Vaginal progesterone is associated with decreased group B streptococcus colonisation at term: a retrospective cohort study.

OBJECTIVE: To investigate whether women using intravaginal progesterone suppositories for preterm birth prevention during pregnancy will have lower rates of group B streptococcus (GBS) colonisation at term, compared with women receiving intramuscular 17-alpha-hydroxyprogesterone caproate. DESIGN: This was a retrospective observational cohort study of women who were prescribed a progestogen during their pregnancy for preterm birth prevention, and who delivered at term. SETTING: A tertiary referral hospital in central Ohio. POPULATION: Patients who were prescribed a progestogen during their pregnancy for preterm birth prevention between 2004 and 2017 were included in the study. Patients who delivered at <37 weeks of pregnancy, switched progestogen type during the pregnancy, or had a pessary or cerclage placed were excluded. METHODS: Baseline characteristics were compared using Mann-Whitney U-test or Chi-square test as appropriate. The association between type of progestogen and GBS colonisation was assessed using bivariate and multivariable analyses. MAIN OUTCOME MEASURES: The primary outcome was GBS colonisation. RESULTS: In all, 565 patients were included in the study, of whom 173 received intravaginal progesterone, and 392 17-alpha-hydroxyprogesterone caproate. Patients receiving intravaginal progesterone were less likely to be colonised with GBS (19.7 versus 28.1%). After adjustments for potential confounders were made in a multivariable logistic regression analysis, receiving intravaginal progesterone suppositories (adjusted odds ratio [OR] 0.61, 95% CI 0.39-0.95) was associated with reduced GBS colonisation. CONCLUSIONS: Intravaginal progesterone is associated with a decreased prevalence of rectovaginal GBS colonisation at term. TWEETABLE ABSTRACT: Vaginal progesterone is associated with a lower incidence of rectovaginal GBS colonisation, compared with 17α-hydroxyprogesterone caproate.

Vitamin D status and recurrent preterm birth: a nested case-control study in high-risk women.

OBJECTIVE: To determine whether vitamin D status is associated with recurrent preterm birth, and any interactions between vitamin D levels and fish consumption. DESIGN: A nested case-control study, using data from a randomised trial of omega-3 fatty acid supplementation to prevent recurrent preterm birth. SETTING: Fourteen academic health centres in the USA. POPULATION: Women with prior spontaneous preterm birth. METHODS: In 131 cases (preterm delivery at <35 weeks of gestation) and 134 term controls, we measured serum 25-hydroxyvitamin D [25(OH)D] concentrations by liquid chromatography-tandem mass spectrometry (LC-MS) from samples collected at baseline (16-22 weeks of gestation). Logistic regression models controlled for study centre, maternal age, race/ethnicity, number of prior preterm deliveries, smoking status, body mass index, and treatment. MAIN OUTCOME MEASURES: Recurrent preterm birth at <37 and <32 weeks of gestation. RESULTS: The median mid-gestation serum 25(OH)D concentration was 67 nmol/l, and 27% had concentrations of <50 nmol/l. Serum 25(OH)D concentration was not significantly associated with preterm birth (OR 1.33; 95% CI 0.48-3.70 for lowest versus highest quartiles). Likewise, comparing women with 25(OH)D concentrations of 50 nmol/l, or higher, with those with <50 nmol/l generated an odds ratio of 0.80 (95% CI 0.38-1.69). Contrary to our expectation, a negative correlation was observed between fish consumption and serum 25(OH)D concentration (-0.18, P < 0.01). CONCLUSIONS: In a cohort of women with a prior preterm birth, vitamin D status at mid-pregnancy was not associated with recurrent preterm birth.

Occupational fatigue and preterm premature rupture of membranes. National Institute of Child Health and Human Development Maternal-Fetal Medicine, Units Network.

