Gunvor Ekman-Ordeberg

Risk of adverse pregnancy outcomes in women with polycystic ovary syndrome: population based cohort study

Objective To study the risk of adverse pregnancy outcomes in women with polycystic ovary syndrome, taking into account maternal characteristics and assisted reproductive technology. Design Population based cohort study. Setting Singleton births registered in the Swedish medical birth register between 1995 and 2007. Participants By linkage with the Swedish patient register, 3787 births among women with a diagnosis of polycystic ovary syndrome and 1 191 336 births among women without such a diagnosis. Main outcome measures Risk of adverse pregnancy outcomes (gestational diabetes, pre-eclampsia, preterm birth, stillbirth, neonatal death, low Apgar score (<7 at five minutes), meconium aspiration, large for gestational age, macrosomia, small for gestational age), adjusted for maternal characteristics (body mass index, age), socioeconomic factors (educational level, and cohabitating with infant’s father), and assisted reproductive technology. Results Women with polycystic ovary syndrome were more often obese and more commonly used assisted reproductive technology than women without such a diagnosis (60.6% v 34.8% and 13.7% v 1.5%). Polycystic ovary syndrome was strongly associated with pre-eclampsia (adjusted odds ratio 1.45, 95% confidence interval 1.24 to 1.69) and very preterm birth (2.21, 1.69 to 2.90) and the risk of gestational diabetes was more than doubled (2.32, 1.88 to 2.88). Infants born to mothers with polycystic ovary syndrome were more prone to be large for gestational age (1.39, 1.19 to 1.62) and were at increased risk of meconium aspiration (2.02, 1.13 to 3.61) and having a low Apgar score (<7) at five minutes (1.41, 1.09 to 1.83). Conclusions Women with polycystic ovary syndrome are at increased risk of adverse pregnancy and birth outcomes that cannot be explained by assisted reproductive technology. These women may need increased surveillance during pregnancy and parturition.

Non-infected preterm parturition is related to increased concentrations of IL-6, IL-8 and MCP-1 in human cervix.

BackgroundHuman cervical ripening is an inflammatory process. In labour at term the mRNA-levels and protein concentrations for interleukin-6 (IL-6) and IL-8 in cervix significantly increase. The aim of this study was to investigate if there are differences in the inflammatory process of preterm and term cervical ripening.MethodsCervical biopsies from 50 singleton pregnant women without clinical signs of infection were allocated to four groups: preterm labour, term labour, preterm not in labour and term not in labour. The protein levels of IL-8, IL-6, monocyte chemotactic protein-1 (MCP-1), regulated upon activation normal t cells expressed and secreted (RANTES) and tumour necrosis factor-alpha (TNF-alpha) were quantified in tissue homogenates by ELISA or Immulite. The mRNA expression of IL-8, MCP-1 and RANTES was studied using RT-PCR. White blood cell count (WBC) and C-reactive protein (CRP) in the blood were determined. For determination of statistically significant differences between study groups Mann-Whitney U test or Kruskal-Wallis test were applied.ResultsProtein concentrations of IL-8, IL-6, and MCP-1 were significantly increased during labour compared to non-labouring groups, whereas no changes were observed for RANTES and TNF-alpha. The mRNA levels of representative cytokines such as IL-8 and MCP-1 increased significantly during labour whereas RANTES mRNA expression remained unchanged. WBC and CRP were significantly higher in the labouring groups as compared to groups not in labour. For neither of the analysed cytokines, WBC or CRP levels were there any changes between preterm and term respective groups.ConclusionOur findings indicate that non-infected preterm cervical ripening is an inflammatory process, just as cervical ripening at term, with cytokines as important mediators.

Changes in paraurethral connective tissue at menopause are counteracted by estrogen

