Labor, and in particular preterm labor (PTL), has been shown to be an inflammatory event.1–3 Infection is thought to be the initiating stimulus in many cases of premature delivery, with the ensuing proinflammatory response leading to a cascade of events in the fetal membranes and myometrium, resulting in cervical ripening and uterine contractions. Similarly, chorioamnionitis has been related to proinflammatory cytokines in the fetal circulation, the “fetal inflammatory response syndrome,” which is thought to play an important role in long-term morbidity after extremely preterm birth, such as white matter injury and bronchopulmonary dysplasia. However, the role of endogenous antiinflammatory mechanisms in labor and neonatal outcome is less well described.
After a major insult such as infection, trauma, or surgery, there is an initial proinflammatory response, with increases in circulating levels of cytokines such as tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6). The inflammatory system then attempts to restore homeostasis by mounting a reactive antiinflammatory response, with increases in antiinflammatory cytokines such as interleukin-10 (IL-10). It is now clear that it is not just the extent of proinflammation that is clinically important.4 Excessive antiinflammatory as well as proinflammatory responses to an insult have also been associated with adverse clinical outcomes.5,6 It seems that it is the balance between these two inflammatory states that may be critical in determining the consequences of an inflammatory stimulus.
Work from this and other teams have shown that an insight into this inflammatory balance can be obtained by measuring major histocompatibility complex (MHC) Class II expression on monocytes7. Studies on patients in critical care have shown that reduced MHC Class II expression implies a state of “immunoparalysis,” which prevents patients from responding appropriately to prevent or limit nosocomial infection.8,9 In vitro this is manifest by a decreased TNF-α production by monocytes exposed to endotoxin.10 Multiple mechanisms are likely to be involved in the development of immunoparalysis11; IL-10 is thought to play a central role through potent inhibition of proinflammatory cytokines.9 These findings have clinical relevance; we have previously shown that a reduction in monocyte MHC Class II expression to less than 60% in the first 72 hours after cardiac surgery was associated with a 13-fold increased odds of the subsequent development of sepsis or systemic inflammation.7 Why such a reduction is associated with an increased risk of postoperative complications is currently unclear, but importantly, reversal of this state also seems to be beneficial clinically.
There has been little work examining the maternal and fetal antiinflammatory response to insults such as chorioamnionitis, but evidence from animal models suggests that antiinflammatory cytokines such as IL-10 and transforming growth factor-β1 (TGFβ1) can be neuroprotective.12,13 Similarly, there have only been a small number of studies examining monocyte MHC Class II expression during normal pregnancy and preterm labor, and the results from these were not conclusive. Overall, it seems unlikely that pregnancy itself has a major effect on MHC Class II expression,14–16 and in the one study reported, PTL also did not seem to affect levels of expression.17,18 These findings are consistent with the observation that TNFα production after stimulation of whole blood with lipopolysaccharide (LPS) was the same in healthy pregnancies and nonpregnant women.19
We investigated the following hypotheses: 1) because the onset of labor (both preterm and term) corresponds to an inflammatory stimulus, there will be systemic evidence of a reactive antiinflammatory response indicated by decreased expression of MHC Class II on monocytes and hyporesponsivity to LPS stimulation and 2) because the nature of the initiating event in preterm and term labor is likely to differ, the size of antiinflammatory response will also differ between women in labor at term and preterm. Improved understanding of the complexity of labor-related changes in inflammatory profile is relevant to understanding the mechanism of labor onset, both preterm and term, as well as postnatal complications related to altered immunity, such as sepsis.