OBJECTIVE: The aim of this study was to prospectively determine the relationship between occupational fatigue and spontaneous preterm delivery segregated into the etiologically distinct categories of spontaneous preterm labor, preterm premature rupture of membranes, and indicated preterm delivery. STUDY DESIGN: A total of 2929 women with singleton pregnancies at 22 to 24 weeks' gestation were enrolled in a multicenter (10 sites) Preterm Prediction Study. Patients reported the number of hours worked per week and answered specific questions designed to determine the following 5 sources of occupational fatigue described by Mamelle et al: posture, work with industrial machines, physical exertion, mental stress, and environmental stress. Fatigue was quantified (0-5 index) according to the number of these sources positively reported. Simple and Mantel-Haenszel chi2 tests were used to test the univariate association and hypothesis of a linear trend between sources of occupational fatigue and spontaneous preterm delivery. Covariables were considered by multivariate logistic regression analysis. Women who did not work outside the home were considered separately from those who worked but did not report any sources of occupational fatigue. RESULTS: Each source of occupational fatigue was independently associated with a significantly increased risk of preterm premature rupture of membranes among nulliparous women but not among multiparous women. The risk of preterm premature rupture of membranes increased (P = .002) with an increasing number of sources of occupational fatigue-not working outside the home, 2.1%; working but not reporting fatigue, 3.7%; working with 1 source of fatigue, 3.2%; working with 2 sources of fatigue, 5.2%; working with 3 sources of fatigue, 5.1%; and working with 4 or 5 sources of fatigue, 7.4%. There was also a significant relationship (P = .01) between preterm premature rupture of membranes and an increasing number of hours worked per week among nulliparous women. Neither spontaneous preterm labor nor indicated preterm delivery was significantly associated with occupational fatigue among either nulliparous or multiparous women. CONCLUSION: The occupational fatigue index of Mamelle et al discriminated a group of nulliparous women at increased risk for preterm premature rupture of membranes. The relationship between preterm premature rupture of membranes and occupational fatigue or hours worked may provide guidelines according to which nulliparous women and their employers can be advised.

The Preterm Prediction Study: association between cervical interleukin 6 concentration and spontaneous preterm birth. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.

OBJECTIVE: The aim of this study was to determine the interrelationship between cervical concentration of interleukin 6 and detection of fetal fibronectin and other risk factors for spontaneous preterm birth. STUDY DESIGN: All patients with spontaneous preterm birth at <35 weeks' gestation (case patients; n = 125) and subjects matched for race, parity, and center delivered at > or = 37 weeks' gestation (n = 125; control subjects) were selected from women enrolled in the National Institute of Child Health and Human Development's Preterm Prediction Study. Interleukin 6 concentrations were determined by enzyme-linked immunosorbent assay in cervical swabs obtained at 22 weeks' to 24 weeks 6 days' gestation. Cutoffs to define an elevated interleukin 6 concentration included the 90th and 95th percentiles for control subjects (>305 and >538 pg/mL, respectively). RESULTS: The mean (+/-SD) interleukin 6 concentration was significantly higher in case patients than in control subjects (212 +/- 339 vs 111 +/- 186 pg/mL; P = .008). With either cutoff value elevated interleukin 6 concentration was significantly associated with spontaneous preterm birth (90th percentile, 20% vs 9.6%; P = .02; 95th percentile, 12% vs 4.8%; P = .04). Cervical interleukin 6 levels were highest within 4 weeks of delivery, and the trend continued until term. Elevated interleukin 6 concentration was not significantly associated with bacterial vaginosis, maternal body mass index <19.8 kg/m2, or a short cervix (< or = 25 mm), but it was significantly associated with a positive cervicovaginal fetal fibronectin test result (90th percentile, odds ratio, 5.5; 95% confidence interval, 2.6-11.9; 95th percentile, odds ratio, 5.3, 95% confidence interval, 2.1-12.9). The mean interleukin 6 concentration among women with a positive fibronectin test result was 373 +/- 406 pg/mL; that among women with a negative fetal fibronectin test result was 130 +/- 239 pg/mL (P = .001). In a regression analysis that adjusted for risk factors significantly associated with spontaneous preterm birth in this population (positive fetal fibronectin test result, body mass index <19.8 kg/m2, vaginal bleeding in the first or second trimester, previous spontaneous preterm birth, and short cervix) elevated cervical interleukin 6 concentration was not independently associated with spontaneous preterm birth (odds ratio, 1.8; 95% confidence interval, 0.8-4.3). CONCLUSIONS: At 24 weeks' gestation cervical interleukin 6 concentration in women who subsequently had a spontaneous preterm birth at <35 weeks' gestation was significantly elevated relative to those who were delivered at term. The association was particularly strong within 4 weeks of testing. A positive fetal fibronectin test result was strongly associated with elevated cervical interleukin 6 concentration, but bacterial vaginosis was not.

