Neurodevelopmental outcome at the age of 4 years according to the planned mode of delivery in term breech presentation: a nationwide, population-based record linkage study.

PURPOSE: To evaluate whether a trial of planned vaginal breech labor affects neurologic development in children. METHODS: This is a nationwide, Finnish, population-based record linkage study. An odds ratio with 95% confidence intervals was used to estimate the relative risk that a child delivered by planned vaginal breech labor would be diagnosed with adverse neurodevelopmental outcome (cerebral palsy, epilepsy, intellectual disability, sensor neural developmental outcome, hyperactivity, speech and language problems) at the age of 4 years. The reference group were children born by planned cesarean section. RESULTS: During a study period of 7 years, 8374 infants were delivered in breech position. Among them, 3907 (46.7%) had an attempted labor and 4467 (53.3%) infants were delivered by planned cesarean section. There were no differences in the neurodevelopmental outcome. In the planned vaginal labor group, 133 (3.4%) children had an abnormal neurodevelopmental outcome at the age of 4 years compared to 142 (3.2%) in the planned cesarean section group. CONCLUSION: The absolute risk of abnormal neurological outcome in breech deliveries at term was low, regardless of planned mode of birth. Planned vaginal breech labor did not increase the risk for abnormal neurological outcome compared to planned cesarean section.

Risk factors associated with adverse perinatal outcome in planned vaginal breech labors at term: a retrospective population-based case-control study.

BACKGROUND: Vaginal breech delivery is associated with adverse perinatal outcome. The aim of this study was to identify factors associated with adverse perinatal outcome in term breech pregnancies, and to provide clinicians an aid in selecting women for a trial of vaginal labor with the fetus in breech position. METHODS: We conducted a retrospective, nationwide, Finnish population-based case-control study. All planned singleton vaginal deliveries at term with the fetus in breech position between the years 2005 and 2014 were analyzed. The study's end point was a composite set of adverse perinatal outcomes. All infants with an adverse outcome were compared to the infants with normal outcomes. A multivariate logistic regression model was used to analyze the data. RESULTS: An adverse perinatal outcome was recorded for 73 (1.5%) infants. According to the study results fetal growth restriction (adjusted odds ratio, 2.94; 95% CI, 1.30-6.67), oligohydramnios (adjusted odds ratio, 2.94; 95% CI, 1.15-7.18), a history of cesarean section (adjusted odds ratio, 2.94; 95% CI, 1.28-6.77, gestational diabetes (adjusted odds ratio, 2.89; 95% CI, 1.54-5.40), epidural anesthesia (adjusted odds ratio, 2.20; 95% CI, 1.29-3.75) and nulliparity (adjusted odds ratio, 1.84; 95% CI, 1.10-3.08) were associated with adverse perinatal outcome. CONCLUSIONS: Adverse perinatal outcome in planned vaginal breech labor at term is associated with fetal growth restriction, oligohydramnios, previous cesarean delivery, gestational diabetes, nulliparity and epidural anesthesia.

Risk factors and outcomes in "well-selected" vaginal breech deliveries: a retrospective observational study.

OBJECTIVE: To assess risk factors for adverse perinatal and neonatal outcomes in "well-selected" singleton vaginal breech deliveries at term. METHODS: During the time span from January 2008 up to April 2015 a total of 786 singleton term breech deliveries with a planned vaginal delivery were identified in a retrospective observational study at Helsinki University Central Hospital, Finland. The study's end point was a composite of adverse perinatal and neonatal outcomes. Infants with an adverse outcome were compared to all spontaneous singleton vaginal breech deliveries with normal perinatal and neonatal outcomes. A multivariate logistic regression model was used to analyze associations between adverse neonatal outcomes and several variables. The secondary outcome was the severe morbidity rate according to the criteria of the term breech trial. RESULTS: An adverse neonatal outcome was recorded for 38 (4.8%) infants. According to the study the second delivery stage lasting <40 min [adjusted odds ratio (aOR): 0.34, 95% confidence interval (95% CI): 0.15-0.79] was associated with lower odds and had a protective effect against adverse outcomes. Epidural anesthesia (aOR: 2.88, 95% CI: 1.08-7.70) was associated with higher adverse outcomes. The incidence rate of severe morbidity was 1.3% (10/787). CONCLUSION: Adverse neonatal outcomes in well-selected breech deliveries are associated with a prolonged second delivery stage lasting >40 min and with epidural anesthesia.

