Role of cytokines in preterm labor and birth

Preterm birth (defined as delivery prior to 37 weeks' gestation) complicates 5-10% of all births. It is a major cause of perinatal mortality and morbidity. Approximately 20% of all preterm births are iatrogenic resulting from obstetric intervention for maternal and/or fetal indications. Of the remainder, 2/3 are spontaneous preterm labor with or without preterm premature rupture of the membranes (pPROM). Preterm labor is a syndrome rather than a diagnosis since the etiologies are varied. Risk factors include, among others, pPROM, cervical insufficiency, pathologic uterine distention (polyhydramnios, multiple gestation), uterine anomalies, intrauterine infection/inflammation, and social factors (stress, smoking, heavy work). The final common pathway appears to be activation of the inflammatory cascade. Bacterial colonization and/or inflammation of the choriodecidual interface induces production of pro-inflammatory cytokines that, in turn, lead to neutrophil activation and the synthesis and release of uterotonins such as prostaglandins (which cause uterine contractions) and metalloproteinases (that weaken fetal membranes and remodel cervical collagen). This monograph reviews the role of cytokines in the pathophysiology of preterm labor and delivery.     

Fetal membrane inflammatory cytokines: a switching mechanism between the preterm premature rupture of the membranes and preterm labor pathways

Inflammatory cytokines are involved in both preterm labor and preterm premature of the membranes pathways; however, the interaction between TNF-alpha and its receptors may dictate the clinical outcome of pregnancy.     

Evaluation of amniotic fluid cytokines in preterm labor and intact membranes.

OBJECTIVE: To compare the amniotic fluid (AF) concentration of pro-inflammatory cytokines between women with preterm labor and intact membranes that delivered within 7 days, with those that delivered after 7 days of the amniocentesis according to the result of the AF culture. METHODS: Fifty-two women with preterm labor and intact membranes between 21 and 35 weeks of gestation were included in the study. Transabdominal amniocentesis was performed to rule out intra-amniotic infection, and AF concentrations of interleukin-1alpha (IL-1alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor (TNF) were determined with sensitive and specific enzyme-linked immunosorbent assays. Amniotic fluid was cultured for aerobic and anaerobic bacteria, Ureaplasma urealyticum, and Mycoplasma hominis. Exclusion criteria included preterm premature rupture of membranes, vaginal bleeding, multiple gestations, uterine anomalies, fetal congenital anomalies, ominous fetal heart rate tracings and fetal deaths. Proportions were compared using chi2 or Fisher's exact test. Receiver operator characteristic (ROC) curve analysis was performed for each cytokine for the prediction of delivery within 7 days. RESULTS: Sixty-two percent (32/52) of women delivered within 7 days and 38% (20/52) delivered after 7 days of amniocentesis. All women that delivered after 7 days of the procedure had negative AF cultures. In contrast, 28% (9/32) of women that delivered within 7 days had positive AF cultures and 72% (23/32) had negative AF cultures. Women that delivered within 7 days regardless of AF cultures had a lower birth weight and a shorter amniocentesis-to-delivery interval than those that delivered after 7 days of amniocentesis. Among women that delivered within 7 days, those with positive AF cultures had a lower gestational age at delivery and a higher frequency of histologic chorioamnionitis than those with negative AF cultures. The AF concentrations of all cytokines were significantly higher in women that delivered within 7 days with positive AF cultures than in those with negative AF cultures. Similarly, the AF concentrations of IL-1alpha, IL-6, and IL-8 were significantly higher in women that delivered within 7 days than those that delivered after 7 days of the amniocentesis, regardless of the AF culture results. Diagnostic indexes were calculated for all cytokines using critical values derived from ROC curve analysis for the prediction of delivery within 7 days. CONCLUSIONS: Women with preterm labor and intact membranes that delivered within 7 days had higher AF concentrations of pro-inflammatory cytokines than those who delivered after 7 days of the amniocentesis regardless of the AF culture results.     

Fetal fibronectin and bacterial vaginosis are associated with preterm birth in women who are symptomatic for preterm labor

OBJECTIVE: The purpose of this study was to codify the relationship between bacterial vaginosis/fetal fibronectin and preterm labor/birth. STUDY DESIGN: In this prospective study, 185 women who were symptomatic for preterm labor were assessed for bacterial vaginosis and fetal fibronectin. RESULTS: These women comprised 4 groups: group A (n=23 women; +bacterial vaginosis/+fetal fibronectin); group B (n=31 women; -bacterial vaginosis/+fetal fibronectin); group C (n=47 women; +bacterial vaginosis/-fetal fibronectin); and group D (n=84 women; -bacterial vaginosis/-fetal fibronectin). The time interval from gestational age at testing until delivery was significantly shorter for groups A and B versus groups C and D (P < or =.05 and P <.001, respectively). Similarly, delivery at <32 weeks of gestation was increased in group B (26%) compared with groups A (9%), C (2%), and D (5%; P <.009; odds ratio, 165.90; 95% CI, 30.02, 916.08). CONCLUSION: Women who are symptomatic for preterm labor should be considered for fetal fibronectin and bacterial vaginosis testing.     