The preterm prediction study: maternal serum relaxin, sonographic cervical length, and spontaneous preterm birth in twins.

OBJECTIVE: The risk of spontaneous preterm birth has been related to decreased cervical length and to increased serum relaxin. To explore a relationship between these findings, we used data collected from two prior studies to correlate relaxin levels with cervical length and risk of spontaneous preterm birth in women with twin pregnancies. METHODS: In a secondary analysis of data collected in two previous observational studies of risk factors for preterm birth, relaxin levels in maternal serum and cervical length were measured at 24 (n= 188) and 28 (n= 145) weeks in women with spontaneous twin pregnancies. Relaxin, as a continuous variable, was related by logistic regression analysis to risk of spontaneous preterm birth before 37, 35, and 32 weeks' gestation, and by Spearman correlation coefficients to cervical length at 24 and 28 weeks. Cervical length at 24 weeks was known to be correlated with spontaneous preterm birth before 37, 35, and 32 weeks (P =.03,.01, and.002, respectively) in this study population. RESULTS: Cervical length did not correlate with relaxin levels at 24 (P=.601) or 28 (P=.304) weeks. Relationships between relaxin and spontaneous preterm birth were observed at 24 weeks for births before 37 weeks (odds ratio [OR] 1.56, 95% confidence interval [CI] 1.00, 2.44; P=.05), and at 28 weeks for births before 35 weeks (OR 1.97, 95% CI 1.05, 3.70; P=.034) and 32 weeks (OR 2.43, 95% CI 1.01, 5.83; P=.048). CONCLUSION: The absence of an association between relaxin and cervical length suggests that increased relaxin does not explain the inverse correlation between cervical length and spontaneous preterm birth in women with spontaneous twin pregnancies.

Preterm prediction study: is socioeconomic status a risk factor for bacterial vaginosis in Black or in White women?

Bacterial vaginosis (BV), an important risk factor for preterm birth, is a more common infection in Black compared with White pregnant women. Because Black women in the United States are more likely to have lower measures of socioeconomic status (SES), this study examined the hypothesis that BV is associated with low SES. The project evaluated data from the Preterm Prediction Study of 2,929 women prospectively followed during their pregnancies. The women, who were screened for BV at 24 and 28 weeks of gestation, underwent a structured interview to evaluate demographic factors, SES, home and work environment, drug or alcohol use, and prior medical history. Black women in the study had many measures of lower SES compared with the White women, and reported less use of tobacco, alcohol and drugs. In neither the Black nor White women was an association found between BV and measures of SES (with the sole exception of "absence of a home telephone"). Most measures of SES do not explain the difference in rates of BV in Black and in White pregnant women.

Effect of digital cervical examination on the expression of fetal fibronectin.

OBJECTIVE: To determine whether oncofetal fibronectin (fFN) assays from symptomatic women are influenced by digital examination of the cervix. STUDY DESIGN: Cervicovaginal fFN specimens were obtained from women at 22-34 weeks' gestational age with symptoms of preterm labor immediately prior to a digital examination of the cervix and two hours after. Fetal fibronectin was assayed by a specific enzyme-linked immunoassay. Results were reported as positive (> or = 50 ng/mL) or negative (< 50 ng/mL). Paired initial and repeat fFN results were compared for statistical difference, and the clinical outcomes were used to assess the accuracy of the initial and repeat results. RESULTS: Fifty symptomatic women at an average gestational age of 29.3 +/- 2.0 weeks were enrolled. Eighty-six percent of the repeat fFN results remained unchanged after a digital examination, (P = .26, beta = .2). The predictive value of a negative fFN obtained after a digital examination was 97% for the absence of spontaneous preterm delivery in < 8 or < 15 days. Two of 16 initially positive results became negative after an examination, and one patient delivered two days later. Five of 34 initially negative fFN results became positive after an examination, and 5/5 delivered more than seven days later. CONCLUSION: Digital examination of the cervix has an effect on fFN results. The routine use of fFN after a digital examination is not recommended.