Breech presentation at term and associated obstetric risks factors-a nationwide population based cohort study.

PURPOSE: The aim of this study was to estimate whether breech presentation at term was associated with known individual obstetric risk factors for adverse fetal outcome. METHODS: This was a retrospective, nationwide Finnish population-based cohort study. Obstetric risks in all breech and vertex singleton deliveries at term were compared between the years 2005 and 2014. A multivariable logistic regression model was used to determine significant risk factors. RESULTS: The breech presentation rate at term for singleton pregnancies was 2.4%. The stillbirth rate in term breech presentation was significantly higher compared to cephalic presentation (0.2 vs 0.1%). The odds ratios (95% CIs) for fetal growth restriction, oligohydramnios, gestational diabetes, a history of cesarean section and congenital fetal abnormalities were 1.19 CI (1.07-1.32), 1.42 CI (1.27-1.57), 1.06 CI (1.00-1.13), 2.13 (1.98-2.29) and 2.01 CI (1.92-2.11). CONCLUSIONS: The study showed that breech presentation at term on its own was significantly associated with antenatal stillbirth and a number of individual obstetric risk factors for adverse perinatal outcomes. The risk factors included oligohydramnios, fetal growth restriction, gestational diabetes, history of caesarean section and congenital anomalies.

Induction of labor in breech presentations at term: a retrospective observational study.

OBJECTIVE: The aim of this study is to evaluate whether induction of breech delivery at term is feasible and safe for mother and child compared with spontaneous vaginal breech delivery. STUDY DESIGN: A total of 268 singleton term breech deliveries with an attempted vaginal delivery were identified in a single-center retrospective observational study. Out of these, 73 cases had an induction of labor for various medical and obstetric reasons and were compared to 195 spontaneous singleton breech deliveries. The main outcome measure was the mode of delivery. Secondary outcomes included maternal and neonatal morbidity and mortality. RESULTS: The vaginal delivery rate in the induction group was 64.4% compared with 80% in the spontaneous delivery group. No statistical differences were observed between the two delivery groups regarding neonatal and maternal morbidity and mortality. CONCLUSIONS: The vaginal delivery rate was significantly lower in induced than in spontaneous breech deliveries. The neonatal and maternal morbidity and mortality rates were similar implying that induction in breech delivery is an option and it is time for clinical reappraisal.

Emergency peripartum hysterectomy and risk factors by mode of delivery and obstetric history: a 10-year review from Helsinki University Central Hospital.

OBJECTIVE: This study aims to estimate the occurrence of emergency peripartum hysterectomy (EPH) and to quantify its risk factors in connection with the mode of delivery and the obstetric history of patients at the Helsinki University Central Hospital, Finland. METHODS: In a retrospective, matched case-control study we identified 124 cases of EPH from 2000 to 2010 at our hospital. These were matched with 248 control patients. RESULTS: The incidence rate of EPH was 9.9/10,000. Patients whose current delivery was vaginal, and had a cesarean section (CS) in their history had a six-fold risk for EPH. Women who underwent their first CS had a nine times higher risk, while patients who currently underwent CS and had a history of previous CS, had a 22 times higher risk. Those who experienced prostaglandin-E1 induction had a five-fold risk. Maternal age >35 years, previous curettage, and twin pregnancy were identified as significant risk factors. In 41 cases, interventions to reduce bleeding were performed. CONCLUSION: Obstetric emergency training and guidelines for massive hemorrhage should be established in any delivery department. Moreover, all possible precautions should be taken to avoid the first CS if it is obstetrically unnecessary. Induction with prostaglandin-E1, maternal age >35 years, previous curettage, twin pregnancies, and early gestation were identified as risk factors for EPH.

