Journal of Obstetrics and Gynaecology
ISSN: 0144-3615 (Print) 1364-6893 (Online) Journal homepage: http://www.tandfonline.com/loi/ijog20
The effect of a Foley catheter balloon on cervical ripening S. Y. Lim, Y. H. Kim, C. H. Kim, M. K. Cho, J. W. Kim, W. D. Kang, S. M. Kim, H. Y. Cho, K. Y. Ahn, K. H. Lee & T. B. Song To cite this article: S. Y. Lim, Y. H. Kim, C. H. Kim, M. K. Cho, J. W. Kim, W. D. Kang, S. M. Kim, H. Y. Cho, K. Y. Ahn, K. H. Lee & T. B. Song (2013) The effect of a Foley catheter balloon on cervical ripening, Journal of Obstetrics and Gynaecology, 33:8, 830-838 To link to this article: http://dx.doi.org/10.3109/01443615.2013.831043
Published online: 12 Nov 2013.
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Date: 13 September 2015, At: 08:31
Journal of Obstetrics and Gynaecology, November 2013; 33: 830–838 © 2013 Informa UK, Ltd. ISSN 0144-3615 print/ISSN 1364-6893 online DOI: 10.3109/01443615.2013.831043
OBSTETRICS
The effect of a Foley catheter balloon on cervical ripening S. Y. Lim1, Y. H. Kim2, C. H. Kim2, M. K. Cho2, J. W. Kim2, W. D. Kang2, S. M. Kim2, H. Y. Cho2, K. Y. Ahn3, K. H. Lee4 & T. B. Song2 1Department of Obstetrics and Gynecology, Gachon University Gil Medical Center, Incheon, Departments of 2Obstetrics and Gynecology
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and 3Anatomy, Chonnam National University Medical School, Gwangju, and 4Department of Obstetrics and Gynecology, Seonam University College of Medicine, Namwon, Korea
The Foley catheter balloon may affect cervical ripening through changes in biochemical mediators by immunoassay and immunohistochemistry, when it is used for pre-induction cervical ripening. The aim of the study was to evaluate the changes in the biochemical mediators from the extra-amniotic space and immunohistochemistry in ripened cervical tissue after the insertion of a Foley catheter balloon (FCB) for pre-induction cervical ripening. A total of 18 pregnant women with a Bishop’s score ⬍ 6, who were undergoing labour induction, were evaluated in this prospective study. The FCB was irrigated with 10 ml of phosphate buffered saline and the irrigant was collected 0, 2, 4 and 8 h after placement of the FCB or until spontaneous expulsion of the FCB occurred. Irrigant specimens were also collected from 10 spontaneous labouring (SL) women in the active phase of labour. The levels of interleukin (IL)-6, IL-8, matrix metalloproteinase (MMP)-8 and NO were measured. Cervical specimens were obtained from 12 women, including four undergoing induction; four SL and four non-pregnant (NP) women. Immunohistochemical staining was performed to localise hyaluronic acid synthase (HAS)-1, IL-6, IL-8, MMP-8, endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS). Results showed that the levels of IL-6, IL-8, and MMP-8 significantly increased over time in FCB group (p ⬍ 0.01). In the immunohistochemical analysis of cervical tissues, immunoreactivity of HAS-1 in the after FCB group was stronger than any of the other groups. The protein expressions of IL-6, IL-8, MMP-8, eNOS and iNOS were more prominent in the after FCB and SL groups than in the NP and the before FCB groups. iNOS was only observed in the after FCB and SL groups. It was concluded that FCB may affect cervical ripening through changes in biochemical mediators by immunoassay and immunohistochemistry, when it is used for pre-induction cervical ripening. Keywords: Biochemical mediators, cervical ripening, Foley catheter balloon, immunohistochemistry
Introduction Labour induction is one of the most common procedures performed in patients with an unfavourable cervix, typically occurring in 20% of pregnancies (ACOG 2009; Vengalil et al. 1998). Various cervical constituents, such as decorin, hyaluronic
acid (HA), hormones and cytokines appear to interact in a complex fashion in cervical ripening (Ludmir and Sehdev 2000). It has been shown that some inflammatory mediators and nitric oxide (NO) play a role in cervical ripening (Aalberts et al. 2007; Kelly 2002; Winkler 2003; Yoshida et al. 2001). The condition or favourability of the cervix is important in the success of labour induction. The success rate of vaginal delivery is low unless appropriate cervical ripening is performed prior to subsequent induction. A variety of pre-induction techniques exist. Both pharmacological (prostaglandins E1 and E2) and mechanical methods (transcervical Foley catheter balloon (FCB); hygroscopic cervical dilators and membrane stripping) are usually used to prepare the cervix for the induction of labour. An FCB for pre-induction is a safe, effective and inexpensive method for cervical ripening (Gelber and Sciscione 2006). The proposed mechanism for FCB-induced cervical ripening is direct stretching pressure of the balloon on the cervix and lower uterine segment, and secretion of endogenous prostaglandin release by membrane stripping (Lin et al. 2007; Lyndrup et al. 1994; Manabe et al. 1982). Inflammatory mediators are postulated to play an important role in cervical ripening and various cervical constituents, including cytokines, HA, hormones and NO, and appear to interact in a complex fashion even though the exact mechanism is still unclear. The aim of this study was to evaluate the effects of FCB for pre-induction cervical ripening on biochemical mediators from the extra-amniotic space and the immunohistochemical changes of ripened cervical tissue.
Materials and methods This was a prospective study of patients with unfavourable cervices who were scheduled to undergo labour induction for obstetric indications, between September 2007 and May 2008, in the Department of Obstetrics and Gynecology of Chonnam National University Hospital (Gwangju, Korea). Written informed consent was obtained from all subjects. This study was approved by the Chonnam National University Hospital Institutional Review Board.
Participants Women were enrolled if they met the following criteria: a singleton gestation; at ⱖ 36 weeks’ gestation; a Bishop’s score of ⬍ 6;
Correspondence: C. H. Kim, Department of Obstetrics and Gynecology, Chonnam National University Medical School, 8, Hakdong, Donggu, Gwangju, Korea. E-mail: [email protected]
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Figure 1. Flowchart of patients. NP, non-pregnant; SL, spontaneously labouring; Before, before Foley catheter balloon; After, after Foley catheter balloon. IL, interleukin; MMP, matrix metalloproteinase; NO, nitric oxide.
intact amniotic membranes; a reassuring fetal heart tracing on admission; a vertex presentation and a medical indication for labour induction. Spontaneously labouring (SL) group and nonpregnant (NP) group women were also enrolled. Patients with an intrauterine fetal demise; vaginal bleeding; cervicitis; evidence of spontaneous labour of ⬎ 3 painful contractions in 10 min and any contraindication to labour induction, were excluded. After a detailed history and thorough clinical examination, a pelvic examination was carried out to determine the Bishop’s score of the cervix. If there were not sufficient uterine contractions after removal of the FCB, additional PGE2 for cervical ripening was used.
