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Progesterone for prevention of recurrent preterm birth: Impact of gestational age at prior delivery
SMFM Abstracts S11 22
PREVENTIVE EFFECT OF RECOMBINANT HUMAN LACTOFERRIN IN A RABBIT PRETERM DELIVERY MODEL AKITOSHI HASEGAWA1, KATSUFUMI OTSUKI1, YASUSHI SASAKI1, MAKI SAWADA1, KAORI MITSUKAWA1, HIROSHI CHIBA1, MASAAKI NAGATSUKA1, TAKASHI OKAI1, 1Showa University Tokyo, Obstetrics and Gynecology, Tokyo, Japan OBJECTIVE: Lactoferrin (LF) is an iron-binding glycoprotein and found in human milk, granulocytes, cervical mucus, sperm and amniotic fluid. It is well known that LF has a defensive function against local mucosal infections. The purpose of this study was to confirm the preventive effects of recombinant human LF (rh-LF) on a rabbit model of preterm delivery. STUDY DESIGN: We conducted this study under the approval of the animal experiment committee in our institution. Timed pregnant New Zealand White Rabbits (3-4 kg) were used in this experiment. Rabbits were anesthetized with an intramuscular injection of ketamine hydrochroride and 0.2ml of Escherichia coli (E coli) or saline solution were inoculated by using a sterile polyethylene canula with hysteroscope. These rabbits were randomly assigned to either receive treatment with rh-LF (5mg/body) (2 hours before inoculation) or to receive no therapy, group A (n = 3): sterile saline plus sterile saline, group B (n = 8): sterile saline plus E coli, group C (n = 7): rh-LF plus E coli. Survival rate of fetuses after inoculation until the seventh day, which fetal death includes stillbirth and neonatal death due to preterm delivery, and the continuation of pregnancy days after inoculation were compared among groups. RESULTS: Survival rate of fetuses in each group were 95.7% (group A), 0% (group B) and 32.6% (group C). Survival rate of group C was significantly (P ! .01) higher than those of group B. The pregnancy continuation days from inoculation in each group were 7.0 G 0 days (group A), 3.3 G 0.4 days (group B) and 4.9 G 1.8 days (group C). The pregnancy continuation days of group C was significantly (P ! .05) longer than those of group B. CONCLUSION: The administration of rh-LF into the cervix increased survival rate of fetuses and caused the extension of the pregnancy continuation. That is conceivably due to not only an anti inflammation action but also an anti bacterial action of LF. The result of this study suggests possible effects of rh-LF to prevent preterm delivery originated from cervical infection in the clinical setting.
24
RELATIONSHIP OF MIDTRIMESTER FETAL FIBRONECTIN (FFN) CONCENTRATION TO ANTIBIOTIC EFFICACY FOR THE PREVENTION OF SPONTANEOUS PRETERM BIRTH IN ASYMPTOMATIC FFN POSITIVE WOMEN PATRICK RAMSEY1, 1National Institutes of Health/NICHD Maternal-Fetal Medicine Units Network, Obstetrics/ Gynecology, Birmingham, Alabama OBJECTIVE: To evaluate whether pretreatment midtrimester quantitative cervicovaginal FFN concentration is related to antibiotic efficacy for the prevention of spontaneous preterm birth (SPTB) in asymptomatic FFN positive women. STUDY DESIGN: This study is a secondary analysis of a multicenter doubleblind, placebo-controlled trial of antibiotic therapy for asymptomatic women with a positive cervicovaginal FFN (R50 ng/mL) at 21-25 wks gestation. Women were randomized to receive either metronidazole 250 mg tid plus erythromycin 250 mg qid for 10 days or identical appearing placebo. The primary study outcome was SPTB !37 wks. Quantitative FFN concentrations were determined by ELISA. RESULTS: Of the 715 women enrolled, 699 had quantitative FFN values and outcomes available. No differences were noted between treatment groups with respect to age, race, gestational age at randomization, history of spontaneous preterm birth, or bacterial vaginosis status. Forty six percent of women had FFN values from 50-99 ng/mL, 17% from 100-149 ng/mL, 8% from 150-199 ng/mL, and 29% R200 ng/mL. Overall incidence of SPTB was 13.4%. The incidence of SPTB increased significantly with increasing quantitative FFN concentration: 12% 50-99 ng/mL, 13% 100-149 ng/mL, 27% 50-199 ng/mL, and 23% R200 ng/mL (P = .0002). No differential effect of antibiotic therapy, however, was noted on the incidence of SPTB relative to quantitative FFN concentration (Table). SPTB !37 Weeks By Quantitative FFN Concentration vs Treatment FFN Concentration (ng/mL)