Smoking is accompanied by a suppressed cervical nitric oxide release in women with high-risk human papillomavirus infection.

OBJECTIVE: Both smoking and the release of nitric oxide (NO) in the uterine cervix are determinants for high-risk human papillomavirus (hrHPV) infection. We compared the cervical NO release between smoking and non-smoking women with and without hrHPV infection. DESIGN: Open clinical cohort study. SETTING: University Hospital in Finland. POPULATION: One hundred and twenty-five smoking and 301 non-smoking women, with (n = 244) and without (n = 182) hrHPV infection. In total, 264 women showed cytological and/or histological cervical epithelial changes. METHODS: The presence of hrHPV was tested by an HPV DNA test and the release of NO was assessed from NO metabolites in the cervical fluid by the Griess reaction. MAIN OUTCOME MEASURES: The difference in cervical NO release between smoking and non-smoking women with and without hrHPV. RESULTS: Infection with hrHPV in smokers (70%) was more frequent (p = 0.001) than in non-smokers (52%). As a whole, smoking was accompanied by a 35% decrease (p = 0.04) in NO release in hrHPV-infected women (35.9 µmol/L, 95% confidence interval 27.0-44.2) compared with non-smoking hrHPV- infected women (48.3 µmol/L, 95% confidence interval 38.0-56.2). No difference in NO release between smokers and non-smokers was seen in women with healthy cervical epithelium, but smoking was accompanied by a suppressed (26%) NO release (p = 0.03) in women with either cytological or histological changes. CONCLUSIONS: Smoking may suppress NO release in the uterine cervix in women with hrHPV infection.

Cervical nitric oxide release and persistence of high-risk human papillomavirus in women.

Nitric oxide may serve as one cofactor for human papillomavirus (HPV)-induced development of cervical cancer. Therefore, we first assessed the levels of cervical fluid nitric oxide metabolite (NOx) in 283 women with and without high-risk (hr) HPV. The NOx level in women with hr HPV (48.4 µmol/L [95% CI: 39.4-56.6], n = 199) was higher (p < 0.001) than that in women without hr HPV (24.6 µmol/L [95% CI: 19.1-38.7], n = 84). Second, we evaluated if cervical fluid NOx levels could predict the persistence of hr HPV. Therefore, we followed up 113 women with detectable hr HPV without any treatment for 12 mo and repeated hr HPV test. High-risk HPV persisted in 72 women (64%) and disappeared in 41 women (36%). The median basal levels of NOx were higher (p = 0.02) in women with persistent hr HPV (56.9 µmol/L [95% CI: 48.7-81.0]) compared to those with eradicated hr HPV (37.7 µmol/L [95% CI: 27.0-58.0]). The NOx level higher than the 75th percentile (>87.0 µmol/L) predicted hr HPV persistence (OR = 4.1 [95% CI: 1.3-13.1]). This cutoff level of NOx showed 33% sensitivity and 90% specificity in predicting the persistence of hr HPV, but it failed to predict cytological progression or regression in 12 mo. In conclusion, high cervical fluid NOx appears to be connected to the persistence of hr HPV, but the low predictive capacity of NOx prevents its clinical use at this phase.

Cervical nitric oxide release in Chlamydia trachomatis and high-risk human papillomavirus infection.