Foley catheter insertion and removal The FCB group had a 22-French Foley catheter placed transcervically above the level of the internal os under direct visualisation during a sterile speculum examination by one investigator. The 60-ml balloon was inflated with saline. After 8 h, the FCB was deflated and removed if not already expelled. If the FCB was not expelled in 8 h, the patient was excluded.
Collection of samples from the extra-amniotic space During cervical ripening, 10 ml of sterile phosphate buffered saline (PBS) was used to flush the extra-amnionic space through the Foley catheter at 0, 2, 4 and 8 h. The irrigant was immediately collected via the Foley catheter and spun at 1,000 g for 20 min. The supernatant was taken and kept at ⫺75°C until assayed. If the FCB was spontaneously expelled from the cervix or the membranes were ruptured, further irrigation was not performed. If the collected samples were not available, the patient was excluded. The irrigant was collected from the SL group once cervical dilatation was ⬎ 4 cm. The irrigant was collected with a Foley catheter and placed in the extra-amniotic space in between Table I. Clinical characteristics in the FCB group (mean ⫾ SE). FCB (n ⫽ 18) Age (years) Gestational age (weeks) Nulliparous women (n, %) Bishop’s score FCB, Foley catheter balloon.
31.3 ⫾ 0.8 37.7 ⫾ 0.6 11 (61.1) 3.4 ⫾ 0.3
uterine contractions. The Foley catheter was placed in the extraamniotic space in between contractions so that it did not exert any mechanical stretching effect on the cervix.
Collection of cervical tissues Cervical tissues were obtained by punch biopsy for immunohistochemical staining. In the FCB group, cervical tissue was obtained before the Foley catheter was inserted (the before FCB group) and immediately after it was expelled (the after FCB group). Cervical tissues were also obtained in the SL and NP group.
IL-6, IL-8, MMP-8 and NO assays The levels of interleukin (IL)-6, IL-8 and matrix metalloproteinase (MMP)-8 in collected irrigant specimens were determined by an enzyme-linked immunosorbent assay (ELISA; Human Quantikine; RandD Systems, Inc., Minneapolis, MN). As an index of synthesis of NO, stable metabolites (nitrite/nitrate, NOx) were measured by a colorimetric NO assay kit (Oxford Biochemical, Oxford, MI). A microplate was used to perform enzyme reactions in vitro. For the spectrophotometric assay of nitrite with Griess reagent, 80 μl of MOPS (50 mM)/EDTA (1 mM) buffer and 5-μl samples were added to the wells. Nitrate reductase (0.01 U) and 10 μl of NADH (2 mM) were added to the reaction mixture, and the plate was shaken for 20 min at room temperature. Colour reagents, sulfanilamide and N-(1-naphthyl) ethylenediamine dihydrochloride were added, and the absorbance values were read at 540 nm in a microtitre plate reader (model 3550; Bio-Rad). NO levels were estimated Table II. Induction outcomes in the FCB group. FCB (n ⫽ 18)
Mode of delivery Vaginal Caesarean Induction to delivery time (h) (mean ⫾ SE) Vaginal delivery (n ⫽ 13) (mean ⫾ SE) Delivered within 24 h Vaginal delivery Additional use of PGE2 FCB, Foley catheter balloon.
n
(%)
13 5 33.3 ⫾ 7.3 24.8 ⫾ 5.8 11 9 5
72.2 27.8
61.1 50.0 27.8
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Figure 2. Levels of biochemical mediators. (A) IL-6, (B) IL-8, (C) MMP-8, (D) NO. ∗p ⬍ 0.01.
from a standard curve that was constructed with the use of standard reagents included in the assay kit.
Protein measurement Total protein content was determined using a bicinchoninic acid (BCA) protein assay kit, (Pierce Chemical Co., Rockford, IL) and bovine albumin was used as a protein standard.
Immunohistochemical localisation in cervical tissues The cervical tissue sections were deparaffinised in xylene, rehydrated in a graded series of ethanol washes, rinsed twice in PBS and then treated with 3% H2O2 in 60% methanol for 30 min to quench endogenous peroxidase activity. After being washed twice (5 min) in PBS, the sections were blocked in PBS containing 5% normal horse or goat serum for 30 min. The sections were incubated for 12–14 h with antibodies against hyaluronic acid synthase 1 (HAS-1; Santa Cruz Biotechnology, Santa Cruz, CA), IL-6 (Santa Cruz Biotechnology), IL-8 (Invitrogen Co., Carlsbad, CA), MMP-8 (Chemicon International Inc., Temecula, CA),
endothelial nitric oxide synthase (eNOS; Transduction Laboratories, Lexington, KY) and inducible NOS (iNOS; Transduction Laboratories) diluted in PBS with 0.3% bovine serum albumin. Negative control sections were incubated in PBS containing only 5% normal horse or goat serum. The sections were then rinsed three times in PBS, and incubated sequentially for 30 min each with biotinylated secondary antibodies and avidin biotin complex (ABC) reagents, followed by a 7-min incubation with the peroxidase substrate solution (diaminobenzidine) contained in the Vectastain ABC Kit (Vector Laboratories, Burlingame, CA). The sections were counterstained with haematoxylin. Finally, the tissue sections were examined and photographed with a light microscope (VANOX-S; Olympus, Tokyo, Japan).
Outcome measures The primary outcome measures that were observed, were the changes in biochemical mediator levels from extra-amniotic space irrigant specimens and histological changes in the ripened cervical tissues. The following induction outcomes in the
Figure 3. Levels of biochemical mediators in SL group. (A) IL-6, IL-8 and MMP-8. (B) NO.
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Figure 4. Immunohistochemical localisation of HAS-1. HAS-1 protein expression is weakly observed in connective tissue and glandular cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling is similar with the NP and the before groups, but the density of cellular labelling is prominently increased (arrows). The density is more prominent in the after FCB group. NP, non-pregnant; SL, spontaneous labouring; Before, before Foley catheter balloon; After, after Foley catheter balloon.
FCB group were recorded: delivery mode, induction-to-delivery interval, delivery rate within 24 h and additional use of PGE2.
nulliparous. The Bishop’s scores averaged 3.4 before induction (Table I).
Flowchart of patients
Induction outcomes in FCB group
A total of 50 patients were enrolled into this study, including 36 undergoing induction; 10 SL; and four NP women. Extraamnionic space irrigant sampling was performed in 36 women undergoing induction. At 0, 2, 4 and 8 h, the irrigant specimens from the extra-amnionic space were collected and the levels of IL-6, IL-8, MMP-8 and NO were estimated. In total, 18 of 36 patients were excluded because the FCB was not expelled in 8 h or samples were not available. Ten SL women were also estimated to be in the active phase of labour. Cervical tissues were taken by punch biopsy in four induction-undergoing, four SL and four NP women. Immunohistochemical staining was performed to localise HAS-1, IL-6, IL-8, MMP-8, eNOS and iNOS. Additional cervical ripening with PGE2 was needed in five women of the FCB group (Figure 1).
