Risk factors for persistent pain and its influence on maternal wellbeing after cesarean section.

OBJECTIVES: To investigate the overall incidence and risk factors for persistent pain and its interference with daily life after cesarean section. DESIGN: Prospective long-term follow-up study. SETTING: Karolinska University Hospital, Stockholm, Sweden. POPULATION: 260 healthy women who underwent elective cesarean section. METHODS: Information on demographics, medical history, postoperative pain and analgesic requirements was collected. A questionnaire consisting of the Brief Pain Inventory was posted at 3, 6 and 12 months after surgery. Women rated pain intensity as well as interference with factors related to general function and quality of life. MAIN OUTCOME MEASURES: The overall incidence and risk factors for persistent postoperative pain at three time points. Persistent pain was considered a secondary outcome. RESULTS: At 3, 6 and 12 months respectively 40, 27 and 22% of patients reported pain in one or more locations, in the surgical site as well as in other areas. A psychological indication, as well as a first cesarean section, increased the risk for pain at 3 months. Severe postoperative pain in the immediate postoperative period or undergoing a first cesarean section were significant independent risk factors for the development of persistent pain up to 6 months after cesarean section. Parameters related to quality of life were significantly impaired in women with persistent pain. CONCLUSION: Several factors, including severe postoperative pain, were shown to influence the risk for persistent pain after cesarean section. Long-term pain markedly affected women's wellbeing.

Observational study of vitamin D levels and pain in pregnant immigrant women living in Sweden.

The aim was to determine the prevalence of vitamin D insufficiency in pregnant immigrant women assessed by the levels of 25-hydroxyvitamin D, parathyroid hormone (PTH) and alkaline phosphatase (ALP) as well as the correlation to musculoskeletal pain. Sixty-eight pregnant immigrant women were included. Fifty-one native Swedish pregnant women served as controls. 25-hydroxyvitamin D, PTH, ALP and musculoskeletal pain, rated on a visual analogue scale, were analyzed in all women in gestational week 12 and in the immigrant women at 6-12 months postpartum. A significantly higher proportion of immigrant women (77.9%) had levels of 25-hydroxyvitamin D <25 nmol/l compared with 3.9% in controls. Of the immigrant women, 29.4% had 25-hydroxyvitamin D levels <12 nmol/l, but none of the controls. Musculoskeletal pain evaluated with a visual analogue scale (VAS) was significantly higher for the immigrant women than for the controls at gestational week 12. However, no within group correlation was seen between 25-hydroxyvitamin D levels, PTH or ALP and pain. A significant negative correlation between changes in 25-hydroxyvitamin D and pain from gestational week 12 to postpartum was observed. Hypovitaminosis D is prevalent in immigrant women living in Sweden. There is an indication that pain might be associated with hypovitaminosis D.

Intraoperative injection of bupivacaine-adrenaline close to the fascia reduces morphine requirements after cesarean section: a randomized controlled trial.

OBJECTIVE: The purpose of this study was to investigate whether a single injection of bupivacaine with adrenaline close to the fascia could decrease opiate consumption and pain in patients undergoing cesarean section in spinal anesthesia. DESIGN: Randomized double-blind controlled study. SETTINGS: Karolinska University Hospital, Huddinge, Sweden. POPULATION: 260 women scheduled for elective cesarean section were enrolled in the study. METHODS: The treatment group (n= 130) received 40 mL bupivacaine (2.5 mg/mL) with adrenaline (5 µg/mL) (Marcain® adrenalin) and the control group (n= 130) received 40 mL saline solution (0.9%), which was, in both groups, injected close to the fascia before closure of the wound. MAIN OUTCOME MEASURES: Morphine consumption and mean resting pain intensity numerical rating scale at 12 and 24 hours were the primary outcome variables. Other assessments for pain as well as mobilization parameters were considered secondary. RESULTS: Morphine requirements were significantly less in the bupivacaine group, 19.0 mg/woman, compared with 24.0 mg/woman in the placebo group, during the first 12 postoperative hours. During this time period there was also a trend towards a difference between groups in mean pain intensity, but significant only during the first six hours. Over the whole first postoperative 24 hours, there were no differences in either morphine requirement or pain intensity between groups. CONCLUSIONS: A single injection of bupivacaine with adrenaline in the surgical wound decreases the need for morphine requirements for the first 12 postoperative hours and contributes to safe and effective pain management in women undergoing cesarean section.