OBJECTIVE: To compare cervical fluid nitric oxide release in women with and without Chlamydia trachomatis and high-risk human papillomavirus infection (hrHPV). DESIGN: An open clinical study. SETTING: University Hospital of Helsinki. POPULATION: Thirty-nine women with (n=21) and without C. trachomatis (n=18). METHODS: Chlamydia trachomatis and/or hrHPV were studied by using specific RNA- and DNA-based tests. Levels of cervical fluid nitric oxide metabolite (NOx) were assessed by the Griess reaction. MAIN OUTCOME MEASURES: The difference in cervical fluid NOx between women with and without C. trachomatis and hrHPV. RESULTS: Fourteen (67%) C. trachomatis-infected women and three (17%) noninfected women had concomitant hrHPV. The level of cervical fluid NOx in women with C. trachomatis (median 37.5 µmol/l, 95% confidence interval 26.1-50.9) was higher (p=0.02) than that in C. trachomatis-noninfected women (median 19.7 µmol/L, 95% confidence interval 5.6-30.0). The presence of hrHPV did not associate with any difference in NOx levels between C. trachomatis-infected or -noninfected women. CONCLUSIONS: Chlamydia trachomatis was associated with increased release of nitric oxide metabolites in the uterine cervix. This stimulus was stronger than that of hrHPV, because no additional rise in NOx was seen in women with concomitant C. trachomatis and hrHPV infection.

Association between high risk papillomavirus DNA and nitric oxide release in the human uterine cervix.

OBJECTIVE: Local cervical factors may determine the outcome of human papillomavirus (HPV) infection. Nitric oxide (NO) may be one such factor, since it is produced by uterine cervical cells and it takes part in both immunological and carcinogenic reactions. We studied the association between the presence of cervical high risk (hr) HPV DNA and NO in the cervical canal in women. METHODS: High risk HPV DNA status was assessed from 328 women by using a specific DNA test and the release of cervical NO was assessed as nitrate/nitrite in cervical fluid. Cervical NO was then compared between women showing different status of hr HPV DNA and different cytological and histological findings. RESULTS: High risk HPV DNA was present in 175/328 (53%) women. The cervical NO release in women with hr HPV DNA was 90% higher compared to hr HPV DNA negative women (p<0.001) (median 45.2 micromol/L; 95% CI 35.2-53.1 vs. 23.8 micromol/L; 95% CI 21.0-26.1). This elevation was not affected by parity, use of oral contraception, intrauterine devices, or signs of bacterial vaginosis or candida infection. Cytologically healthy epithelium and epithelium with mild cytological or histological changes showed elevated NO release if hr HPV DNA was present. CONCLUSIONS: The presence of hr HPV DNA is associated with an increased release of NO in the human uterine cervix. The clinical significance of this phenomenon remains open.

Abnormal cervical cytology is associated with increased nitric oxide release in the uterine cervix.

OBJECTIVE: The human uterine cervix is capable of producing nitric oxide (NO). We studied the impact of cytological changes on the release of cervical NO. DESIGN: Population-based case-control study. SETTING: City of Helsinki, Finland. POPULATION: Cervical cytology tests and cervical fluid samples were collected in 297 women. METHODS: Cervical cytology tests, classified according to Bethesda criteria, were specifically analyzed for changes typically seen in human papillomavirus (HPV) infection, and the level of NO metabolites (NOx) in cervical fluid was assessed by Griess reaction. MAIN OUTCOME MEASURES: The difference in cervical fluid NOx between normal and abnormal cytology. RESULTS: Cervical cytology was normal in 219 women and abnormal in 78 women. Among women with abnormal cytology there was both a higher detection rate (89% vs. 71%) and a higher concentration of NOx (median 22.5 micromol/l, 95% CI 14.6-31.9 vs. 11.0 micromol/l, 95% CI 8.0-16.7) compared to women with normal cytology. Age, parity, use of oral contraceptives, phase of the menstrual cycle, or history of miscarriage or termination of early pregnancy were not linked to an increased cervical NOx level. CONCLUSIONS: Cervical cell changes (suggestive of HPV infection) are accompanied by an increased release of NO in the human cervix. The significance of this finding remains uncertain, but in theory, increased release of NO could modify the outcome of cervical infection.

Serum cholesterol efflux potential in postmenopausal women treated with isolated isoflavones.