Blood pH and gases in fetuses in preterm labor with and without systemic inflammatory response syndrome

Objective: Fetal hypoxemia has been proposed to be one of the mechanisms of preterm labor (PTL) and delivery. This may have clinical implications since it may alter: (i) the method/frequency of fetal surveillance and (ii) the indications and duration of tocolysis to an already compromised fetus. The aim of this study was to examine whether there is a difference in the fetal blood gas analysis [pH, PaO₂ and base excess (BE)] and in the prevalence of fetal acidemia and hypoxia between: (i) patients in PTL who delivered within 72 hours vs. those who delivered more than 72 hours after cordocentesis and (ii) patients with fetal inflammatory response syndrome (FIRS) vs. those without this condition. Study design: Patients admitted with PTL underwent amniocentesis and cordocentesis. Ninety women with singleton pregnancies and PTL were classified according to (i) those who delivered within 72 hours (n?=?30) and after 72 hours of the cordocentesis (n?=?60) and (ii) with and without FIRS. FIRS was defined as a fetal plasma concentration of IL-6?>?11 pg/mL. Fetal blood gases were determined. Acidemia and hypoxemia were defined as fetal pH and PaO₂ below the 5th percentile for gestational age, respectively. For comparisons between the two study groups, ΔpH and ΔPaO₂ were calculated by adjusting for gestational age (Δ?=?observed value – mean for gestational age). Non-parametric statistics were employed. Results: No differences in the median Δ pH (?0.026 vs. ?0.016), ΔPaO₂ (0.25 mmHg vs. 5.9 mmHg) or BE (?2.4 vs. ?2.6 mEq/L) were found between patients with PTL who delivered within 72 hours and those who delivered 72 hours after the cordocentesis (p?>?0.05 for all comparisons). Fetal plasma IL-6 concentration was determined in 63% (57/90) of fetuses and the prevalence of FIRS was 28% (16/57). There was no difference in fetal pH, PaO₂ and BE between fetuses with and without FIRS (p?>?0.05 for all comparisons). Moreover, there was no difference in the rate of fetal acidemia between fetuses with and without FIRS (6.3 vs. 9.8%; p?>?0.05) and fetal hypoxia between fetuses with or without FIRS (12.5 vs. 19.5%; p?>?0.05). Conclusions: Our data do not support a role for acute fetal hypoxemia and metabolic acidemia in the etiology of PTL and delivery.     

Infection and preterm labor

There are many conditions, such as non-white race, young maternal age, and uterine malformations, that have been associated with preterm birth that are not amenable to intervention. Maternal cervical and intrauterine infection and inflammation may have a primary causative role in a fraction of the cases of preterm birth and preterm rupture of membranes and may also interact adversely with a variety of maternal (shortened cervix, smoking) and fetal factors (polyhydramnios, multifetal gestation) to decrease the threshold to preterm birth. Further studies are needed to better-define the link between various maternal microbial colonizations and preterm delivery, with the possibility to establish new screening and treatment recommendations. Because of the innumerable causes of preterm birth, a new strategy of targeted treatment of cervical or vaginal infections may lead to only a modest reduction in the incidence of this devastating problem of modern obstetrics.     