MATERIALS AND METHODS
This prospective observational study of pregnant women booked at University College Hospital, London, was conducted from October 2003 to September 2006. The study was approved by the University College London/University College London Hospital Research Ethics Committee, and informed written consent was obtained from all participants. The following groups of women were studied: 1) nonpregnant female volunteers of reproductive age (n=17), 2) a cross-sectional cohort of women with normal healthy pregnancies, either in the first, second, or third trimesters, recruited at random during routine visits to the antenatal clinic; all eventually delivered at term. In addition to providing data about changes in inflammatory markers during normal pregnancy, all the women in this group who had a gestation matched to that of the preterm groups were selected to provide a reference group for the preterm labor (PTL) and preterm premature rupture of membranes (PROM) groups. This gestation-matched reference group included all women recruited with gestations between 24 and 32 weeks (n=15), 3) women having an elective (prelabor) cesarean delivery after 37 weeks of gestation n=23), 4) women admitted in spontaneous labor after 37 weeks of gestation, at 4 cm or more cervical dilatation with regular uterine contractions (n=29), and 5) women with preterm PROM or PTL at less than 32 completed weeks of gestation, in labor (at 4 cm or more cervical dilatation with regular uterine contractions) (PTL n=26, preterm PROM n=25). We excluded women if they had the following complications: immunosuppressive disorders, preeclampsia, gestational diabetes mellitus or preexisting diabetes mellitus, or if there was a congenital anomaly detected antenatally. Women were also excluded from the normal pregnancy group if they had evidence of infection. Women were considered to have clinical chorioamnionitis if they had a combination of maternal pyrexia of 38°C or more with uterine tenderness and/or offensive vaginal discharge. The placenta was collected routinely in all women delivering before 32 weeks of gestation and histologic chorioamnionitis was diagnosed if there was polymorph infiltration of the amnion and chorion.
We collected heparinized blood samples (10 Internation Units/mL) and analyzed them in vitro within 20 minutes to minimize artifact from monocyte adherence and activation. Blood was sampled once in established labor (regular uterine contractions and cervical dilatation of 4 cm or more) in the PTL, preterm PROM, and term spontaneous labor groups. In the elective cesarean delivery group, blood was sampled before epidural anesthesia. Blood was taken from nonlaboring women in normal pregnancy at routine antenatal visits.
A dual-staining technique was used to determine monocyte MHC Class II expression. Monocytes were identified by size, granularity, and by using an R-phycoerythrin conjugated antibody to CD14 (TUK4, Dako, Ely, UK). MHC Class II expression was determined with fluorescein isothiocyanate conjugated antibody to MHC Class II (CR3/43, Dako). Fifty microliters of whole blood was incubated with 5 μL of each of the antibodies for 10 minutes at room temperature. Red cells were then removed by lysis with FACS lysing solution (Becton Dickson, Oxford, UK), and the samples were fixed in 1% formaldehyde and 0.1% sodium azide (CellFIX, Becton Dickson). The cells were analyzed on a FACScalibur flow cytometer by using Cellquest software (Becton Dickson). Nonspecific staining was determined with a mouse immunoglobulin G1 monoclonal antibody raised against keyhole limpet hemocyanin for MHC Class II (Dako). Monocytes were identified on physical characteristics and positive CD14 staining. Major histocompatibility complex Class II expression was determined on 2,500 events and was expressed as the percentage positive fluorescence (percentage of monocytes staining more than 98% of that observed with the negative control G1 monoclonal antibody) or as the median fluorescence intensity.
Whole blood was spun at 1,200g for 10 minutes. The plasma fraction was stored at –70°C in aliquots, to avoid interference with assay results from repeated freeze-thaw cycles. Tumor necrosis factor-α, interleukin-1β (IL-1β), IL-6, IL-8, IL-10, and IL-12p70 were assayed using a commercially available cytometric bead array kit (BD Cytometric Bead Array Human Inflammation Kit, BD Bioscience, Oxford, UK). Each bead has distinct fluorescence intensity and was coated with a capture antibody specific for one of the six cytokines. The beads were mixed together to form a suspension. Flow cytometry was used for quantification of fluorescence, using a FACScalibur. The cytometer set up beads were used to adjust the gating and compensation settings. Eighteen hundred events were recorded to ensure each sample file contained approximately 300 events per capture bead. Standard curves were generated from known concentrations, using a data program from BD CBA software, and then samples were quantified using these curves. The sensitivity of the assay was 3 pg/mL for TNFα, IL-6, IL-8, IL-10, and IL-12p70, and 100 pg/mL for IL-1β.