Five patients underwent caesarean section for failed induction and 13 patients were delivered vaginally. The mean induction to delivery interval was 33.3 ⫾ 7.3 h and 11 patients were delivered within 24 h. The induction-to-vaginal delivery interval was 24.8 ⫾ 5.8 h and nine patients delivered vaginally within 24 h. Five patients had additional use of prostaglandin E2 vaginal pessary (Table II).
Statistical analysis The data were analysed by the Mann–Whitney U-test using SPSS statistical software (version 12.0; SPSS Inc., Chicago, IL). The results are expressed as the means ⫾ SE. A p value of ⬍ 0.05 was considered statistically significant. The graphs were obtained using SigmaPlot 10 (Systat Software Inc., San Jose, CA).
Results Clinical characteristics in FCB group The patients had an average age of 31.3 ⫾ 0.8 years, with an average gestational age of 37.7 ⫾ 0.6. A total of 11 patients were
Analysis of biochemical mediators in FCB group Samples were obtained from 18, 18, 15 and 10 patients at 0, 2, 4 and 8 h, respectively. IL-6 levels. The levels of IL-6 increased over time in FCB group (2.1 ⫾ 0.6, 38.0 ⫾ 6.3, 70.6 ⫾ 7.4 and 77.7 ⫾ 11.7 pg/mg protein at 0, 2, 4 and 8 h, respectively; p ⬍ 0.01; Figure 2A). IL-8 levels. The levels of IL-8 increased over time in FCB group (0.6 ⫾ 0.2, 2.9 ⫾ 0.9, 6. 9 ⫾ 1.22 and 7.8 ⫾ 2.1 pg/mg protein at 0, 2, 4 and 8 h, respectively; p ⬍ 0.01; Figure 2B). MMP-8 levels. The levels of MMP-8 increased over time in FCB group (20.0 ⫾ 4.4, 117.7 ⫾ 53.2, 227.3 ⫾ 91.4 and 371.5 ⫾ 162.9 pg/mg protein at 0, 2, 4 and 8 h, respectively; p ⬍ 0.01; Figure 2C). NO levels. The levels of NO in FCB group were 8.3 ⫾ 1.1, 10.8.1 ⫾ 1.1, 9.5 ⫾ 1.2 and 10.9 ⫾ 1.2 mM/ml at 0, 2, 4 and 8 h, respectively (Figure 2D).
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Figure 5. Immunohistochemical localisation of IL-6. IL-6 protein expression is weakly observed in surface epithelial cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling is similar with NP and the before FCB groups, but density of cellular labelling is prominently increased (arrows). NP, non-pregnant; SL, spontaneous labouring; Before, before Foley catheter balloon; After, after Foley catheter balloon.
Clinical characteristics and analysis of biochemical mediators in the SL group The patients had an average age of 30.3 ⫾ 1.26 years, with pregnancies at 37.5 ⫾ 1.0 weeks’ gestation. Seven patients were nulliparous. The Bishop’s score averaged 10 in the active phase of labour. Nine patients delivered vaginally and one patient had a caesarean section. Irrigant specimens were also collected in 10 SL women in the active phase of labour. The levels of IL-6, IL-8 and MMP-8 in the SL group were 42.3 ⫾ 9.8, 7.4 ⫾ 2.3 and 819.3 ⫾ 366.2 pg/mg protein, respectively (Figure 3A). The NO level was 28.9 ⫾ 6.1 mM/ml (Figure 3B).
Immunohistochemical analysis of cervical tissues Abundant HAS-1 protein expression in the after FCB group. The expression of HAS-1 was weakly observed in connective tissue and glandular cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling was similar with NP and the before FCB groups, but the density of cellular labelling was prominently increased. Although immunoreactivity of HAS-1 was also detected in the SL group, the density was more prominent in the after FCB group (Figure 4).
IL-6 and IL-8 protein expression. The expression of IL-6 and IL-8 was weakly observed in surface epithelial cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling was similar with NP and the before FCB groups, but the density of cellular labelling was prominently increased (Figures 5 and 6).
MMP-8 protein expression. The expression of MMP-8 was weakly observed in the connective tissue cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling was similar with NP and the before FCB groups, but the density of cellular labelling was prominently increased (Figure 7). eNOS protein expression. The expression of eNOS was observed in vascular endothelial and surface epithelial cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling was similar with NP and the before FCB groups, but the density of cellular labelling was prominently increased (Figure 8).
iNOS protein expression. iNOS protein expression was not observed in the NP and the before FCB groups; however, it was detected in connective cells of the after FCB and SL groups (Figure 9).
Discussion We performed a prospective study to evaluate the changes in the biochemical mediators from the extra-amniotic space and immunohistochemistry in ripened cervical tissue after the insertion of FCB for pre-induction cervical ripening. Our results show that FCB may affect cervical ripening through changes in biochemical mediators by immunoassay and immunohistochemistry. The levels of biochemical mediators from extra-amnionic irrigant specimens increased with time and it corresponded with earlier studies which reported that inflammation and NO
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Figure 6. Immunohistochemical localisation of IL-8. IL-8 protein expression is weakly observed in surface epithelial cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling is similar with NP and the before FCB groups, but the density of cellular labelling is prominently increased (arrows). NP, non-pregnant; SL, spontaneous labouring; Before, before Foley catheter balloon; After, after Foley catheter balloon.
Figure 7. Immunohistochemical localisation of MMP-8. MMP-8 protein expression is weakly observed in connective tissue cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling is similar with NP and the before FCB groups, but the density of cellular labelling is prominently increased (arrows). NP, non-pregnant; SL, spontaneous labouring; Before, before Foley catheter balloon; After, after Foley catheter balloon.
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Figure 8. Immunohistochemical localisation of eNOS. eNOS protein expression is observed in vascular endothelial and surface epithelial cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling is similar to NP and the before FCB groups, but the density of cellular labelling is prominently increased (arrows). NP, non-pregnant; SL, spontaneous labouring; Before, before Foley catheter balloon; After, after Foley catheter balloon.