Oral oxycodone for pain after caesarean section: A randomized comparison with nurse-administered IV morphine in a pragmatic study.

Background and aims The present randomized open label parallel group study was conducted to evaluate if an oral oxycodone (OXY) regimen can be at least equally effective and as safe for postoperative analgesia after caesarean section (CS) as a standard of care program using nurse-administered intravenous morphine (IVM), followed by oral codeine. Methods Eighty women (40 + 40) were scheduled for elective CS under spinal anaesthesia. All patients received postoperative multimodal analgesic therapy, including ibuprofen and paracetamol. The OXY group got standardized extended release and short acting oral treatment (and in a few cases intravenous OXY) as needed and the other group received current standard of care, IVM as needed for 24 h, followed by codeine. Opioid treatment lasted maximum five days. Outcome measures were pain intensity (numerical rating scale, NRS), opioid requirements, duration of administering opioids and safety for mother and newborn. All opioids in the study were expressed in OXY equivalents, using a conversion table. As the bioavailability of each opioid has a certain extent of interindividual bioavailability this conversion represents an approximation. The possible influence of opioids on the newborns was evaluated by the Neurological Adaptive Capacity Score at birth and at 24 and 48 h. Results During the first 24 h, there were no differences between treatments in opioid requirements or mean pain intensity at rest but pain intensity when asking for rescue medication was lower in the OXY than in the IVM group (mean ± SD; 5.41 ± 6.42 vs. 6.42 ± 1.61; p = 0.027). Provoked pain (uterus palpation) during the first 6h was also less in the OXY group (3.26 ± 2.13 vs. 4.60 ± 2.10; p = 0.007). During the 25-48 h period postoperatively, patients on OXY reported significantly lower pain intensity at rest (2.9 ± 1.9 vs. 3.8 ± 1.8; p = 0.039) and consumed less opioids (OXY equivalents; mg) (31.5 ± 9.6 vs. 38.2 ± 38.2; p = 0.001) than those on IVM/codeine. The total amount of opioids 0-5 days postoperatively was significantly lower in the OXY than in the IVM/codeine group (108.7 ± 37.6 vs. 138.2 ± 45.1; p = 0.002). Duration of administering opioids was significantly shorter in the OXY group. Time to first spontaneous bowel movement was shorter in the OXY group compared with the IVM/codeine group. No serious adverse events were recorded in the mothers but the total number of common opioid adverse effects was higher among women on IVM/codeine than among those receiving OXY (15 vs. 3; p = 0.007). No adverse outcomes in the newborns related to treatment were observed in either group. Conclusions In a multimodal protocol for postoperative analgesia after CS better pain control and lower opioid intake was observed in patients receiving oral OXY as compared to those on IVM/codeine. No safety risks for mother and child were identified with either protocol. Implications Our findings support the view that use of oral OXY is a simple, effective and time saving treatment for postoperative pain after CS.

Expression of Bcl-2, Bcl-x, Mcl-1, Bax and Bak in human uterine leiomyomas and myometrium during the menstrual cycle and after menopause.

To investigate the expression of Bcl-2, Bcl-x, Mcl-1, Bax and Bak proteins in human uterine leiomyomas and homologous myometrium during the menstrual cycle and after menopause. The expression of Bcl-2, Bcl-x, Mcl-1, Bax and Bak in leiomyomas (n=24) and myometrial samples (n=22) from women with leiomyomas was measured by immunohistochemistry and Western blot. Measured by immunohistochemistry, a significant difference between leiomyomas and myometrium was observed only for the Bax protein, in tissues obtained from women in the secretory phase of the menstrual cycle. The Bcl-2 staining was more abundant in leiomyomas than in myometrium only in tissues obtained in the proliferative phase of the cycle. Bcl-2 was more abundant in leiomyomas from women of fertile age than in leiomyomas from menopausal women. No significant differences were observed for the Bcl-x or Bak proteins, whereas the Mcl-1 protein was significantly less abundant in secretory phase leiomyomas than in leiomyomas from menopausal women. Western blot analysis based on pools of tissue extracts from the different groups essentially confirmed the data obtained by immunohistochemistry. Bcl-2 family proteins are expressed in leiomyomas and myometrium in different phases related to and influenced by gonadal steroids. These proteins are suggested to interact with each other in the regulation of programmed cell death, apoptosis, but their specific role in growth control of uterine leiomyomas remains to be investigated.