The preterm prediction study: failure of midtrimester cervical sialidase level elevation to predict subsequent spontaneous preterm birth.

OBJECTIVE: Our objective was to determine any associations among midtrimester cervical fluid sialidase activity, bacterial vaginosis, and subsequent spontaneous preterm birth. STUDY DESIGN: In this nested case-control study all patients (n = 126) with spontaneous preterm birth at <35 weeks' gestation and selected control subjects delivered at >/=37 weeks' gestation (n = 126, matched for race, parity, and center) were derived from women enrolled in the multicenter National Institute of Child Health and Human Development Preterm Prediction Study. Sialidase activity and presence of bacterial vaginosis according to Gram stain were determined in cervical swabs and vaginal smears, respectively, obtained at 22 weeks' to 24 weeks 6 days' gestation. RESULTS: The mean +/- SD sialidase activities were similar in case patients and control subjects (0.64 +/- 1.60 vs 0.41 +/- 0.94 nmol. mL-1. min-1, P =.21). Neither sialidase activity above the 90th percentile (10.3% vs 9.5%, P =.8) nor sialidase activity above the 95th percentile (7.9% vs 4. 8%, P =.3) of control specimens (>1.43 and >2.23 nmol. mL-1. min-1, respectively) was associated with spontaneous preterm birth. The frequency of combinations of bacterial vaginosis and elevated sialidase activity was similar (P >/=.63 with either cutoff) in case patients and control subjects. Sialidase activity was significantly higher among women with bacterial vaginosis than among those without bacterial vaginosis (1.35 +/- 1.87 vs 0.03 +/- 0.14 nmol. mL-1. min-1, P <.0001). CONCLUSIONS: Elevated cervical fluid sialidase activity at 22 to 24 weeks' gestation did not distinguish women at increased risk for spontaneous preterm birth, nor did it discriminate a subgroup of patients who had bacterial vaginosis associated with spontaneous preterm birth.

Regulation of parturition update. Endocrine and paracrine effectors of term and preterm labor.

This article summarizes the role of endocrine and paracrine mediators of human parturition. Gonadal steroids (17 beta--estradiol and progesterone) mediate many of the decidual and uterine contractile functions during early events in labor. Proinflammatory cytokines and chemokines orchestrate many of the events triggering or sustaining active labor at term and in the preterm setting. Several autacoids (prostaglandins, platelet-activating factor) serve proximal activities such as uterine contractility and remodeling of the cervical extracellular matrix leading to dilatation and effacement. As the biochemical participants during parturition become more clearly understood, it will be possible to develop improved surveillance, management, and treatment strategies for preterm labor.

Obstetric determinants of neonatal survival: influence of willingness to perform cesarean delivery on survival of extremely low-birth-weight infants. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.

OBJECTIVE: Our purpose was to evaluate the relationship between the approach to obstetric management and survival of extremely low-birth-weight infants. STUDY DESIGN: In this prospective observational study we evaluated 713 singleton births of infants weighing < or = 1000 gm during 1 year at the 11 tertiary perinatal care centers of the National Institutes of Child Health and Human Development network of maternal-fetal medicine units. Major anomalies, extramural delivery, antepartum stillbirth, induced abortion, and gestational age < 21 weeks were excluded. The obstetrician's opinion of viability and willingness to perform cesarean delivery in the event of fetal distress were ascertained from the medical record or interview when documentation was unclear. Grade 3 and 4 intraventricular hemorrhage, grade 3 and 4 retinopathy of prematurity, necrotizing enterocolitis requiring surgery, oxygen dependence at discharge or 120 days, and seizures were considered serious morbidity. Survival without serious morbidity was considered intact survival. Logistic regression was used to evaluate the influence of the approach to obstetric management, adjusted for birth weight, growth, gender, presentation, and ethnicity. RESULTS: Willingness to perform cesarean delivery was associated with increased likelihood of both survival (adjusted odds ratio 3.7, 95% confidence interval 2.3 to 6.0) and intact survival (adjusted odds ratio 1.8, 95% confidence interval 1.0 to 3.3). Willingness to intervene for fetal indications appeared to virtually eliminate intrapartum stillbirth and to reduce neonatal mortality. Below 800 gm or 26 weeks, however, willingness to perform cesarean delivery was linked to an increased chance of survival with serious morbidity. Although obstetricians were willing to intervene for fetal indications in most cases by 24 weeks, willingness to perform cesarean delivery was associated with twice the risk for serious morbidity at that gestational age. CONCLUSIONS: The approach to obstetric management significantly influences the outcome of extremely low-birth-weight infants. Above 800 gm or 26 weeks the obstetrician should usually be willing to perform cesarean delivery for fetal indications. Between 22 and 25 weeks willingness to intervene results in greater likelihood of both intact survival and survival with serious morbidity. In these cases patients and physicians should be aware of the impact of the approach to obstetric management and consider the likelihood of serious morbidity and mortality when formulating plans for delivery.