Whole blood was incubated with an equal volume of Roswell Park Memorial Institute 1640 with L-glutamate and 100 ng of Escherichiacoli 0111.B4 lipopolysaccharide (Sigma, Poole, UK) per mL of whole blood for 24 hours at 37°C in 5% CO2. A control sample was also prepared and incubated for 24 hours. After incubation, the supernatant was stored at –70°C in aliquots, to avoid interference with assay results from repeated freeze-thaw cycles. Cytokine concentrations were assayed using the cytometric bead array kit described above.
Analysis was performed with the Statistical Package for the Social Sciences 12.0 (SPSS Inc, Chicago, IL). To determine the effects of labor on MHC Class II expression and LPS-stimulated cytokine production, each group of women in labor were compared with an appropriate group of nonlaboring women (for PTL and preterm PROM, this was a gestation-matched reference group, and for term labor, it was women having a cesarean delivery or in the third trimester); comparisons between groups in labor and their reference groups were performed with the Mann-Whitney U test, because the data were not normally distributed. The Spearman rank correlation test was used to examine correlations among MHC Class II expression, gestational age, and cytokine levels. Sample size was based on an initial estimate designed to detect a 15% difference in MHC Class II expression between women in PTL and the reference group, with a power of 90% to detect differences at a 5% level of significance.
A total of 118 pregnant women and 17 nonpregnant controls were studied. Six women declined participation. The demographic characteristics and gestational ages of the participants are shown in Table 1. The women undergoing elective cesarean delivery at term were slightly older than the other groups and had a median parity of 1, because the most common reason for elective cesarean was a previous cesarean delivery. The women studied in the first, second, and third trimesters all went on to deliver at term. The median gestation at delivery was 26 weeks (range 23–32 weeks) for the preterm PROM group and 28 weeks (range 16–32 weeks) for the PTL group.
Pregnancy and advancing gestation did not affect the numbers of monocytes expressing MHC Class II or the intensity of its expression that remained the same as that observed in women who were not pregnant. Similarly, pregnancy and advancing gestation did not affect either the levels of cytokines in maternal blood or the cytokine response to LPS stimulation. All cytokines remained at low or nondetectable levels throughout pregnancy.
Labor at term was associated with a significant fall in the numbers of monocytes expressing MHC Class II and their intensity of staining, compared with those in the third trimester, P<.05; women having an elective cesarean delivery did not show a similar fall in MHC Class II expression (Table 2 and Fig. 1). Although the overall fall in MHC Class II expression in term labor was not pronounced, there was large individual variation, with some labors being associated with a fall in percentage expression to less than 50%, whereas in others, percentage expression remained at similar levels to those observed in the third-trimester comparison group.
Compared with women having an elective cesarean delivery, those in term labor had significantly higher median levels of the proinflammatory cytokines IL-6 (37.2, interquartile range [IQR] 13.0–65.3) compared with 1.0 (interquartile range 1.0–4.0) pg/mL, P<.01) and IL-8 (17.5 [interquartile range 11.1–23.7] compared with 9.4 [interquartile range 7.8–11.9] pg/mL, P<.01). Tumor necrosis factor-α, an early response proinflammatory cytokine, was not detected in significant amounts in any unstimulated blood sample. There were no significant differences in levels of IL-1β or IL-12 detected among the groups, and so these results are not shown. However, there was evidence of an antiinflammatory response to term labor with a small but significant increase in IL-10 compared with the elective cesarean delivery group (5.5 [interquartile range 3.8–7.7] compared with 1.0 [interquartile range 1.0–3.9] pg/mL, P<.01). Term labor was also associated with an impaired in vitro response to LPS with a significant reduction in TNFα production compared with the elective cesarean group (Fig. 2C).
Women in established preterm labor, with or without preterm PROM, had a significant fall in the numbers of monocytes expressing MHC Class II and the intensity of staining (median fluorescence intensity), compared with the reference group (Table 2 and Fig. 1). This reduction in MHC Class II expression was more extreme than the fall seen in term labor P<.01. There was no correlation between gestational age and levels of MHC Class II expression in either the PTL or preterm PROM groups.
There was no significant difference in levels of MHC Class II expression between women in the PTL group who had and had not received antenatal steroid injections. All women in the preterm PROM group had received steroids, and there was no correlation between monocyte MHC Class II expression and interval from steroid administration and labor.