Expression of progesterone receptors A and B and insulin-like growth factor-I in human myometrium and fibroids after treatment with a gonadotropin-releasing hormone analogue.

OBJECTIVE: To determine mRNA and protein expression of the progesterone receptor (PR) and insulin-like growth factor-I (IGF-I) in myometrium and fibroids. DESIGN: Retrospective clinical study. SETTING: Hospital-based and university-affiliated research laboratories. PATIENT(S): Twelve women in the proliferative phase and six women treated with GnRH analogue (GnRH-a). INTERVENTION(S): Blood sampling and collection of myometrium and fibroids. MAIN OUTCOME MEASURE(S): PR and IGF-I mRNA levels in fibroids and myometrium were analyzed by solution hybridization and in situ hybridization whereas the proteins were localized by immunohistochemistry. RESULT(S): Fibroids and myometrium from women in the proliferative phase showed significantly higher PR mRNA than the corresponding tissues from GnRH-a-treated women. The amount of cells positively stained for PR-AB and PR-B in fibroids and myometrium decreased after GnRH-a treatment compared with in the proliferative phase. The IGF-I mRNA in both fibroids and myometrium in the proliferative phase was significantly higher than those after GnRH-a treatment. The immunostaining of IGF-I showed no difference between the two tissues. There was weaker immunostaining in the GnRH-a-treated group compared with in the proliferative phase group. CONCLUSION(S): The shrinkage of fibroids after steroid deprivation is associated with alterations in PR and IGF-I expression.

Vitamin D levels in children born to vitamin D-deficient mothers.

AIM: To determine whether a standard daily dose of 400 IU vitamin D is sufficient to normalize vitamin D levels in infants born to vitamin D-deficient mothers. METHODS: The children were recruited from a study cohort of 68 immigrant and 51 non-immigrant pregnant women living in Stockholm. The women were monitored at 12 weeks of pregnancy, at delivery and together with their children, 6-18 months after birth. During pregnancy, most immigrant women (78%) had 25(OH)D3 levels <25 nmol/l. We here report the outcome of 25 infants born to these mothers. All infants received a daily supplementation dose of 400 IU vitamin D from 2 weeks of age. RESULTS: At birth, most children in the immigrant group were vitamin D-deficient (23.3 nmol/l (12-54); mean and range) while at 6-18 months of age vitamin D levels were essentially normalized (82.8 nmol/l (38-142)) although 4 children still had subnormal levels consistent with vitamin D insufficiency. CONCLUSION: A daily recommended supplementation dose of 400 IU vitamin D is sufficient in most children of vitamin D-deficient immigrant women living in Sweden.

Targeted routine antenatal anti-D prophylaxis in the prevention of RhD immunisation--outcome of a new antenatal screening and prevention program.

OBJECTIVE: To estimate the incidence of RhD immunisation after implementation of first trimester non-invasive fetal RHD screening to select only RhD negative women carrying RHD positive fetuses for routine antenatal anti-D prophylaxis (RAADP). MATERIALS AND METHODS: We present a population-based prospective observational cohort study with historic controls including all maternity care centres and delivery hospitals in the Stockholm region, Sweden. All RhD negative pregnant women were screened for fetal RHD genotype in the first trimester of pregnancy. Anti-D immunoglobulin (250-300 µg) was administered intramuscularly in gestational week 28-30 to participants with RHD positive fetuses. Main outcome measure was the incidence of RhD immunisation developing during or after pregnancy. RESULTS: During the study period 9380 RhD negative women gave birth in Stockholm. Non-invasive fetal RHD genotyping using cell-free fetal DNA in maternal plasma was performed in 8374 pregnancies of which 5104 (61%) were RHD positive and 3270 (39%) RHD negative. In 4590 pregnancies with an RHD positive test the women received antenatal anti-D prophylaxis. The incidence of RhD immunisation in the study cohort was 0.26 percent (24/9380) (95% CI 0.15-0.36%) compared to 0.46 percent (86/18546) (95% CI 0.37 to 0.56%) in the reference cohort. The risk ratio (RR) for sensitisation was 0.55 (95% CI 0.35 to 0.87) and the risk reduction was statistically significant (p = 0.009). The absolute risk difference was 0.20 percent, corresponding to a number needed to treat (NNT) of 500. CONCLUSIONS: Using first trimester non-invasive antenatal screening for fetal RHD to target routine antenatal anti-D prophylaxis selectively to RhD negative women with RHD positive fetuses significantly reduces the incidence of new RhD immunisation. The risk reduction is comparable to that reported in studies evaluating the outcome of non selective RAADP to all RhD negative women. The cost-effectiveness of this targeted approach remains to be studied.