OBJECTIVE To study whether the transition to menopause is accompanied by changes in the paraurethral connective tissue and if these changes are modified by estrogen replacement therapy. STUDY DESIGN Biopsies were obtained from the paraurethral tissue from 34 women; 12 menstruating, 14 postmenopausal without estrogen treatment, and 8 with estrogen treatment. Collagen concentration and collagen extractability by pepsin digestion were measured. Proteoglycan composition and concentration were analysed using Alcian blue. The mRNA levels for collagen I and III, the small proteoglycans (PGS) decorin and biglycan, and the large proteoglycan versican, were estimated. RESULTS The paraurethral biopsies consisted of fibrous connective tissue, with collagen fibers as dominating structure. Several proteoglycans were identified; versican, heparansulphate proteoglycans, biglycan and decorin. The small proteoglycan decorin represented 85% of all proteoglycans. The collagen concentration was almost doubled in postmenopausal biopsies compared to premenopausal. The collagen fibril organization was also changed with higher cross-linking after menopause whereas the amount and the composition of the proteoglycans were unchanged. The proteoglycan/collagen ratio was significantly decreased. Estrogen replacement therapy resulted in decreased collagen concentration, decreased cross-linking of the collagen and reversal of the PGS/collagen ratio to almost premenopausal level. The therapy resulted in increased levels of mRNA for collagen I and III which suggests that the changes are due to an increased turnover. CONCLUSION The decrease in estrogen levels at menopause results in a connective tissue with different qualities after menopause. Estrogen replacement therapy tends to restore the metabolism of the genitourinary connective tissue to premenopausal conditions.

Different organization of collagen fibrils in stress-incontinent women of fertile age

OBJECTIVE The objective was to test the hypothesis that stress urinary incontinence in women is correlated to changes in the paraurethral connective tissue ultrastructure and metabolism. METHODS Transvaginal biopsies were obtained from the paraurethral connective tissue in women of fertile age with stress urinary incontinence and in matched continent controls. All the stress-incontinent women were characterized with urodynamic investigation. In the biopsies, collagen concentration, measured as hydroxyproline, and the degree of extraction by pepsin digestion were quantified. Proteoglycan composition and concentration were analyzed using Alcian blue precipitation, followed by electrophoretic separation and quantification. Using Northern blots mRNA levels for the collagens I and III, the small proteoglycans decorin and biglycan, and the large proteoglycan versican, were quantified. Collagen organization was examined with transmission electron microscopy and the diameters of collagen fibrils were analyzed with an interactive image analysis system (IBAS, Zeiss/Kontron). RESULTS The biochemical and morphological analyses exposed a significant difference in the paraurethral connective tissue between stress urinary incontinent women before menopause and comparable controls. The collagen concentration was almost 30% higher and the diameters of the collagen fibrils were 30% larger in the incontinent group of women. Also the organization of the collagen fibrils differed, with considerably higher cross-linking. A higher level of mRNA for collagen I and III in the incontinent group indicates that the differences can be related to an altered collagen metabolism. No change of proteoglycan amount or composition was observed, resulting in a significantly lower proteoglycan/collagen ratio in the incontinent group of women. CONCLUSION Stress urinary incontinence in fertile women is associated with a change in collagen metabolism resulting in an increased concentration of collagen and larger collagen fibrils. These alterations should result in a more rigid form of extracellular matrix, suggesting a connective tissue with impaired mechanical function.

Paraurethral connective tissue in stress‐incontinent women after menopause

OBJECTIVE To study whether stress urinary incontinence after menopause is correlated to changes in the paraurethral connective tissue ultrastructure and metabolism. METHODS Transvaginal biopsies were obtained from the paraurethral connective tissue in stress urinary incontinent women after menopause with and without estrogen replacement therapy, and from comparable controls. All the stress-incontinent women underwent urodynamic investigation. In the specimens, collagen concentration, measured as hydroxyproline, and the degree of extractability by pepsin digestion, were quantified. Proteoglycan composition and concentration were analyzed using Alcian Blue precipitation, followed by electro-phoretic separation and quantification. Using Northern blots, mRNA levels for the collagens I and III, the small proteoglycans decorin and biglycan, and the large proteoglycan versican, were quantified. Collagen structure was examined with transmission electron microscopy, and the diameters of collagen fibrils were analyzed with an interactive image analysis system (IBAS, Zeiss/Kontron). RESULTS No significant difference in paraurethral connective tissue biochemistry or ultrastructure was registered between women with stress incontinence and controls. Estrogen replacement therapy resulted in a lower collagen concentration both between the controls (p = 0.02) and between the incontinent women (0.02). In the women with stress incontinence also the extractability by pepsin digestion was higher in the group with estrogen treatment (p = 0.004), indicating a decrease in cross-linking. The proteoglycan/collagen ratio was higher in the control group with estrogen treatment compared to untreated (p = 0.02), but no difference was found between estrogen treated and untreated incontinent women. The median collagen fibril diameter was 15% larger in the incontinent group of women without estrogen therapy compared to the control group and 5% larger when comparing the incontinent group on estrogen replacement therapy to the corresponding control group. CONCLUSION The extracellular matrix of paraurethral connective tissue in stress urinary incontinent women after menopause reacted differently to estrogen replacement therapy compared to continent controls. In contrast to incontinent women of fertile age no major changes in collagen metabolism were found in stress urinary incontinent women after menopause.