Placebo (n = 346)
Antibiotic (n = 353)
P value
50–99 100–149 150–199 R200
9.8% 8.3% 31.0% 14.0%
8.7% 11.7% 19.2% 24.2%
.85 .76 .37 .07
CONCLUSION: The incidence of spontaneous preterm birth !37 wks increases significantly with increasing quantitative FFN concentration. Irrespective of pretreatment cervicovaginal FFN concentration, antibiotic use in asymptomatic FFN positive women is ineffective to prevent SPTB.
23
PROGESTERONE FOR PREVENTION OF RECURRENT PRETERM BIRTH: IMPACT OF GESTATIONAL AGE AT PRIOR DELIVERY CATHERINE Y. SPONG1, 1NICHD MFMU Network, Bethesda, Maryland OBJECTIVE: Preterm birth occurs in one of eight pregnancies and when very early results in significant morbidity and mortality. 17-alpha hydroxyprogesterone caproate (17P) has been found to be efficacious in reducing subsequent preterm delivery in women who have had a prior spontaneous preterm birth (SPB). This analysis was undertaken to evaluate if 17P is more effective for women with an earlier gestational age of their prior preterm delivery. We hypothesized that treatment with 17P is more effective in prolonging pregnancy in patients with prior very early (20-27.9 or 28-33.9 wks) than near-term (34-36.9 wks) prior SPB. STUDY DESIGN: Secondary analysis of women with a prior SPB enrolled in a randomized controlled trial evaluating 17P vs placebo. Gestational age of the prior SPBs were documented. Effectiveness of progesterone for pregnancy prolongation was evaluated based on gestational age at prior delivery (2027.9, 28-33.9, and 34-36.9 wks). Statistical analysis included Kruskal-Wallis with P ! .05 considered significant. RESULTS: Gestational age at qualifying delivery was similar between women treated with 17P or placebo (P = .12). Women with qualifying delivery at 2027.9 wks and at 28-33.9 wks delivered at significantly more advanced gestational age if treated with progesterone than placebo (P = .038 and .045 respectively, Table). CONCLUSION: 17P therapy given to prevent recurrent PTB is associated with a prolongation of pregnancy overall, and especially for women with a prior spontaneous PTB at an early gestational age. Qualifying delivery
Placebo GA del meanGSD
17P GA del meanGSD
P value
20.0-27.9 (wks) 28.0-33.9 (wks) 34.0-36.9 (wks) Entire cohort
33.5 35.6 35.8 35.3
35.1 36.8 36.7 36.3
.038 .045 .143 .002
G G G G
5.5 4.6 4.2 4.7
n = 29 n = 65 n = 59 n = 153
G G G G
6.5 4.1 4.0 4.8
n = 82 n = 107 n = 117 n = 306
25
CERVICAL ANTI-INFLAMMATORY CYTOKINE CONCENTRATIONS ARE DECREASED AMONG PREGNANT WOMEN WITH BACTERIAL VAGINOSIS HYAGRIV SIMHAN1, STEVE CARITIS1, SHARON HILLIER1, MARIJANE KROHN1, 1University of Pittsburgh, Obstetrics, Gynecology and Reproductive Sciences, Pittsburgh, Pennsylvania OBJECTIVE: Bacterial vaginosis (BV) is known to alter many aspects of reproductive immunity. The production and activity of anti-inflammatory cytokines are thought to be a critical element of the lower genital tract innate immune defense with respect to STDs and infection-related spontaneous preterm birth. We sought to ascertain the impact of BV among pregnant women on the production of the three most important anti-inflammatory cytokines (IL-4, IL-10, and IL-13) in the cervix. STUDY DESIGN: In this cohort study, ninety-eight gravid women from 4 to 16 weeks´ gestation (median 8.4 weeks´ ) without N