play a role in cervical ripening (Hebisch et al. 2001; Kelly 2002; Sennstrom et al. 2003; Sennstrom et al. 2000; Vaisanen-Tommiska 2008). However, the results were different from earlier studies, in that cervical tissue and serum were measured through a timetable, instead of being measured at one point in time. The results of immunohistochemical staining of IL-6, IL-8, MMP-8, eNOS and iNOS were also consistent with those of previous studies (Stygar et al. 2002; Winkler 2003; Winkler et al. 1999; Young et al. 2002). More prominent expression was demonstrated in the after FCB and SL groups than the NP and the before FCB groups. These results also demonstrated the involvement of inflammation and NO in the cervical ripening process. Cervical ripening usually begins before the onset of labour and it is the result of a series of complex biochemical processes, whereby various enzymes stimulate chemical reactions that result in rearrangement and realignment of the collagen fibres, thus the cervix thins, softens, relaxes and opens in response to uterine contractions, which advance the cervix over the presenting fetal part. The mediators of the cervical ripening process are still largely unknown, but investigators have reported PGE2 (Calder et al. 1974; Ulmsten et al. 1982) and hormones, such as oestrogen (Stjernholm et al. 1996) as enhancing agents, whereas progesterone (Radestad et al. 1988) is a negative factor for cervical ripening. Several studies have also implicated iNOS to be an important mediator (Calder 1998; Norman et al. 1998; Romero 1998) and support the hypothesis that inflammatory mediators are important factors for the final remodelling of cervical ripening. They advocated that cervical ripening is an inflammatory process mediated by cytokines, such as IL-8, IL-6 and G-CSF
(Hebisch et al. 2001; Kelly 2002; Sennstrom et al. 2000; Yoshida et al. 2001). The mechanism of FCB for cervical ripening is postulated as direct stretching pressure of the balloon on the cervix and lower uterine segment, and secretion of endogenous prostaglandin release by membrane stripping (Lin et al. 2007; Lyndrup et al. 1994; Manabe et al. 1982). Nevertheless, there have been no reports to substantiate this mechanism based on objective evidence. Cervical ripening is characterised by two dramatic phenomena, namely intensive local leukocyte infiltration and the rapid remodelling of extracellular matrix protein, such as collagen, proteoglycans and structural glycoprotein (Danforth et al. 1974; Ito et al. 1979; Junqueira et al. 1980; Kelly 1994; Kleissl et al. 1978). Local increase in HA in the cervix has been hypothesised to play a crucial role (Cabrol et al. 1990; Golichowski et al. 1980; Kobayashi and Terao 1997; Obara et al. 2001; Rath et al. 1993) because of the high affinity for water and collagenolytic, as well as inflammatory effects, of these fragments (Haslinger et al. 2001; Kobayashi and Terao 1997; McKee et al. 1996; Sun et al. 2001). It has been reported that parturition significantly increases the plasma HA levels (Rajabi et al. 1992). HA accumulation in the extracellular matrix results in cervical softening and swelling because of its unique elastic properties associated with its high affinity for water (Rajabi et al. 1992). HA also triggers various biological events, such as inflammation, proliferation, angiogenesis, invasion, transformation and migration (Hascall et al. 2004; McDonald and Camenisch 2002). Results of earlier studies correspond with those of the present study, which presented high levels of biochemical mediators in SL group.
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Figure 9. Immunohistochemical localisation of iNOS. iNOS protein expression is not observed in NP and before FCB groups; however, it is detected in connective cells of the after FCB and SL groups (arrows). NP, non-pregnant; SL, spontaneous labouring; Before, before Foley catheter balloon; After, after Foley catheter balloon.
Cyclic mechanical stretch to the cervix in parturition augments HA production in cultured human uterine cervical fibroblast cells (Takemura et al. 2005). In present study, HAS-1 was not detected in the NP and the before FCB group sections by immunohistochemical staining for HAS-1. Although HAS-1 was also detected in the SL group, the expression was more prominent in the after FCB group. So, it is postulated that FCB with saline would affect the cervix as a powerful mechanical stretcher, and contribute to cervical ripening. No objective evidence derived from either the extra-amnionic space or ripening cervix has been published. This study is the first evaluation of a biochemical mediator from the extra-amnionic space and pathophysiological analysis during cervical ripening. It is different from earlier studies, in that this study evaluated cervical ripening with FCB. Irrigant was obtained from the SL group at only one interval. Biochemical mediators were analysed but we were unable to compare the results with those of the FCB group because the status of cervical ripening was different. The patients in the SL group were enrolled after they had regular uterine contractions, so the uterine cervix was already ripened. We could not evaluate the biochemical status in the unripened cervix. So irrigant was obtained from the SL group at only one interval. We checked the induction outcomes in the FCB group. Because there was no other group for pre-induction cervical ripening, the results could not be compared. In a meta-analysis, intravaginal prostaglandin and transcervical Foley catheter have similar effectiveness as induction agents. There were no significant differences in the mean time to delivery, the rate of caesarean delivery or in the rate of chorioamnionitis (Fox et al. 2011). There were some limitations to this study. First, there were a small number of patients. Second, small punch biopsies of the
cervix may not have been deep enough to analyse the stromal collagenous region of the cervix, especially near the internal cervical os where cervical ripening occurs. Third, cervical tissue sampling was performed in the active phase of labour in the SL group. Thus, when comparing the after FCB and SL groups, it should be considered that the timing of cervical tissue sampling may be different. Fourth, we did not analyse the correlation between the level of the biochemical mediators and induction outcomes, due to the small sample size. Finally, if HAS-1 were estimated from extra-amnionic space irrigant specimens, it would help to analyse the results. Nevertheless, this study has provided ample evidence to suggest mechanisms of cervical ripening with an FCB. It is suggested that FCB may affect cervical ripening through changes in biochemical mediators by immunoassay and immunohistochemistry, when it is used for pre-induction cervical ripening. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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alveolar macrophages. The role of HA size and CD44. Journal of Clinical Investigation 98:2403–2413. Norman JE, Thomson AJ, Greer IA. 1998. Cervical ripening after nitric oxide. Human Reproduction 13:251–252. Obara M, Hirano H, Ogawa M, Tsubaki H, Hosoya N, Yoshida Y et al. 2001. Changes in molecular weight of hyaluronan and hyaluronidase activity in uterine cervical mucus in cervical ripening. Acta Obstetricia et Gynecologica Scandinavica 80:492–496. Radestad A, Christensen NJ, Stromberg L. 1988. Induced cervical ripening with Mifepristone in first trimester abortion. A double-blind randomized biomechanical study. Contraception 38:301–312. Rajabi MR, Quillen EW Jr., Nuwayhid BS, Brandt R, Poole AR. 1992. Circulating hyaluronic acid in nonpregnant, pregnant, and postpartum guinea pigs: elevated levels observed at parturition. American Journal of Obstetrics and Gynecology 166:242–246. Rath W, Osmers R, Adelmann-Grill BC, Stuhlsatz HW, Szevereny M, Kuhn W. 1993. Biochemical changes in human cervical connective tissue after intracervical application of prostaglandin E2. Prostaglandins 45:375–384. Romero R. 1998. Clinical application of nitric oxide donors and blockers. Human Reproduction 13:248–250. Sennstrom MB, Brauner A, Bystrom B, Malmstrom A, Ekman G. 2003. Matrix metalloproteinase-8 correlates with the cervical ripening process in humans. Acta Obstetricia et Gynecologica Scandinavica 82:904–911. Sennstrom MB, Ekman G, Westergren-Thorsson G, Malmstrom A, Bystrom B, Endresen U et al. 2000. Human cervical ripening, an inflammatory process mediated by cytokines. Molecular Human Reproduction 6:375–381. Stjernholm Y, Sahlin L, Akerberg S, Elinder A, Eriksson HA, Malmstrom A et al. 1996. Cervical ripening in humans: potential roles of estrogen, progesterone, and insulin-like growth factor-I. American Journal of Obstetrics and Gynecology 174:1065–1071. Stygar D, Wang H, Vladic YS, Ekman G, Eriksson H, Sahlin L. 2002. Increased level of matrix metalloproteinases 2 and 9 in the ripening process of the human cervix. Biology of Reproduction 67:889–894. Sun LK, Beck-Schimmer B, Oertli B, Wuthrich RP. 2001. Hyaluronaninduced cyclooxygenase-2 expression promotes thromboxane A2 production by renal cells. Kidney International 59:190–196. Takemura M, Itoh H, Sagawa N, Yura S, Korita D, Kakui K et al. 2005. Cyclic mechanical stretch augments hyaluronan production in cultured human uterine cervical fibroblast cells. Molecular Human Reproduction 11:659–665. Ulmsten U, Wingerup L, Belfrage P, Ekman G, Wiqvist N. 1982. Intracervical application of prostaglandin gel for induction of term labor. Obstetrics and Gynecology 59:336–339. Vaisanen-Tommiska MR. 2008. Nitric oxide in the human uterine cervix: endogenous ripening factor. Annals of Medicine 40:45–55. Vengalil SR, Guinn DA, Olabi NF, Burd LI, Owen J. 1998. A randomized trial of misoprostol and extra-amniotic saline infusion for cervical ripening and labor induction. Obstetrics and Gynecology 91:774–779. Winkler M, Fischer DC, Ruck P, Marx T, Kaiserling E, Oberpichler A et al. 1999. Parturition at term: parallel increases in interleukin-8 and proteinase concentrations and neutrophil count in the lower uterine segment. Human Reproduction 14:1096–1100. Winkler M. 2003. Role of cytokines and other inflammatory mediators. British Journal of Obstetrics and Gynaecology 110(Suppl 20):118–123. Yoshida M, Sagawa N, Itoh H, Yura S, Korita D, Kakui K et al. 2001. Nitric oxide increases matrix metalloproteinase-1 production in human uterine cervical fibroblast cells. Molecular Human Reproduction 7:979–985. Young A, Thomson AJ, Ledingham M, Jordan F, Greer IA, Norman JE. 2002. Immunolocalization of proinflammatory cytokines in myometrium, cervix, and fetal membranes during human parturition at term. Biology of Reproduction 66:445–449.
ISSN: 0144-3615 (Print) 1364-6893 (Online) Journal homepage: http://www.tandfonline.com/loi/ijog20
The effect of a Foley catheter balloon on cervical ripening S. Y. Lim, Y. H. Kim, C. H. Kim, M. K. Cho, J. W. Kim, W. D. Kang, S. M. Kim, H. Y. Cho, K. Y. Ahn, K. H. Lee & T. B. Song To cite this article: S. Y. Lim, Y. H. Kim, C. H. Kim, M. K. Cho, J. W. Kim, W. D. Kang, S. M. Kim, H. Y. Cho, K. Y. Ahn, K. H. Lee & T. B. Song (2013) The effect of a Foley catheter balloon on cervical ripening, Journal of Obstetrics and Gynaecology, 33:8, 830-838 To link to this article: http://dx.doi.org/10.3109/01443615.2013.831043
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Journal of Obstetrics and Gynaecology, November 2013; 33: 830–838 © 2013 Informa UK, Ltd. ISSN 0144-3615 print/ISSN 1364-6893 online DOI: 10.3109/01443615.2013.831043
OBSTETRICS
The effect of a Foley catheter balloon on cervical ripening S. Y. Lim1, Y. H. Kim2, C. H. Kim2, M. K. Cho2, J. W. Kim2, W. D. Kang2, S. M. Kim2, H. Y. Cho2, K. Y. Ahn3, K. H. Lee4 & T. B. Song2 1Department of Obstetrics and Gynecology, Gachon University Gil Medical Center, Incheon, Departments of 2Obstetrics and Gynecology
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and 3Anatomy, Chonnam National University Medical School, Gwangju, and 4Department of Obstetrics and Gynecology, Seonam University College of Medicine, Namwon, Korea
The Foley catheter balloon may affect cervical ripening through changes in biochemical mediators by immunoassay and immunohistochemistry, when it is used for pre-induction cervical ripening. The aim of the study was to evaluate the changes in the biochemical mediators from the extra-amniotic space and immunohistochemistry in ripened cervical tissue after the insertion of a Foley catheter balloon (FCB) for pre-induction cervical ripening. A total of 18 pregnant women with a Bishop’s score ⬍ 6, who were undergoing labour induction, were evaluated in this prospective study. The FCB was irrigated with 10 ml of phosphate buffered saline and the irrigant was collected 0, 2, 4 and 8 h after placement of the FCB or until spontaneous expulsion of the FCB occurred. Irrigant specimens were also collected from 10 spontaneous labouring (SL) women in the active phase of labour. The levels of interleukin (IL)-6, IL-8, matrix metalloproteinase (MMP)-8 and NO were measured. Cervical specimens were obtained from 12 women, including four undergoing induction; four SL and four non-pregnant (NP) women. Immunohistochemical staining was performed to localise hyaluronic acid synthase (HAS)-1, IL-6, IL-8, MMP-8, endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS). Results showed that the levels of IL-6, IL-8, and MMP-8 significantly increased over time in FCB group (p ⬍ 0.01). In the immunohistochemical analysis of cervical tissues, immunoreactivity of HAS-1 in the after FCB group was stronger than any of the other groups. The protein expressions of IL-6, IL-8, MMP-8, eNOS and iNOS were more prominent in the after FCB and SL groups than in the NP and the before FCB groups. iNOS was only observed in the after FCB and SL groups. It was concluded that FCB may affect cervical ripening through changes in biochemical mediators by immunoassay and immunohistochemistry, when it is used for pre-induction cervical ripening. Keywords: Biochemical mediators, cervical ripening, Foley catheter balloon, immunohistochemistry
Introduction Labour induction is one of the most common procedures performed in patients with an unfavourable cervix, typically occurring in 20% of pregnancies (ACOG 2009; Vengalil et al. 1998). Various cervical constituents, such as decorin, hyaluronic
acid (HA), hormones and cytokines appear to interact in a complex fashion in cervical ripening (Ludmir and Sehdev 2000). It has been shown that some inflammatory mediators and nitric oxide (NO) play a role in cervical ripening (Aalberts et al. 2007; Kelly 2002; Winkler 2003; Yoshida et al. 2001). The condition or favourability of the cervix is important in the success of labour induction. The success rate of vaginal delivery is low unless appropriate cervical ripening is performed prior to subsequent induction. A variety of pre-induction techniques exist. Both pharmacological (prostaglandins E1 and E2) and mechanical methods (transcervical Foley catheter balloon (FCB); hygroscopic cervical dilators and membrane stripping) are usually used to prepare the cervix for the induction of labour. An FCB for pre-induction is a safe, effective and inexpensive method for cervical ripening (Gelber and Sciscione 2006). The proposed mechanism for FCB-induced cervical ripening is direct stretching pressure of the balloon on the cervix and lower uterine segment, and secretion of endogenous prostaglandin release by membrane stripping (Lin et al. 2007; Lyndrup et al. 1994; Manabe et al. 1982). Inflammatory mediators are postulated to play an important role in cervical ripening and various cervical constituents, including cytokines, HA, hormones and NO, and appear to interact in a complex fashion even though the exact mechanism is still unclear. The aim of this study was to evaluate the effects of FCB for pre-induction cervical ripening on biochemical mediators from the extra-amniotic space and the immunohistochemical changes of ripened cervical tissue.