Except for TNFα, which was not present, low levels of the other cytokines were detected in the PTL and preterm PROM groups. However, only IL-6 was significantly raised compared with the reference group (P<.01), and the median levels in both groups were much lower than those observed in term labor (less than 10 pg/mL). There were no correlations between monocyte MHC Class II expression and any of the cytokines assayed. The PTL and preterm PROM groups showed evidence of an attenuated response to an inflammatory stimulus with significantly smaller amounts of IL-6, IL-10, and TNF produced after in vitro LPS stimulation than gestation-matched controls (Fig. 2A, B, and C).
Overall, 42% and 76% of the PTL and preterm PROM groups had histologic evidence of chorioamnionitis, and 27% and 40% had clinical chorioamnionitis. Several different organisms were isolated from placental microbiology swabs, such as Group B Streptococcus, Listeria sp, Candida, and Mycoplasma hominis. Eighty-eight percent of women with clinical chorioamnionitis were subsequently found to have evidence of histologic chorioamnionitis. In contrast, 50% of women with histologic chorioamnionitis did not have a clinical diagnosis of chorioamnionitis.
There was no difference in monocyte MHC Class II expression between women with histologic chorioamnionitis and those without. Clinical chorioamnionitis was associated with a lower percentage of monocytes expressing MHC Class II. Median MHC Class II percent for those with clinical chorioamnionitis was 63.6% (interquartile range 37.8–87.8%) compared with 81.1% (interquartile range 56.4–92.6%) for those without. However this did not reach statistical significance. There was no significant difference in TNF production with LPS stimulation in those with or without clinical or histologic chorioamnionitis.
These data describing the expression of MHC Class II antigen on monocytes, systemic levels of cytokines with known proinflammatory and antiinflammatory actions, as well as an in vitro assessment of monocyte function, provide a comprehensive picture of the maternal immune environment during labor, both at term and preterm. The data show that labor at any gestation is associated with significant alterations in systemic markers of inflammation, with evidence that by the time labor has started there is an element of immune compromise, indicated by reduced expression of MHC Class II antigen on maternal monocytes and reduced cytokine production on stimulation in vitro with LPS. It is also clear that there are important differences between the inflammatory milieu in preterm and term labor; the fall in MHC Class II expression is greater in preterm than term labor. The failure of monocytes to respond to in vitro stimulation is also greater in the preterm groups, whereas the levels of proinflammatory cytokines are lower in the preterm groups. These differences could be summarized as indicating a more pronounced antiinflammatory environment in the preterm group, possibly as a result of the different initiating factors for term and preterm labor.
The most striking finding from this study was the fall in monocyte MHC Class II expression during spontaneous labor at term and an even greater fall in preterm labor. Our data suggest that labor at term is associated with a proinflammatory profile and that the fall in Class II expression may be consequent to this. In term labor there were increases in IL-8 and IL-6 compared with both the third-trimester and elective cesarean delivery groups. Interleukin-8 is known to play an important role in cervical ripening and dilatation and membrane rupture20–22 and is known to increase with gestational age and in labor.23 Interleukin-6 is an important inflammatory cytokine that increases levels of prostaglandins and metalloproteases and is known to be increased during labor.2,3 Evidence of an antiinflammatory response was seen in the term labor group, with a rise in plasma IL-10 levels. Interleukin-10 has been shown to downregulate monocyte MHC Class II expression through posttranslational effects24 and may contribute to the fall in monocyte MHC Class II expression observed in women in term labor. However, the nonhomogeneous nature of the fall in MHC Class II expression in term labor suggests that this might not reflect normal labor physiology, but rather that some women drop their MHC Class II expression, perhaps because of differences in genetic background, exposure to immunostimuli, or infection.