gonorrhoeae, C trachomatis, or T vaginalis were queried regarding clinical and demographic history and underwent pelvic examination for collection of vaginal swabs for Gram stain and cervical swabs for STDs and cytokines. BV was defined as a Nugent score of R7. Concentrations of cytokines were determined in duplicate using Luminex multiplex assay. Race and smoking status was determined by self-report. Statistical analyses were performed using Stata 8.0. RESULTS: BV was present in 30 (30.6%) women. The median cervical concentrations of IL-4, 10, and 13 were all significantly lower among women with BV than women without BV (P = .02, .03, .006, respectively). Even after adjustment for African-American race and cigarette smoking, women with BV had increased odds of having anti-inflammatory cytokine concentrations in the lowest quartile compared with women who did not have BV(see Table). CONCLUSION: BV in pregnancy is associated with an alteration of cervical innate immunity, as represented by a decreased concentration of the three most important anti-inflammatory cytokines. This may have an important impact upon the host response to immune challenges, such as STDs or infection-related preterm birth. Relationship of BV with anti-inflammatory cytokine concentrations in lowest quartile
BV + vs BV ÿ
Adjusted odds ratio for IL-4 ! 25th %ile
Adjusted odds ratio for IL-10 ! 25th %ile
Adjusted odds ratio for IL-13 ! 25th %ile
4.4(1.5-12.8)
10.4(3.0-36.1)
5.2(1.8-15.0)
PREVENTIVE EFFECT OF RECOMBINANT HUMAN LACTOFERRIN IN A RABBIT PRETERM DELIVERY MODEL AKITOSHI HASEGAWA1, KATSUFUMI OTSUKI1, YASUSHI SASAKI1, MAKI SAWADA1, KAORI MITSUKAWA1, HIROSHI CHIBA1, MASAAKI NAGATSUKA1, TAKASHI OKAI1, 1Showa University Tokyo, Obstetrics and Gynecology, Tokyo, Japan OBJECTIVE: Lactoferrin (LF) is an iron-binding glycoprotein and found in human milk, granulocytes, cervical mucus, sperm and amniotic fluid. It is well known that LF has a defensive function against local mucosal infections. The purpose of this study was to confirm the preventive effects of recombinant human LF (rh-LF) on a rabbit model of preterm delivery. STUDY DESIGN: We conducted this study under the approval of the animal experiment committee in our institution. Timed pregnant New Zealand White Rabbits (3-4 kg) were used in this experiment. Rabbits were anesthetized with an intramuscular injection of ketamine hydrochroride and 0.2ml of Escherichia coli (E coli) or saline solution were inoculated by using a sterile polyethylene canula with hysteroscope. These rabbits were randomly assigned to either receive treatment with rh-LF (5mg/body) (2 hours before inoculation) or to receive no therapy, group A (n = 3): sterile saline plus sterile saline, group B (n = 8): sterile saline plus E coli, group C (n = 7): rh-LF plus E coli. Survival rate of fetuses after inoculation until the seventh day, which fetal death includes stillbirth and neonatal death due to preterm delivery, and the continuation of pregnancy days after inoculation were compared among groups. RESULTS: Survival rate of fetuses in each group were 95.7% (group A), 0% (group B) and 32.6% (group C). Survival rate of group C was significantly (P ! .01) higher than those of group B. The pregnancy continuation days from inoculation in each group were 7.0 G 0 days (group A), 3.3 G 0.4 days (group B) and 4.9 G 1.8 days (group C). The pregnancy continuation days of group C was significantly (P ! .05) longer than those of group B. CONCLUSION: The administration of rh-LF into the cervix increased survival rate of fetuses and caused the extension of the pregnancy continuation. That is conceivably due to not only an anti inflammation action but also an anti bacterial action of LF. The result of this study suggests possible effects of rh-LF to prevent preterm delivery originated from cervical infection in the clinical setting.