Materials and methods This was a prospective study of patients with unfavourable cervices who were scheduled to undergo labour induction for obstetric indications, between September 2007 and May 2008, in the Department of Obstetrics and Gynecology of Chonnam National University Hospital (Gwangju, Korea). Written informed consent was obtained from all subjects. This study was approved by the Chonnam National University Hospital Institutional Review Board.
Participants Women were enrolled if they met the following criteria: a singleton gestation; at ⱖ 36 weeks’ gestation; a Bishop’s score of ⬍ 6;
Correspondence: C. H. Kim, Department of Obstetrics and Gynecology, Chonnam National University Medical School, 8, Hakdong, Donggu, Gwangju, Korea. E-mail: [email protected]
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Figure 1. Flowchart of patients. NP, non-pregnant; SL, spontaneously labouring; Before, before Foley catheter balloon; After, after Foley catheter balloon. IL, interleukin; MMP, matrix metalloproteinase; NO, nitric oxide.
intact amniotic membranes; a reassuring fetal heart tracing on admission; a vertex presentation and a medical indication for labour induction. Spontaneously labouring (SL) group and nonpregnant (NP) group women were also enrolled. Patients with an intrauterine fetal demise; vaginal bleeding; cervicitis; evidence of spontaneous labour of ⬎ 3 painful contractions in 10 min and any contraindication to labour induction, were excluded. After a detailed history and thorough clinical examination, a pelvic examination was carried out to determine the Bishop’s score of the cervix. If there were not sufficient uterine contractions after removal of the FCB, additional PGE2 for cervical ripening was used.
Foley catheter insertion and removal The FCB group had a 22-French Foley catheter placed transcervically above the level of the internal os under direct visualisation during a sterile speculum examination by one investigator. The 60-ml balloon was inflated with saline. After 8 h, the FCB was deflated and removed if not already expelled. If the FCB was not expelled in 8 h, the patient was excluded.
Collection of samples from the extra-amniotic space During cervical ripening, 10 ml of sterile phosphate buffered saline (PBS) was used to flush the extra-amnionic space through the Foley catheter at 0, 2, 4 and 8 h. The irrigant was immediately collected via the Foley catheter and spun at 1,000 g for 20 min. The supernatant was taken and kept at ⫺75°C until assayed. If the FCB was spontaneously expelled from the cervix or the membranes were ruptured, further irrigation was not performed. If the collected samples were not available, the patient was excluded. The irrigant was collected from the SL group once cervical dilatation was ⬎ 4 cm. The irrigant was collected with a Foley catheter and placed in the extra-amniotic space in between Table I. Clinical characteristics in the FCB group (mean ⫾ SE). FCB (n ⫽ 18) Age (years) Gestational age (weeks) Nulliparous women (n, %) Bishop’s score FCB, Foley catheter balloon.
31.3 ⫾ 0.8 37.7 ⫾ 0.6 11 (61.1) 3.4 ⫾ 0.3
uterine contractions. The Foley catheter was placed in the extraamniotic space in between contractions so that it did not exert any mechanical stretching effect on the cervix.
Collection of cervical tissues Cervical tissues were obtained by punch biopsy for immunohistochemical staining. In the FCB group, cervical tissue was obtained before the Foley catheter was inserted (the before FCB group) and immediately after it was expelled (the after FCB group). Cervical tissues were also obtained in the SL and NP group.
IL-6, IL-8, MMP-8 and NO assays The levels of interleukin (IL)-6, IL-8 and matrix metalloproteinase (MMP)-8 in collected irrigant specimens were determined by an enzyme-linked immunosorbent assay (ELISA; Human Quantikine; RandD Systems, Inc., Minneapolis, MN). As an index of synthesis of NO, stable metabolites (nitrite/nitrate, NOx) were measured by a colorimetric NO assay kit (Oxford Biochemical, Oxford, MI). A microplate was used to perform enzyme reactions in vitro. For the spectrophotometric assay of nitrite with Griess reagent, 80 μl of MOPS (50 mM)/EDTA (1 mM) buffer and 5-μl samples were added to the wells. Nitrate reductase (0.01 U) and 10 μl of NADH (2 mM) were added to the reaction mixture, and the plate was shaken for 20 min at room temperature. Colour reagents, sulfanilamide and N-(1-naphthyl) ethylenediamine dihydrochloride were added, and the absorbance values were read at 540 nm in a microtitre plate reader (model 3550; Bio-Rad). NO levels were estimated Table II. Induction outcomes in the FCB group. FCB (n ⫽ 18)
Mode of delivery Vaginal Caesarean Induction to delivery time (h) (mean ⫾ SE) Vaginal delivery (n ⫽ 13) (mean ⫾ SE) Delivered within 24 h Vaginal delivery Additional use of PGE2 FCB, Foley catheter balloon.
n
(%)
13 5 33.3 ⫾ 7.3 24.8 ⫾ 5.8 11 9 5
72.2 27.8
61.1 50.0 27.8
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Figure 2. Levels of biochemical mediators. (A) IL-6, (B) IL-8, (C) MMP-8, (D) NO. ∗p ⬍ 0.01.
from a standard curve that was constructed with the use of standard reagents included in the assay kit.
Protein measurement Total protein content was determined using a bicinchoninic acid (BCA) protein assay kit, (Pierce Chemical Co., Rockford, IL) and bovine albumin was used as a protein standard.
Immunohistochemical localisation in cervical tissues The cervical tissue sections were deparaffinised in xylene, rehydrated in a graded series of ethanol washes, rinsed twice in PBS and then treated with 3% H2O2 in 60% methanol for 30 min to quench endogenous peroxidase activity. After being washed twice (5 min) in PBS, the sections were blocked in PBS containing 5% normal horse or goat serum for 30 min. The sections were incubated for 12–14 h with antibodies against hyaluronic acid synthase 1 (HAS-1; Santa Cruz Biotechnology, Santa Cruz, CA), IL-6 (Santa Cruz Biotechnology), IL-8 (Invitrogen Co., Carlsbad, CA), MMP-8 (Chemicon International Inc., Temecula, CA),
endothelial nitric oxide synthase (eNOS; Transduction Laboratories, Lexington, KY) and inducible NOS (iNOS; Transduction Laboratories) diluted in PBS with 0.3% bovine serum albumin. Negative control sections were incubated in PBS containing only 5% normal horse or goat serum. The sections were then rinsed three times in PBS, and incubated sequentially for 30 min each with biotinylated secondary antibodies and avidin biotin complex (ABC) reagents, followed by a 7-min incubation with the peroxidase substrate solution (diaminobenzidine) contained in the Vectastain ABC Kit (Vector Laboratories, Burlingame, CA). The sections were counterstained with haematoxylin. Finally, the tissue sections were examined and photographed with a light microscope (VANOX-S; Olympus, Tokyo, Japan).