Factors involved in the inflammatory events of cervical ripening in humans

BackgroundCervical ripening is an inflammatory reaction. The glucocorticoid receptor (GR) mediates glucocorticoid anti-inflammatory reactions, whereas nuclear factor (NF)kappaB is a key pro-inflammatory transcription factor. Prostaglandins as well as platelet activating factor (PAF) are inflammatory mediators. Inducible nitric oxide synthase (iNOS) regulates the level of nitric oxide (NO) in response to various inflammatory stimuli. We hypothesize that a changed biological response to glucocorticoids could be a mechanism regulating the inflammatory events resulting in cervical ripening.MethodsWe monitored GR and NFkappaB, prostaglandin synthases cyclooxygenase (COX)-1 and -2, iNOS, as well as the PAF-receptor (PAF-R) in the uterine cervix from term pregnant women (with unripe cervices) before the onset of labor (TP), immediately after parturition (PP), as compared to non-pregnant (NP), using immunohistochemistry and RT-PCR.ResultsThe GR protein was detected by immunohistochemistry in the nuclei of stroma and squamous epithelium (SQ). Stromal GR staining was increased in TP as compared to the NP group and decreased again after parturition. GR staining in SQ was decreased after parturition as compared to term. NFkappaB was present in SQ and glandular epithelium (GE), stroma and vascular endothelium. Increased nuclear NFkappaB staining was observed postpartum as compared to term pregnancy in stroma and GE. Stromal immunostaining for COX-1 as well as COX-2 was increased in the TP and PP groups as compared to the NP, and GE displayed an intensely increased COX-2 immunostaining at term and postpartum. Stromal PAF-R immunostaining was highest at term, while it was greatly increased in GE postpartum.No difference in the immunostaining for iNOS was found between the groups. RT-PCR showed a predominance of GRalpha to GRbeta mRNA in cervical tissue. The COX-2 mRNA level was increased in the PP group as compared to the TP group.ConclusionsThere is a decrease in GR levels in human cervix at parturition. Concomitantly there is an increase of factors such as NFkappaB, PAF-R, COX-1 and COX-2, suggesting that they may participate in the sequence of events leading to the final cervical ripening.

Maternal risk factors for postterm pregnancy and cesarean delivery following labor induction

Objective. To investigate risk factors associated with postterm pregnancy and cesarean delivery following labor induction. Design. Population‐based cohort study. Setting. Sweden. Population. From the Swedish Medical Birth Register, a total of 1,176,131 singletons births from gestational week 37 and onwards, between 1992 and 2006. Methods. Unconditional logistic regression analysis. Main outcome measures. Risk of postterm pregnancy (delivery at ≥42 weeks) and cesarean delivery following labor induction. Results. Among 1,176,131 births, 8.94% were delivered postterm. Compared to normal weight women, the risk of postterm pregnancy in obese women was almost doubled (adjusted OR: 1.63, 95% CI 1.59–1.67). The risk of postterm pregnancy increased with increasing maternal age and was higher among primiparous women. The risk of cesarean section (CS) following labor induction postterm, increased with maternal age and BMI, and was more than doubled among women 35 years and older (adjusted OR 2.28, 95% CI 2.04–2.56). A fivefold risk of CS was seen among nulliparous women (adjusted OR 5.05, 95% CI 4.71–5.42). Parous women with a previous CS undergoing labor induction had a sevenfold increased risk of CS postterm (adjusted OR 7.19, 95% CI 5.93–8.71). Conclusions. Nulliparity, advanced maternal age and obesity were the strongest risk factors for postterm pregnancy and CS following labor induction in postterm pregnancy. Including maternal risk factors to the cervical assessment may improve prediction of vaginal delivery following labor induction in postterm pregnancy.