24
RELATIONSHIP OF MIDTRIMESTER FETAL FIBRONECTIN (FFN) CONCENTRATION TO ANTIBIOTIC EFFICACY FOR THE PREVENTION OF SPONTANEOUS PRETERM BIRTH IN ASYMPTOMATIC FFN POSITIVE WOMEN PATRICK RAMSEY1, 1National Institutes of Health/NICHD Maternal-Fetal Medicine Units Network, Obstetrics/ Gynecology, Birmingham, Alabama OBJECTIVE: To evaluate whether pretreatment midtrimester quantitative cervicovaginal FFN concentration is related to antibiotic efficacy for the prevention of spontaneous preterm birth (SPTB) in asymptomatic FFN positive women. STUDY DESIGN: This study is a secondary analysis of a multicenter doubleblind, placebo-controlled trial of antibiotic therapy for asymptomatic women with a positive cervicovaginal FFN (R50 ng/mL) at 21-25 wks gestation. Women were randomized to receive either metronidazole 250 mg tid plus erythromycin 250 mg qid for 10 days or identical appearing placebo. The primary study outcome was SPTB !37 wks. Quantitative FFN concentrations were determined by ELISA. RESULTS: Of the 715 women enrolled, 699 had quantitative FFN values and outcomes available. No differences were noted between treatment groups with respect to age, race, gestational age at randomization, history of spontaneous preterm birth, or bacterial vaginosis status. Forty six percent of women had FFN values from 50-99 ng/mL, 17% from 100-149 ng/mL, 8% from 150-199 ng/mL, and 29% R200 ng/mL. Overall incidence of SPTB was 13.4%. The incidence of SPTB increased significantly with increasing quantitative FFN concentration: 12% 50-99 ng/mL, 13% 100-149 ng/mL, 27% 50-199 ng/mL, and 23% R200 ng/mL (P = .0002). No differential effect of antibiotic therapy, however, was noted on the incidence of SPTB relative to quantitative FFN concentration (Table). SPTB !37 Weeks By Quantitative FFN Concentration vs Treatment FFN Concentration (ng/mL)
Placebo (n = 346)
Antibiotic (n = 353)
P value
50–99 100–149 150–199 R200
9.8% 8.3% 31.0% 14.0%
8.7% 11.7% 19.2% 24.2%
.85 .76 .37 .07
CONCLUSION: The incidence of spontaneous preterm birth !37 wks increases significantly with increasing quantitative FFN concentration. Irrespective of pretreatment cervicovaginal FFN concentration, antibiotic use in asymptomatic FFN positive women is ineffective to prevent SPTB.