Antibiotics and preterm labor

In summary, a definite association has been demonstrated between preterm labor and genital tract infection. Conclusions regarding the true benefits of antibiotics as adjunctive therapy in treatment of preterm labor are inconsistent. Whereas some of the studies were able to demonstrate significant prolongation of pregnancy, no consistent reduction in either maternal or neonatal morbidity has been demonstrated. However, because the actual incidental morbidity rate is low in the populations studied, the power of this finding is also low. The potential risks for using antimicrobials has yet to be adequately addressed. It has been shown that bacterial resistance can develop when antibiotics are used without specific aim or when a specific bacteria is undertreated. It has been recently shown that prenatal and intrapartum antibiotic use is associated with an increased risk for antibiotic resistant neonatal sepsis if infection occurs. Because of these reasons, we discourage the administration of antibiotic treatment to women in preterm labor for the purpose of pregnancy prolongations. Treatment should be directed towards those with specific indications for treatment (e.g., intrapartum, group B streptococci prophylaxis, urinary tract infection, etc). The primary flaw in these many evaluations of preterm labor is the true incidence of preterm birth. The clinical diagnosis of preterm labor is a difficult one. Approximately one-half of those individuals with preterm contractions will not deliver until term. So, the use of antibiotics for all women in idiopathic preterm labor is destined to treat many women who are unlikely to benefit. If we were able to truly identify those who were in "true" labor, perhaps we could be more selective in determining who may benefit from antibiotics. Biochemical markers such as onco-fetal fibronectin could well-be a helpful marker. Goldberg et al evaluated FFN in vaginal and cervical secretions while attempting to better-predict who would have upper genital tract infection. In this large, multicenter trial, patients were tested for FFN every 2 weeks from 23 to 30 weeks gestation. In those patients who proceeded to deliver before 32 weeks gestation, increased levels of cervical FFN (> 50 ng/ml) were identified in approximately one-quarter. Fetal fibronectin was positive in 4% of their samples and was found to be twice as likely in one with bacterial vaginosis. They showed that the presence of increased FFN was associated with upper genital tract infection (clinical and histologic chorioamnionitis) as a main reason for preterm labor and delivery (increased risk 16-20-fold). Those with increased FFN levels were also shown to have an increased incidence of neonatal sepsis as well. Peaceman et al used FFN to attempt to identify those at risk for preterm delivery among women with contractions between 24 and 34 6/7 weeks gestation. Those with negative FFN were less likely to deliver within 7 days of the test. The negative predictive value was 99.7%, suggesting that this test may be helpful in identifying women who would not benefit from antibiotic treatment. However, if in the absence of prospective clinical trials demonstrating the efficacy of this approach, we discourage the use of FFN screening for this indication.     

Uterine electromyography characteristics for early diagnosis of mifepristone-induced preterm labor

OBJECTIVE: Differentiating uterine contractions leading to preterm birth from ineffective uterine activity is difficult with current tools. Uterine electromyographic activity is recordable and consists of bursts (group of action potentials) characterized by characteristics that are different during pregnancy and labor. Our aim was to identify the chronology of the changes in uterine pressure and electromyographic characteristics during mifepristone-induced preterm labor in pregnant rats and to determine the earliest characteristic to change. METHODS: On day 17 of gestation, intrauterine catheter and electromyography electrodes were implanted in the uterus. On day 18, rats were allocated for treatment with mifepristone or placebo. Intrauterine pressure and electromyography integral activities and electromyography mean were calculated before treatment and 6, 12, 18, 20, 22, and 24 hours after treatment. After mathematical transformation, burst analysis was performed by using power density spectrum energy, peak amplitude, and frequency. RESULTS: As expected, delivery rate within 24 hours was higher in the mifepristone-treated group. Changes in electromyography integral activity and mean, power density spectrum energy, and intrauterine pressure integral activity occurred late during preterm labor, in a range of 2-4 hours before delivery. Electromyography peak frequency of the power density spectrum exhibited early changes, with a shift from low to high frequencies starting at 12 hours before delivery. CONCLUSION: Electromyography peak frequency of the power density spectrum from individual bursts was the first characteristic to change after antiprogestin treatment, preceding any change in intrauterine pressure, making it a potentially useful marker for the early diagnosis of preterm labor.     

Abnormal glucose tolerance is associated with preterm labor and increased neonatal complications in Taiwanese women

ObjectiveTo investigate the relationship between abnormal degrees of oral glucose tolerance test (OGTT) results and pregnancy outcomes.Materials and methodsA total of 7513 singleton pregnancies screened for gestational diabetes mellitus were enrolled in this retrospective observational study. The pregnancy outcomes of six different groups with different degrees of glucose intolerance using the OGTT were compared [both the National Diabetes Data Group (NDDG) and Carpenter and Coustan (C&C) criteria were used]. The pregnancies were classified into the following groups: the normal group, consisting of pregnancies with a negative 50-g glucose challenge test (GCT), and Grade 0, 1, 2, 3 and 4 groups, consisting of pregnancies with positive 50-g GCT, and abnormal values of 0, 1, 2, 3 and 4 from the 100-g OGTT, respectively.ResultsThe adjusted odds ratios (95% confidence interval) for preterm labor and admission to the neonatal intensive care unit (NICU) were shown to be increased in the Grade 4 groups [3.31 (1.47–7.43) and 6.31 (3.14–12.70) by the NDDG criteria; 4.13 (2.30–7.43) and 5.25 (3.00–9.19) by the C&C criteria] compared with the normal group.ConclusionThe results indicated an increased risk for preterm labor and admission to the NICU as the abnormal value of the OGTT increased.     