OBJECTIVE: Based on the low cardiovascular risk in Asian populations, phytoestrogens are believed to provide vascular benefits. To elucidate the mechanisms behind the possible cardiovascular effects of phytoestrogens, we evaluated reverse cholesterol transport by assessing the capacity of serum to promote cholesterol efflux in postmenopausal women treated with isolated isoflavones. DESIGN: Thirty postmenopausal women were treated in a randomized, placebo-controlled, crossover trial with isoflavones or placebo for 3 months interrupted by a 2-month washout period. Serum samples were collected before and after each treatment period, and the cholesterol efflux potential was investigated by using H-cholesterol--labeled Fu5AH cells in culture. RESULTS: Serum promoted 20.2% +/- 3.0% and 19.9% +/- 3.4% (mean +/- SD) cholesterol efflux after isoflavonoid treatment and after placebo treatment, respectively. Thus, the isoflavone treatment did not affect serum cholesterol efflux. We also studied separately women who produced high concentrations of the isoflavone metabolite equol into serum because some studies suggest that equol could exert favorable vascular effects. However, there was no difference in serum cholesterol efflux capacity between the equol producers (n = 15) and non-equol producers (n = 15). CONCLUSIONS: In conclusion, isoflavone treatment did not affect serum cholesterol efflux potential in postmenopausal women. Based on our findings, isolated isoflavones do not provide vascular benefits by improving cholesterol efflux.

Increased release of cervical nitric oxide in spontaneous abortion before clinical symptoms: a possible mechanism for preabortal cervical ripening.

Nitric oxide (NO) affects cervical ripening. We studied cervical NO release in women with nonviable pregnancy before signs of abortion. Women with missed abortion (n = 56), blighted ovum (n = 36), or tubal pregnancy (n = 7) were selected by means of vaginal ultrasonographic examination from a population seeking early pregnancy termination; 140 women with amenorrhea-matched normal gestation were studied as controls. Cervical fluid samples were assessed for NO metabolites (Nox) by means of Griess reaction. Cervical fluid Nox was more often detectable in women with missed abortion (90%) and blighted ovum (87%) than in the control women (55%; P = 0.01), and Nox levels in women with missed abortion [median, 59.4 mumol/liter; 95% confidence interval (CI), 30.3-81.8] and blighted ovum (25.6 mumol/liter; 95% CI, 14.1-53.0) were 14 and 6 times higher (P < 0.001 and P = 0.002, respectively) than in the control group (4.3 mumol/liter; 95% CI, <3.8 to 6.4). Nox levels in women with tubal pregnancy were normal. In women with nonviable pregnancy, the lower the level of progesterone, expressed as a percentage of that in the control women, the higher (r = -0.69; P < 0.001) the level of cervical fluid Nox, and those with low pretreatment Nox levels failed to abort completely after mifepristone-misoprostol or expectant management more often (P = 0.04) than women with high Nox levels (28% vs. 4%); no such relationship was seen in the control group. Increased preabortal cervical NO release may contribute to cervical ripening and the onset of clinical abortion.

Cervical nitric oxide release in women postterm.

OBJECTIVE: Nitric oxide may be a factor in cervical ripening. We compared the nitric oxide metabolite levels in cervical fluid in women going beyond term and in women delivering spontaneously at term. METHODS: We studied a total of 208 women with singleton pregnancies: 108 women who went beyond term (294 days or longer), and 100 women who went spontaneously into labor at term. Cervical fluid samples, collected well before the initiation of labor, were assessed for nitric oxide metabolites using an assay with a detection limit of 3.8 micromol/L. RESULTS: Women going beyond term had detectable levels of nitric oxide metabolites in their cervical fluid (60%) less often (P =.001) than women delivering at term (87%). The nitric oxide metabolite concentration in cervical fluid in women going beyond term (median 23.5 micromol/L; 95% confidence interval less than 3.8, 31.8) was 4.5 times lower (P <.001) than that in women delivering at term (median 106.0 micromol/L; 95% confidence interval 81.8, 135.0). Such a difference (14.0 versus 106.0 micromol/L) also existed when only the 66 women going into spontaneous postterm labor were included in the comparison. Both nulliparous (median less than 3.8 micromol/L) and parous (median 31.3 micromol/L) women going beyond term had lower (P <.01) cervical fluid nitric oxide metabolite levels than nulliparous and parous women delivering at term (medians 76.1 and 101.3 micromol/L, respectively). In the postterm group, women with cervical fluid nitric oxide metabolite concentrations at or below the median failed more often (P <.001) to progress in labor and had longer (P =.02) duration of labor than those with cervical fluid nitric oxide metabolite concentrations above the median. CONCLUSION: Reduced cervical nitric oxide release may contribute to prolonged pregnancy. LEVEL OF EVIDENCE: II-2