Outcome measures The primary outcome measures that were observed, were the changes in biochemical mediator levels from extra-amniotic space irrigant specimens and histological changes in the ripened cervical tissues. The following induction outcomes in the
Figure 3. Levels of biochemical mediators in SL group. (A) IL-6, IL-8 and MMP-8. (B) NO.
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Figure 4. Immunohistochemical localisation of HAS-1. HAS-1 protein expression is weakly observed in connective tissue and glandular cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling is similar with the NP and the before groups, but the density of cellular labelling is prominently increased (arrows). The density is more prominent in the after FCB group. NP, non-pregnant; SL, spontaneous labouring; Before, before Foley catheter balloon; After, after Foley catheter balloon.
FCB group were recorded: delivery mode, induction-to-delivery interval, delivery rate within 24 h and additional use of PGE2.
nulliparous. The Bishop’s scores averaged 3.4 before induction (Table I).
Flowchart of patients
Induction outcomes in FCB group
A total of 50 patients were enrolled into this study, including 36 undergoing induction; 10 SL; and four NP women. Extraamnionic space irrigant sampling was performed in 36 women undergoing induction. At 0, 2, 4 and 8 h, the irrigant specimens from the extra-amnionic space were collected and the levels of IL-6, IL-8, MMP-8 and NO were estimated. In total, 18 of 36 patients were excluded because the FCB was not expelled in 8 h or samples were not available. Ten SL women were also estimated to be in the active phase of labour. Cervical tissues were taken by punch biopsy in four induction-undergoing, four SL and four NP women. Immunohistochemical staining was performed to localise HAS-1, IL-6, IL-8, MMP-8, eNOS and iNOS. Additional cervical ripening with PGE2 was needed in five women of the FCB group (Figure 1).
Five patients underwent caesarean section for failed induction and 13 patients were delivered vaginally. The mean induction to delivery interval was 33.3 ⫾ 7.3 h and 11 patients were delivered within 24 h. The induction-to-vaginal delivery interval was 24.8 ⫾ 5.8 h and nine patients delivered vaginally within 24 h. Five patients had additional use of prostaglandin E2 vaginal pessary (Table II).
Statistical analysis The data were analysed by the Mann–Whitney U-test using SPSS statistical software (version 12.0; SPSS Inc., Chicago, IL). The results are expressed as the means ⫾ SE. A p value of ⬍ 0.05 was considered statistically significant. The graphs were obtained using SigmaPlot 10 (Systat Software Inc., San Jose, CA).
Results Clinical characteristics in FCB group The patients had an average age of 31.3 ⫾ 0.8 years, with an average gestational age of 37.7 ⫾ 0.6. A total of 11 patients were
Analysis of biochemical mediators in FCB group Samples were obtained from 18, 18, 15 and 10 patients at 0, 2, 4 and 8 h, respectively. IL-6 levels. The levels of IL-6 increased over time in FCB group (2.1 ⫾ 0.6, 38.0 ⫾ 6.3, 70.6 ⫾ 7.4 and 77.7 ⫾ 11.7 pg/mg protein at 0, 2, 4 and 8 h, respectively; p ⬍ 0.01; Figure 2A). IL-8 levels. The levels of IL-8 increased over time in FCB group (0.6 ⫾ 0.2, 2.9 ⫾ 0.9, 6. 9 ⫾ 1.22 and 7.8 ⫾ 2.1 pg/mg protein at 0, 2, 4 and 8 h, respectively; p ⬍ 0.01; Figure 2B). MMP-8 levels. The levels of MMP-8 increased over time in FCB group (20.0 ⫾ 4.4, 117.7 ⫾ 53.2, 227.3 ⫾ 91.4 and 371.5 ⫾ 162.9 pg/mg protein at 0, 2, 4 and 8 h, respectively; p ⬍ 0.01; Figure 2C). NO levels. The levels of NO in FCB group were 8.3 ⫾ 1.1, 10.8.1 ⫾ 1.1, 9.5 ⫾ 1.2 and 10.9 ⫾ 1.2 mM/ml at 0, 2, 4 and 8 h, respectively (Figure 2D).
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Figure 5. Immunohistochemical localisation of IL-6. IL-6 protein expression is weakly observed in surface epithelial cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling is similar with NP and the before FCB groups, but density of cellular labelling is prominently increased (arrows). NP, non-pregnant; SL, spontaneous labouring; Before, before Foley catheter balloon; After, after Foley catheter balloon.
Clinical characteristics and analysis of biochemical mediators in the SL group The patients had an average age of 30.3 ⫾ 1.26 years, with pregnancies at 37.5 ⫾ 1.0 weeks’ gestation. Seven patients were nulliparous. The Bishop’s score averaged 10 in the active phase of labour. Nine patients delivered vaginally and one patient had a caesarean section. Irrigant specimens were also collected in 10 SL women in the active phase of labour. The levels of IL-6, IL-8 and MMP-8 in the SL group were 42.3 ⫾ 9.8, 7.4 ⫾ 2.3 and 819.3 ⫾ 366.2 pg/mg protein, respectively (Figure 3A). The NO level was 28.9 ⫾ 6.1 mM/ml (Figure 3B).
Immunohistochemical analysis of cervical tissues Abundant HAS-1 protein expression in the after FCB group. The expression of HAS-1 was weakly observed in connective tissue and glandular cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling was similar with NP and the before FCB groups, but the density of cellular labelling was prominently increased. Although immunoreactivity of HAS-1 was also detected in the SL group, the density was more prominent in the after FCB group (Figure 4).
IL-6 and IL-8 protein expression. The expression of IL-6 and IL-8 was weakly observed in surface epithelial cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling was similar with NP and the before FCB groups, but the density of cellular labelling was prominently increased (Figures 5 and 6).
MMP-8 protein expression. The expression of MMP-8 was weakly observed in the connective tissue cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling was similar with NP and the before FCB groups, but the density of cellular labelling was prominently increased (Figure 7). eNOS protein expression. The expression of eNOS was observed in vascular endothelial and surface epithelial cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling was similar with NP and the before FCB groups, but the density of cellular labelling was prominently increased (Figure 8).
iNOS protein expression. iNOS protein expression was not observed in the NP and the before FCB groups; however, it was detected in connective cells of the after FCB and SL groups (Figure 9).
Discussion We performed a prospective study to evaluate the changes in the biochemical mediators from the extra-amniotic space and immunohistochemistry in ripened cervical tissue after the insertion of FCB for pre-induction cervical ripening. Our results show that FCB may affect cervical ripening through changes in biochemical mediators by immunoassay and immunohistochemistry. The levels of biochemical mediators from extra-amnionic irrigant specimens increased with time and it corresponded with earlier studies which reported that inflammation and NO
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Figure 6. Immunohistochemical localisation of IL-8. IL-8 protein expression is weakly observed in surface epithelial cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling is similar with NP and the before FCB groups, but the density of cellular labelling is prominently increased (arrows). NP, non-pregnant; SL, spontaneous labouring; Before, before Foley catheter balloon; After, after Foley catheter balloon.
