did not show a difference in early pretem birth rates with progesterone treatment (P⫽0.327), however, the later dosing interval demonstrated a trend (P⫽.059). Note for Table: P-value for treatment effect adjusting for dosing time using CMH was 0.056. CONCLUSION: The timing of progesterone initiation influences early preterm delivery among women with midtrimester cervical shortening. Based on the stratification of gestational age at first dose evaluated, a later gestational age (20⫹0 to 22⫹6) likely improves the utility of the therapy. Larger study populations may better define an optimal time for risk screening and initiation of progesterone prophylaxis.
Timing of cervical scan (Weeks)
Progesterone (n⫽58)
Placebo (n⫽58)
P-value
18⫹0- 19⫹6 (n⫽ 59) 20⫹0 to 22⫹6 (n⫽ 57)
3 of 28 (10.7%) 1 of 30 (3.3%)
5 of 31 (16.1%) 6 of 27 (22.2%)
0.710 0.045
0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.754
726
FUNISITIS AND FETAL INFLAMMATORY RESPONSE SYNDROME (FIRS) DANIEL SURBEK1, SILKE JOHANN1, MARKUS BERGER2, ANTONELLA CROMI3, FABIO GHEZZI3, LUIGI RAIO1, 1University of Berne, Dept. of Obstetrics and Gynecology, Berne, Switzerland, 2University of Berne, Dept. of Pediatrics, Berne, Switzerland, 3University Hospital Varese, Dept. of Obstetrics and Gynecology, Varese, Italy OBJECTIVE: Intrauterine infection is associated with premature rupture of membranes (PROM) and preterm delivery (PD). The identification of a fetal infection is of major relevance regarding short- and longterm morbidity. Funisitis (inflammation of the umbilical cord with leucocytal invasion of the Wharton=s jelly and/or vessels) is –in contrast to acute chorioamnitis – a histological marker for a purely fetal inflammatory response, the “Fetal Inflammatory Response Syndrome” (FIRS). STUDY DESIGN: Preterm neonates (24⫹0 - 36⫹6 weeks of gestation) with histological evidence of funisitis were retrospectively compared to a control group of neonates without funisitis matched for gestational age, sex and year of birth. All children were inborn and taken care at the neonatal intensive care unit of our hospital and followed up in the postnatal development center. Respiratory, inflammatory and neurological parameters were compared. RESULTS: 66 neonates with funisitis and 66 control children were included into the study. There were no significant differences regarding gestational age at delivery (30.8⫾3.8 vs. 30.9⫾3.5 weeks), birthweight (1595⫾677 vs. 1578⫾707g), incidence of SGA (7.6% vs. 9.1%), Apgar ⬍4 at 5= (15.2% vs. 7.6%), higher grade intracranial hemorrhage (1.6% vs. 1.5%), periventricular leucomalacia (0% vs. 4.6%), cerebral palsy (1.6% vs. 1.5%), sepsis (3.9% s. 4.8%), neonatal respiratory distress syndrome (39.3% vs. 26.2%) or neonatal death (13.6% vs. 6.1%). A higher incidence of hypertensive disorders (31.3% vs. 3.2%; p⬍0.05), in particular preeclampsia (21.9% vs. 1.6%; p⬍0.001) was found in the control group whereas PROM (58.7% vs. 28.1%;p⬍0.001) or preterm labor (81% vs. 60.9%; p⬍0.05) occured more often in the funisitis group. CONCLUSION: No significant difference in short and longterm outcome could be demonstrated between the groups. We suppose that both, infectious and noninfectious cause of PD induces the same inflammatory processes. Therefore, it should be discussed, if the defintion of FIRS may only be restricted to infectious events. 0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.755
S206
American Journal of Obstetrics & Gynecology Supplement to DECEMBER 2007