High-risk human papillomavirus-induced expression of endothelial and inducible nitric oxide synthase in human uterine cervix.

INTRODUCTION: Levels of nitric oxide metabolites are elevated in the cervical fluid of women with high-risk human papillomavirus (hrHPV). To elucidate the origin of this elevation we studied the cervical expression and localization of endothelial and inducible nitric oxide synthases (eNOS, iNOS) in women. MATERIAL AND METHODS: Expression of eNOS and iNOS was studied by Western blotting in the uterine cervixes of 86 women with (n = 41) and without (n = 45) hrHPV infection. The localization of eNOS and iNOS in cervical cells was studied by immunohistochemistry in 32 randomly selected women. RESULTS: Expression of eNOS and iNOS (in mean [95% CI] density units relative to actin) was higher in women with hrHPV versus those without (eNOS: 33.8 [22.5-45.1] versus 20.2 [6.1-34.3], P = 0.007; iNOS: 12.0 [7.1-16.9]) versus 5.6 [2.0-9.2], P = 0.003). Smoking reduced 64% eNOS (P = 0.001) and 68% iNOS (P = 0.008) in women with hrHPV. Endothelial NOS was localized in the vascular endothelium, while iNOS was present in basal squamous epithelial cells. Low-grade histological lesions were accompanied by elevated expression of both eNOS and iNOS. CONCLUSIONS: High-risk HPV-associated elevation in cervical fluid nitric oxide metabolites results from both eNOS and iNOS stimulation. However, smoking seems to suppress this stimulation in hrHPV-infected women.

Nitric oxide in the human uterine cervix: endogenous ripening factor.

The human uterine cervix can produce nitric oxide (NO), a free radical with an ultra-short half-life. The release of NO changes during pregnancy and is increased in early nonviable pregnancies compared to normal uncomplicated pregnancies. This review concentrates on the role of NO release in cervical ripening in pregnant women. Also some suggestions on future aspects are discussed.

Mifepristone-induced nitric oxide release and expression of nitric oxide synthases in the human cervix during early pregnancy.

BACKGROUND: Nitric oxide (NO) is a factor in cervical ripening, perhaps under the control of progesterone. We studied the effects of the antiprogesterone mifepristone on the release of NO and on the expression of inducible NO synthase (iNOS) and endothelial NO synthase (eNOS) in the uterine cervix of women in early pregnancy. METHODS: Thirteen women were treated with oral mifepristone (200 mg), and 15 women were studied as controls. Cervical fluid samples were collected before treatment then hourly up to 3 h, and the samples were assayed for the concentration of nitric oxide metabolites (NOx). In addition, cervical biopsy samples from six women treated with mifepristone and from six controls were assessed for iNOS and eNOS by immunohistochemistry and Western blotting. RESULTS: In 1-3 h, mifepristone induced 7.4- to 17.2-fold elevations in cervical fluid NOx concentrations; no change was seen in the controls. The expression of both iNOS and eNOS was detected in the cervical cells. The expression of cervical iNOS was strong in five of the six women treated with mifepristone but was not strong in any of the six control women. CONCLUSION: This is the first study to show that mifepristone stimulates the release of NO and the expression of iNOS in cervical cells of women in early pregnancy. This may be one mechanism by which mifepristone initiates cervical ripening.