Fetal fibronectin improves the accuracy of diagnosis of preterm labor.

OBJECTIVE: Our purpose was to assess the utility of cervicovaginal expression of fetal fibronectin in the diagnosis of preterm labor. STUDY DESIGN: Women seen between 24 and 34 weeks' gestation with symptoms of preterm labor, intact membranes, and cervical dilatation < 3 cm were enrolled at five university medical centers. Cervicovaginal swabs were obtained and assayed for the presence of fetal fibronectin by means of a monoclonal antibody assay. Results were compared with cervical dilatation and uterine contraction frequency as indicators of interval to delivery and delivery before 37 weeks. RESULTS: A total of 192 eligible women at a mean gestational age of 30.8 +/- 2.9 weeks were enrolled from a population of 418 subjects screened. The rate of preterm birth was 32.3% (62/192). The mean interval from presentation to delivery was 25.3 +/- 24.1 days in the 45 subjects with a positive fibronectin assay and 52.4 +/- 24.8 days in the 147 subjects with a negative assay (p = 0.0001). The sensitivity, specificity, and positive and negative predictive values of fetal fibronectin expression for delivery < 37 weeks were 44% (27/62), 86% (112/130), 60% (27/45), and 76% (112/147). The fetal fibronectin assay was especially useful in predicting risk of delivery within 7 days (sensitivity 93% [13/14], specificity 82% [146/178], positive predictive value 29% [13/45], and negative predictive value 99% [146/147]) and was notably superior to both cervical dilatation > 1 cm and contraction frequency greater than or equal to eight per hour (sensitivities 29% and 42%, specificities 82% and 67%, positive predictive values 11% and 9%, and negative predictive values 94% and 94%, respectively. CONCLUSION: Cervicovaginal fetal fibronectin predicts delivery within 7 days more accurately than do cervical dilatation and contraction frequency in a population of women evaluated for early preterm labor.

Effect of prolonged oral terbutaline therapy on glucose tolerance in pregnancy.

OBJECTIVE: Our objective was to elucidate the pathophysiologic effects and potential reversibility of terbutaline-induced changes in carbohydrate metabolism. STUDY DESIGN: We prospectively evaluated serum glucose, insulin, glucagon, C-peptide, and pancreatic polypeptide levels in response to a 100 gm glucose challenge (oral 3-hour glucose tolerance test) in 17 obstetric patients without complications who were given terbutaline (5 mg orally every 4 hours) for 5 consecutive days between 24 and 32 weeks' gestation. Each patient served as her own control, with day 1 representing pretreatment, day 7 the treatment phase, and day 14 the posttreatment evaluation. Body mass index and posttreatment serum terbutaline levels were also measured. RESULTS: A significant initial treatment effect (day 1 versus 7) was observed for glucose (elevated), insulin (elevated), insulin/glucose ratio (elevated), and pancreatic polypeptide (elevated). A significant delayed treatment effect (day 1 versus 14) was also observed for insulin (elevated), insulin/glucose ratio (elevated), and pancreatic polypeptide (elevated). Body mass index directly correlated with postchallenge measures of insulin, insulin/glucose ratio, pancreatic polypeptide, and C-peptide. Posttreatment serum terbutaline levels directly correlated with pancreatic polypeptide, but not with other parameters. CONCLUSIONS: Our data support a dose-independent, terbutaline-induced glucose intolerance mediated by glucagon and caused by diminished insulin sensitivity.