mRNA-expression of often used house-keeping genes and the relation between RNA and DNA are sex steroid-dependent parameters in human myometrium and fibroids.

The content of RNA and DNA in human myometrium and fibroids obtained at different endocrine conditions varied, with the highest RNA/DNA ratio in tissues from pregnant patients, intermediate ratios in women during the menstrual cycle and the lowest in tissues from postmenopausal and GnRHa-treated patients. mRNA expression of two house-keeping genes, gamma-actin and GAPDH, was highest in myometrium from pregnant women, intermediate in untreated women of fertile age and lowest in tissues from GnRHa-treated and postmenopausal women. To control for degradation of nucleic acids when measuring mRNA expression, we suggest additional analysis of gene(s), where the expression pattern is known, and that expression, whenever possible, is related to DNA, which is a more stable parameter than RNA and total nucleic acids, when there are differences in proliferation between tissues and/or groups of patients.

Gene expression profiling of the effects of castration and estrogen treatment in the rat uterus.

The development and functions of female reproductive tissues are regulated by the actions of two major sex steroid hormones, estrogen and progesterone. To investigate estrogen-dependent gene expression in the rat uterus, we studied the effect of ovariectomy with or without estrogen treatment on the uterine expression of 3000 genes using cDNA microarrays. Many genes were regulated by either treatment, but only few were reciprocally regulated by these contrasting treatments. The present study confirms previous findings and identifies several genes with expressions not previously known to be influenced by estrogen. These genes include follistatin-related protein, Thy-1 glycoprotein, alpha-fodrin, CD24, immediate early response 5, insulin-like growth factor-binding protein 2, growth response protein CL-6 (INSIG-1), ladinin1, class I major histocompatibility complex heavy chain, lactadherin, ezrin, and Fas-activated serine/threonine kinase. Because of their function as regulators of proliferation and apoptosis, CD24, insulin-like growth factor-binding protein 2, and Fas/Fas ligand were examined further by immunohistochemical expression and tissue localization analysis. Our analysis confirms a contrasting regulation of these gene products by ovariectomy and estrogen treatment. The present study identifies novel mediators of estrogen actions in the uterus and provides genome-wide expression data from which novel hypotheses regarding uterine function can be generated.

Identification of genes with higher expression in human uterine leiomyomas than in the corresponding myometrium.

We used a PCR-based subtraction method, representational difference analysis of cDNA (cDNA--RDA), to identify genes with a higher expression in leiomyomas in comparison with the corresponding myometrium during the proliferative phase of the menstrual cycle. Increased expression of the genes for pregnancy-associated plasma protein A (PAPPA), tomoregulin, cellular retinoid acid binding protein 1 (CRABP1), zinc finger protein 185 (ZFP 185) and latent transforming growth factor beta binding protein 2 (LTBP2) was demonstrated in individual leiomyoma samples compared with corresponding myometrium. Additionally, a specific positive immunostaining of LTBP2 was found in the smooth muscle cells of both leiomyomas and myometrium. These genes may be part of previously unidentified molecular mechanisms responsible for the selective growth advantage of leiomyomas compared with myometrium. This work expands our knowledge about the molecular nature of leiomyomas and provides novel candidate genes to further explore in relation to their function during leiomyoma growth.