Pro-inflammatory and anti-inflammatory cytokines in human preterm and term cervical ripening

Cervical ripening is necessary for successful delivery. Since cytokines are believed to be involved in this process, the aim of this study was to investigate possible changes in the mRNA and protein expression of pro-inflammatory cytokines (interleukin (IL)-1alpha, IL-1beta, IL-12, IL-18) and anti-inflammatory cytokines (IL-4, IL-10, IL-13) in the human cervix during pregnancy, term and preterm labor. Cervical biopsies were taken from 59 women: 21 at preterm labor, 24 at term labor, 10 at term not in labor and 4 from non-pregnant women. mRNA was analyzed with real-time RT-PCR and protein expression and/or secretion with immunohistochemistry and ELISA. There was an upregulation of mRNA for IL-10, IL-13, IL-1alpha and IL-1beta in the laboring groups, while mRNA for IL-12 and IL-18 was downregulated. IL-4 mRNA was detected more frequently, while IL-12 mRNA expression was lower, in the preterm labor group than in the term labor group. The protein levels of IL-4 and IL-12 were lower and IL-18 tended to be higher in the labor groups, while IL-10 protein levels were unaffected by labor. IL-4 protein levels were significantly higher in the preterm subgroup with bacterial infection than in the non-infected group. IL-10 had higher expression in squamous epithelium at preterm labor than at term. In conclusion, the major changes in pro-inflammatory and anti-inflammatory cytokine mRNA and protein expression in cervix occur during the labor process irrespective of the length of gestation. Our results indicate that dysregulation of anti-inflammatory cytokines in the human cervix could be involved in the pathogenesis of preterm labor.

mRNA expression and localization of bNOS, eNOS and iNOS in human cervix at preterm and term labour

BackgroundPreterm birth is the primary cause of the neonatal mortality and morbidity. There will be no preterm birth without a cervical softening. Nitric oxide (NO) is shown to be a mediator of term cervical ripening. The aim of this study was to investigate mRNA expression of the three isomers of NO synthases (NOS) and to identify them by immunohistochemistry in the human cervix at preterm birth compared to term.MethodsThe three isomers of NOS- inducible (iNOS), endothelial (eNOS) and neuronal (bNOS) – were investigated in the human cervix. The expression of mRNA was determined using Real-Time Multiplex RT-PCR. The localisation of synthases in the cervical tissue was analysed using immunohistochemistry. Cervical biopsies were obtained from 4 groups of women without clinical signs of infection: preterm (PTL), term labour (TL), preterm not in labour (PTnotL) and term not in labour (TnotL) patients. One-Way ANOVA, Kruskal-Wallis, Student t-test or Mann-Whitney test were applied as appropriate to determine statistically significant differences among the groups.ResultsPatients in preterm labour had significantly (p < 0.01) higher mRNA levels of all the three NOS isomers compared to those in term labour. Women not in labour, irrespective of gestational age, thus with unripe cervices, had significantly lower eNOS mRNA levels compared to those in labour (p < 0.01). Immunoreactivity for all three NO synthases was observed in each examined sample in all groups. The bNOS staining was the most prominent.ConclusionThe mRNA levels were higher in the preterm labour group compared to the women at term labour. The significant increase of the eNOS mRNA expression, from the unripe to the favourable cervical state during labour, may indicate a role of eNOS and supports the role of NO in the cervical ripening process. All the three synthases were identified by immunohistochemistry in all the groups of study.

Post-partum urinary retention: a comparison between two methods of epidural analgesia

OBJECTIVE To compare two methods of epidural labor analgesia regarding the incidence of post-partum urinary retention. STUDY DESIGN One thousand parturients who requested epidural analgesia for the relief of labor pain received, at random, either bupivacaine 0.25% with adrenaline 1:200 000 (n = 500) or bupivacaine 0.125% with 10 micrograms sufentanil (n = 500). During the same observation period all women with clinically significant urinary retention (> 500 ml, requiring indwelling catheter) were registered. RESULT Altogether 30/3.364 parturients had clinically significant urinary retention. Twenty-seven of these had received epidural analgesia (EDA) (17 with bupivacaine/adrenaline and ten with bupivacaine/sufentanil, a non-significant differences). The number of parturients with urinary retention was highly increased following EDA (27/1000) as compared to those not receiving EDA (3/2364), P < 0.001 (Fishers exact test). In patients with EDA and urinary retention there were no difference between the groups in the incidence of instrumental deliveries or vaginal/perirectal tears. All parturients regained normal bladder function. CONCLUSION EDA significantly increased the risk of post-partum urinary retention but no difference was found between the two epidural techniques.