Proinflammatory cytokines interact synergistically with epidermal growth factor to stimulate PGE2 production in amnion-derived cells.

Recent evidence has implicated cytokines and growth factors in the initiation of parturition in women. In the present study, the amnion-derived cell line WISH was used to determine whether proinflammatory cytokines (interleukins 1 beta, 6, and 8, tumor necrosis factor-alpha, and granulocyte/macrophage colony stimulating factor) could amplify epidermal growth factor-induced prostaglandin E2 production. WISH cells were preincubated with cytokines (0.0001-10 ng/ml) for 60 min and then challenged with EGF (10 ng/ml) for 4 hrs after which PGE2 production was measured by radioimmunoassay. EGF, IL-1 beta and TNF-alpha alone caused a dose-dependent increase in PGE2 production, while IL-6, IL-8 and GM-CSF were ineffective over the dose range tested. When cells were preincubated with IL-1 beta or TNF-alpha, there was a dose-dependent potentiation of EGF-induced PGE2 production that was greater than the sum of EGF alone and IL-1 beta or TNF-alpha alone. In each case, the minimum dose of IL-1 beta or TNF-alpha which amplified EGF-induced PGE2 production was 0.1 ng/ml (p less than 0.05, Student's t-test). These data show that low concentrations of IL-1 beta or TNF-alpha may serve to amplify EGF-mediated PGE2 biosynthesis in amnion-derived cells and suggest that cytokines may modulate EGF function in responsive cells.

Etiology of preterm premature rupture of membranes.

Numerous factors have been indicted as playing a role in causing preterm premature rupture of membranes (PPROM). After discussing the development of the amnion and chorion, this article focuses primarily on the effects that infection, nutrition, smoking, and cervical incompetence have on the fetal membrane and the subsequent advent of PPROM. However, evidence continues to support a multifactorial etiology for this entity, with numerous factors acting in concert.

Spontaneous regression of a large intrathoracic fetal lesion before birth.

All fetal intrapulmonary lesions diagnosed antenatally reported in the literature to date have persisted as an ultrasound finding for the remainder of the pregnancy, although spontaneous improvement in utero has been reported recently. We describe a case of a large intrathoracic lesion diagnosed at 24 weeks' gestation by ultrasound that became indistinguishable from the rest of the lungs as the pregnancy approached term. Although the frequency with which this process occurs cannot yet be assessed, the possibility of significant spontaneous regression must now be considered when counseling the parents on an affected fetus.

Does extra-amniotic infection cause preterm labor? Gas-liquid chromatography studies of amniotic fluid in amnionitis, preterm labor, and normal controls.

Gas-liquid chromatography (GLC) was used to identify short-chain organic acid byproducts of bacterial metabolism in amniotic fluid from seven normal control patients, six women with overt amnionitis, and six preterm labor patients. Microbiologic culture for aerobic and anaerobic bacteria was also carried out. Positive GLC findings were generally associated with positive cultures, except in five of the preterm labor patients whose GLCs were positive despite negative cultures. The origin of the short-chain organic acids found in these women is unclear; extra-amniotic bacterial growth may explain this finding.

Capillary gas chromatographic-mass spectrometric profiles of trimethylsilyl derivatives of organic acids from amniotic fluids of different gestational age.

Amniotic fluid from different gestational age patients was partitioned into neutral, acidic and basic fractions. The organic acids were trimethylsilylated and analyzed by glass capillary gas chromatography-mass spectrometry. A marked difference in the level of hippuric acid was observed between samples from early (15-22 weeks) and late (30-38.5 weeks) pregnancy. This difference probably reflects the degree of maturity in the fetal liver and kidney. The procedures establish amniotic fluid profiles of substances of varying gestational age and should be useful in determining alterations caused by diseases.