23
PROGESTERONE FOR PREVENTION OF RECURRENT PRETERM BIRTH: IMPACT OF GESTATIONAL AGE AT PRIOR DELIVERY CATHERINE Y. SPONG1, 1NICHD MFMU Network, Bethesda, Maryland OBJECTIVE: Preterm birth occurs in one of eight pregnancies and when very early results in significant morbidity and mortality. 17-alpha hydroxyprogesterone caproate (17P) has been found to be efficacious in reducing subsequent preterm delivery in women who have had a prior spontaneous preterm birth (SPB). This analysis was undertaken to evaluate if 17P is more effective for women with an earlier gestational age of their prior preterm delivery. We hypothesized that treatment with 17P is more effective in prolonging pregnancy in patients with prior very early (20-27.9 or 28-33.9 wks) than near-term (34-36.9 wks) prior SPB. STUDY DESIGN: Secondary analysis of women with a prior SPB enrolled in a randomized controlled trial evaluating 17P vs placebo. Gestational age of the prior SPBs were documented. Effectiveness of progesterone for pregnancy prolongation was evaluated based on gestational age at prior delivery (2027.9, 28-33.9, and 34-36.9 wks). Statistical analysis included Kruskal-Wallis with P ! .05 considered significant. RESULTS: Gestational age at qualifying delivery was similar between women treated with 17P or placebo (P = .12). Women with qualifying delivery at 2027.9 wks and at 28-33.9 wks delivered at significantly more advanced gestational age if treated with progesterone than placebo (P = .038 and .045 respectively, Table). CONCLUSION: 17P therapy given to prevent recurrent PTB is associated with a prolongation of pregnancy overall, and especially for women with a prior spontaneous PTB at an early gestational age. Qualifying delivery
Placebo GA del meanGSD
17P GA del meanGSD
P value
20.0-27.9 (wks) 28.0-33.9 (wks) 34.0-36.9 (wks) Entire cohort
33.5 35.6 35.8 35.3
35.1 36.8 36.7 36.3
.038 .045 .143 .002
G G G G
5.5 4.6 4.2 4.7
n = 29 n = 65 n = 59 n = 153
G G G G
6.5 4.1 4.0 4.8
n = 82 n = 107 n = 117 n = 306
25
CERVICAL ANTI-INFLAMMATORY CYTOKINE CONCENTRATIONS ARE DECREASED AMONG PREGNANT WOMEN WITH BACTERIAL VAGINOSIS HYAGRIV SIMHAN1, STEVE CARITIS1, SHARON HILLIER1, MARIJANE KROHN1, 1University of Pittsburgh, Obstetrics, Gynecology and Reproductive Sciences, Pittsburgh, Pennsylvania OBJECTIVE: Bacterial vaginosis (BV) is known to alter many aspects of reproductive immunity. The production and activity of anti-inflammatory cytokines are thought to be a critical element of the lower genital tract innate immune defense with respect to STDs and infection-related spontaneous preterm birth. We sought to ascertain the impact of BV among pregnant women on the production of the three most important anti-inflammatory cytokines (IL-4, IL-10, and IL-13) in the cervix. STUDY DESIGN: In this cohort study, ninety-eight gravid women from 4 to 16 weeks´ gestation (median 8.4 weeks´ ) without N gonorrhoeae, C trachomatis, or T vaginalis were queried regarding clinical and demographic history and underwent pelvic examination for collection of vaginal swabs for Gram stain and cervical swabs for STDs and cytokines. BV was defined as a Nugent score of R7. Concentrations of cytokines were determined in duplicate using Luminex multiplex assay. Race and smoking status was determined by self-report. Statistical analyses were performed using Stata 8.0. RESULTS: BV was present in 30 (30.6%) women. The median cervical concentrations of IL-4, 10, and 13 were all significantly lower among women with BV than women without BV (P = .02, .03, .006, respectively). Even after adjustment for African-American race and cigarette smoking, women with BV had increased odds of having anti-inflammatory cytokine concentrations in the lowest quartile compared with women who did not have BV(see Table). CONCLUSION: BV in pregnancy is associated with an alteration of cervical innate immunity, as represented by a decreased concentration of the three most important anti-inflammatory cytokines. This may have an important impact upon the host response to immune challenges, such as STDs or infection-related preterm birth. Relationship of BV with anti-inflammatory cytokine concentrations in lowest quartile
BV + vs BV ÿ
Adjusted odds ratio for IL-4 ! 25th %ile
Adjusted odds ratio for IL-10 ! 25th %ile
Adjusted odds ratio for IL-13 ! 25th %ile
4.4(1.5-12.8)
10.4(3.0-36.1)
5.2(1.8-15.0)