Cervical incompetence and preterm labor

The ability of the cervix to function as a competent sphincter to retain the fetoplacental unit in utero until term is dependent on a complex set of biochemical, biophysical, and environmental events. The understanding of these interactions is limited at present and requires that cervical incompetence be a diagnosis of exclusion. Currently, differentiation of cervical incompetence from preterm labor is a major problem. Advances in ultrasonography, ambulatory uterine activity monitoring, cervical histomorphology, and biochemistry should improve the understanding of both normal and abnormal cervical and uterine function and may provide new techniques to distinguish between true cervical incompetence and preterm labor. Well-designed and strictly executed randomized clinical trials of cervical cerclage should answer the question of therapeutic efficacy for this popular technique when the diagnosis of cervical incompetence is made.     

Intrauterine infection and preterm labor

Preterm birth remains the leading cause of perinatal mortality and morbidity. Evidence suggests that intrauterine infection plays an important role in the pathogenesis of preterm labor. This article reviews the clinical data supporting this theory and the cellular and biochemical mechanisms by which intrauterine infection may initiate uterine contractions. The clinical and laboratory methods of diagnosing clinical chorioamnionitis and asymptomatic bacterial invasion of the intraamniotic cavity are also reviewed. Finally, the management of clinical chorioamnionitis and asymptomatic microbial invasion of the amniotic fluid and the use of adjunctive antibiotic therapy in the treatment of preterm labor are presented.     

Phenotypic and metabolic characteristics of maternal monocytes and granulocytes in preterm labor with intact membranes.

OBJECTIVE: Experimental and clinical studies support a role for the fetus in the control of the onset of labor. Fetal systemic inflammation, but not a maternal inflammatory response, has been linked to the onset of preterm labor and delivery on the basis of the determination of inflammatory cytokines in fetal and maternal blood. We propose that parturition requires fetomaternal cooperation and that inflammation is an integral part of the parturitional process. This study used flow cytometry, a sensitive technique for the detection of intravascular inflammation, to assess whether maternal inflammation is present in preterm labor. STUDY DESIGN: A prospective cross-sectional study was performed including patients with preterm labor (n = 55) and women with normal pregnancy (n = 50). Intravascular inflammation was studied by using flow cytometry. Maternal blood was assayed to determine granulocyte and monocyte phenotype by using monoclonal antibodies, which included the following cluster of differentiation (CD) markers: CD11b, CD14, CD15, CD16, CD18, CD49d, CD62L, CD64, CD66b, and HLA-DR. Oxidative burst and generation of basal intracellular oxygen radical species were assessed. Statistical analysis was conducted with the use of nonparametric methods. A P value of <.01 was considered statistically significant. RESULTS: Preterm labor was associated with a significant increase in the median mean channel brightness of CD11b, CD15, and CD66b on granulocytes and median mean channel brightness of CD11b and CD15 on monocytes. The ratio of oxidative burst over basal intracellular oxygen radical species in both granulocytes and monocytes was increased in preterm labor (P <. 01). CONCLUSION: Preterm labor with intact membranes is associated with phenotypic and metabolic changes of maternal granulocytes and monocytes.     

Late pregnancy associated plasma protein A levels decrease in preterm labor

Objective.?The purpose of the present study is to evaluate late, ‘at admission’, Pregnancy-associated plasma protein-A (PAPP-A) levels as a predictor of preterm birth in women with complaints of preterm labor or preterm painful contractions.

Methods.?Prospective cohort study of singleton gestations, 23–37 weeks, and symptoms of preterm labor. Primary end point was delivery?<?37 weeks. Predictive PAPP-A values were calculated both for preterm delivery and threatened preterm delivery on receiver operator curve.

Results.?In all, 41 women (38.3%) delivered before 37 weeks (Group 1); 32 women (30.7%) had symptoms of preterm labor but did not deliver preterm (Group 2); 31 women (29.7%) delivered term (Group 3, control). Mean PAPP-A levels in preterm-labor and its matched control were 33.4?±?19.9 and 52.5?±?25.4?mIU/ml, respectively, and difference was statistically significant (p?=?0.003). Mean PAPP-A level in threatened preterm labor group was 47.6?±?25.3?mIU/ml and difference was significant compared to preterm-labor, but not significant compared to control group (p?=?0.028 and p?=?0.74, respectively).

Conclusion.?Late PAPP-A levels decreased in preterm labor, levels?<?29.8?mIU/ml was associated with increased risk for preterm birth, supporting active management whereas cutoff value of 33.6?mIU/ml is useful for discrimination of preterm birth from threatened preterm birth reaching to term.