What is intriguing is that MHC Class II expression was even lower in women in PTL or after preterm PROM than those in term labor, and yet systemic levels of all cytokines were less. Levels of IL-6, but not IL-8 or TNFα, were raised. This finding is consistent with other data that vary from showing a proinflammatory cytokine response to PTL and preterm PROM3,25,26 to reporting no change.27,28 Perhaps even more surprisingly, no increase in maternal plasma IL-10 levels was seen in PTL or preterm PROM groups where the fall in monocyte MHC Class II expression was greatest. There was therefore no correlation between circulating IL-10 levels and monocyte MHC Class II expression. This lack of correlation has previously been described by other groups.29 Plasma levels may not be indicative of levels in other compartments, such as the amniotic cavity, and a single measurement may miss the peak levels of IL-10. However, the data emphasize the fact that there are many factors besides IL-10 that regulate monocyte MHC Class II expression; these include components of the hypothalamic-pituitary-adrenal axis, such as cortisol, that may also be involved in the initiation of labor.30,31 Other unknown factors could also have a confounding effect; for instance, it was not possible to control for the effects of antenatal steroids or duration of labor, both of which could influence MHC Class II expression.
The final piece of evidence supporting an altered immune response in labor is the reduction in LPS-stimulated production of proinflammatory cytokines observed in both the term and preterm labor groups. This reduction was particularly marked in the spontaneous preterm labor group, compared with either the preterm PROM or term labor group. In combination with a significant reduction in monocyte MHC Class II expression, these changes are indicative of a degree of immune paresis.32,33 One other group has also described reduced production of TNFα in women in term labor compared with 3 months postpartum.34 In contrast Amory et al35 found that in nonpregnant women with a history of premature labor, whole blood stimulation with LPS produced more TNFα than women with a history of term delivery.
We speculate that the differences we observed between the immune profile of women in term and preterm labor relate to the different nature and timing of the factors initiating labor in these two circumstances. At term it is possible that neuroendocrine changes, known to be involved in the initiation of labor,31 might also alter surface expression of MHC Class II on monocytes, as has been shown to occur in other models.30 In contrast, the stimulatory factor for many preterm deliveries is thought to be infective, although endocrine changes might form a common final pathway. We suggest that the profound inflammatory effect of chorioamnionitis, occurring over the days before preterm delivery, leads to a fall in monocyte reactivity and expression of Class II antigen, compatible with relative immune paresis. In addition, by the time that labor actually starts, the initial proinflammatory wave of cytokines has declined, so that although still raised, levels are lower than those during term labor. A shortcoming of this study is that data were not collected longitudinally, for the main reason that this would have meant studying many hundreds of women to detect those who would eventually go into PTL. Longitudinal sampling would clarify the chain of events leading to decreased MHC Class II expression; it would also demonstrate whether measurement of MHC Class II expression is a potentially valuable indicator of the likelihood of labor occurring in a woman with preterm PROM or early signs suggestive of PTL. The effect of a reduced MHC Class II expression is unclear. The direct effect could be to reduce antigen-driven immune responses to fetal tissue. However, it is probably more important that the reduced MHC Class II is indicative of a state of immune hyporesponsiveness, which may protect the mother from further proinflammatory insults during and after labor. Another possibility that this study was not powered to investigate is that women with particularly low MHC Class II expression (eg, less than 60%) during labor may be more susceptible to postnatal infections and should be candidates for antibiotic prophylaxis.
In summary, although these data are compatible with the concept of inflammation being linked to the onset of both preterm and term labor, they show that by the time labor has actually started some women are in a state of relative immune paresis with monocyte hyporesponsiveness indicated by reduced monocyte MHC Class II expression and reactivity to LPS. It is possible that this might have some evolutionary benefit in terms of protecting women from the potentially deleterious, proinflammatory effects of trophoblast fragments entering the circulation toward the end of labor.36 Equally, if the immune paresis were to last for days after delivery, it would make the mother more prone to puerperal infections. Further investigations are indicated to develop this hypothesis further. Detection of this state may provide insights into the maternal inflammatory status and be of use in the management of women with threatened PTL or preterm PROM.
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© 2007 The American College of Obstetricians and Gynecologists
36. Knight M, Redman CW, Linton EA, Sargent IL. Shedding of syncytiotrophoblast microvilli into the maternal circulation in pre-eclamptic pregnancies. Br J Obstet Gynaecol 1998;105:632–40.