Figure 7. Immunohistochemical localisation of MMP-8. MMP-8 protein expression is weakly observed in connective tissue cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling is similar with NP and the before FCB groups, but the density of cellular labelling is prominently increased (arrows). NP, non-pregnant; SL, spontaneous labouring; Before, before Foley catheter balloon; After, after Foley catheter balloon.
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Figure 8. Immunohistochemical localisation of eNOS. eNOS protein expression is observed in vascular endothelial and surface epithelial cells of NP and the before FCB groups. In the after FCB and SL groups, the pattern of cellular labelling is similar to NP and the before FCB groups, but the density of cellular labelling is prominently increased (arrows). NP, non-pregnant; SL, spontaneous labouring; Before, before Foley catheter balloon; After, after Foley catheter balloon.
play a role in cervical ripening (Hebisch et al. 2001; Kelly 2002; Sennstrom et al. 2003; Sennstrom et al. 2000; Vaisanen-Tommiska 2008). However, the results were different from earlier studies, in that cervical tissue and serum were measured through a timetable, instead of being measured at one point in time. The results of immunohistochemical staining of IL-6, IL-8, MMP-8, eNOS and iNOS were also consistent with those of previous studies (Stygar et al. 2002; Winkler 2003; Winkler et al. 1999; Young et al. 2002). More prominent expression was demonstrated in the after FCB and SL groups than the NP and the before FCB groups. These results also demonstrated the involvement of inflammation and NO in the cervical ripening process. Cervical ripening usually begins before the onset of labour and it is the result of a series of complex biochemical processes, whereby various enzymes stimulate chemical reactions that result in rearrangement and realignment of the collagen fibres, thus the cervix thins, softens, relaxes and opens in response to uterine contractions, which advance the cervix over the presenting fetal part. The mediators of the cervical ripening process are still largely unknown, but investigators have reported PGE2 (Calder et al. 1974; Ulmsten et al. 1982) and hormones, such as oestrogen (Stjernholm et al. 1996) as enhancing agents, whereas progesterone (Radestad et al. 1988) is a negative factor for cervical ripening. Several studies have also implicated iNOS to be an important mediator (Calder 1998; Norman et al. 1998; Romero 1998) and support the hypothesis that inflammatory mediators are important factors for the final remodelling of cervical ripening. They advocated that cervical ripening is an inflammatory process mediated by cytokines, such as IL-8, IL-6 and G-CSF
(Hebisch et al. 2001; Kelly 2002; Sennstrom et al. 2000; Yoshida et al. 2001). The mechanism of FCB for cervical ripening is postulated as direct stretching pressure of the balloon on the cervix and lower uterine segment, and secretion of endogenous prostaglandin release by membrane stripping (Lin et al. 2007; Lyndrup et al. 1994; Manabe et al. 1982). Nevertheless, there have been no reports to substantiate this mechanism based on objective evidence. Cervical ripening is characterised by two dramatic phenomena, namely intensive local leukocyte infiltration and the rapid remodelling of extracellular matrix protein, such as collagen, proteoglycans and structural glycoprotein (Danforth et al. 1974; Ito et al. 1979; Junqueira et al. 1980; Kelly 1994; Kleissl et al. 1978). Local increase in HA in the cervix has been hypothesised to play a crucial role (Cabrol et al. 1990; Golichowski et al. 1980; Kobayashi and Terao 1997; Obara et al. 2001; Rath et al. 1993) because of the high affinity for water and collagenolytic, as well as inflammatory effects, of these fragments (Haslinger et al. 2001; Kobayashi and Terao 1997; McKee et al. 1996; Sun et al. 2001). It has been reported that parturition significantly increases the plasma HA levels (Rajabi et al. 1992). HA accumulation in the extracellular matrix results in cervical softening and swelling because of its unique elastic properties associated with its high affinity for water (Rajabi et al. 1992). HA also triggers various biological events, such as inflammation, proliferation, angiogenesis, invasion, transformation and migration (Hascall et al. 2004; McDonald and Camenisch 2002). Results of earlier studies correspond with those of the present study, which presented high levels of biochemical mediators in SL group.
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Figure 9. Immunohistochemical localisation of iNOS. iNOS protein expression is not observed in NP and before FCB groups; however, it is detected in connective cells of the after FCB and SL groups (arrows). NP, non-pregnant; SL, spontaneous labouring; Before, before Foley catheter balloon; After, after Foley catheter balloon.
Cyclic mechanical stretch to the cervix in parturition augments HA production in cultured human uterine cervical fibroblast cells (Takemura et al. 2005). In present study, HAS-1 was not detected in the NP and the before FCB group sections by immunohistochemical staining for HAS-1. Although HAS-1 was also detected in the SL group, the expression was more prominent in the after FCB group. So, it is postulated that FCB with saline would affect the cervix as a powerful mechanical stretcher, and contribute to cervical ripening. No objective evidence derived from either the extra-amnionic space or ripening cervix has been published. This study is the first evaluation of a biochemical mediator from the extra-amnionic space and pathophysiological analysis during cervical ripening. It is different from earlier studies, in that this study evaluated cervical ripening with FCB. Irrigant was obtained from the SL group at only one interval. Biochemical mediators were analysed but we were unable to compare the results with those of the FCB group because the status of cervical ripening was different. The patients in the SL group were enrolled after they had regular uterine contractions, so the uterine cervix was already ripened. We could not evaluate the biochemical status in the unripened cervix. So irrigant was obtained from the SL group at only one interval. We checked the induction outcomes in the FCB group. Because there was no other group for pre-induction cervical ripening, the results could not be compared. In a meta-analysis, intravaginal prostaglandin and transcervical Foley catheter have similar effectiveness as induction agents. There were no significant differences in the mean time to delivery, the rate of caesarean delivery or in the rate of chorioamnionitis (Fox et al. 2011). There were some limitations to this study. First, there were a small number of patients. Second, small punch biopsies of the
cervix may not have been deep enough to analyse the stromal collagenous region of the cervix, especially near the internal cervical os where cervical ripening occurs. Third, cervical tissue sampling was performed in the active phase of labour in the SL group. Thus, when comparing the after FCB and SL groups, it should be considered that the timing of cervical tissue sampling may be different. Fourth, we did not analyse the correlation between the level of the biochemical mediators and induction outcomes, due to the small sample size. Finally, if HAS-1 were estimated from extra-amnionic space irrigant specimens, it would help to analyse the results. Nevertheless, this study has provided ample evidence to suggest mechanisms of cervical ripening with an FCB. It is suggested that FCB may affect cervical ripening through changes in biochemical mediators by immunoassay and immunohistochemistry, when it is used for pre-induction cervical ripening. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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