Misoprostol induces cervical nitric oxide release in pregnant, but not in nonpregnant, women.

OBJECTIVE: The cells of the human uterine cervix synthesize nitric oxide, which may be a factor in cervical ripening. We studied the effect of misoprostol on cervical nitric oxide release in nonpregnant and pregnant women. STUDY DESIGN: Seventy-two nonpregnant (n=15) and pregnant (n=57; 26 in early pregnancy, 31 in late pregnancy) women were treated with either vaginal misoprostol (n=54) or vaginal placebo (n=18). The dose of misoprostol was 400 mug in nonpregnant and early pregnancy group, and 25 mug in late pregnancy group. Serial cervical fluid samples, collected before and up to 3 hours after misoprostol/placebo, were assessed for the concentration of nitric oxide metabolites by means of the Griess reaction. RESULTS: Placebo had no effect on cervical fluid nitric oxide metabolite level. In 1 to 3 hours, misoprostol induced 4.3- to 5.2-fold elevations in cervical fluid Nox concentrations in early pregnancy (P < .01), and 4.4- to 18.2-fold elevations in late pregnancy (P < .01), but these responses did not differ significantly from each other. Misoprostol had no effect on cervical fluid nitric oxide metabolites in nonpregnant women. There was a trend towards a relationship between cervical nitric oxide stimulation after misoprostol and cervical ripening. CONCLUSION: Vaginal misoprostol stimulates cervical nitric oxide release in pregnancy. This suggests a joint action of nitric oxide and prostaglandins in cervical ripening.

Nitric oxide metabolites in cervical fluid during pregnancy: further evidence for the role of cervical nitric oxide in cervical ripening.

OBJECTIVE: Cervical tissue expresses all the isoenzymes of nitric oxide synthase. We studied the concentrations of nitric oxide metabolites in the cervical fluid in nonpregnant (n = 11) and pregnant women (n = 106). STUDY DESIGN: Cervical fluid was collected into a Dacron polyester swab, and nitric oxide metabolites were eluted into physiologic saline solution, which was assayed for nitric oxide metabolites with the Griess reaction. The detection limit of the method is 0.2 micromol/L. RESULTS: Cervical fluid nitric oxide metabolite was detectable in 46% of nonpregnant women (median, <0.2 micromol/L; 95% CI, 0-49), in 63% of women in early pregnancy (median, 11 micromol/L; 95% CI, 0-23) and in 82% of women in late pregnancy (median, 128 micromol/L; 95% CI, 21-276). In late pregnancy, the cervical fluid nitric oxide metabolite level was higher in women with Bishop score of > or =6 (median, 163 micromol/L; 95% CI, 105-276) than in women with Bishop score of <6 (median, 86 micromol/L; 95% CI, 21-99). Cervical fluid nitric oxide metabolite concentration before the onset of labor in parous women (median, 97 micromol/L; 95% CI, 78-283) was higher (P =.008) than that in nulliparous women (median, 28 micromol/L; 95% CI, 0-95). Cervical fluid nitric oxide metabolites before the initiation of labor (median, 33 micromol/L; 95% CI, 0-95) rose to 3.5-fold (median, 115 micromol/L; 95% CI, 78-284) after the commencement of uterine contractions and showed a significant relationship to Bishop score (r = 0.39, P =.01). Cervical fluid nitric oxide metabolite concentrations were not relative to simultaneous plasma nitric oxide metabolite levels (n = 41 women, r = 0.14, P =.41). Rupture of fetal membranes tended to decrease cervical fluid nitric oxide metabolite levels, whereas gentle cervical manipulation elevated it 6.6-fold in 1 minute. The administration of glyceryl trinitrate (0.5 mg, nitric oxide donor) intracervically resulted in a significant rise in the cervical fluid nitric oxide metabolite level in 2 minutes. CONCLUSION: Cervical fluid nitric oxide metabolite level rises after cervical ripening, nitric oxide donor administration, or cervical manipulation, which supports a role for cervical nitric oxide in cervical ripening.