Tafoxiparin, a novel drug candidate for cervical ripening and labor augmentation: results from 2 randomized, placebo-controlled studies.

BACKGROUND: Slow progression of labor is a common obstetrical problem with multiple associated complications. Tafoxiparin is a depolymerized form of heparin with a molecular structure that eliminates the anticoagulant effects of heparin. We report on 2 phase II clinical studies of tafoxiparin in primiparas. Study 1 was an exploratory, first-in-pregnant-women study and study 2 was a dose-finding study. OBJECTIVE: Study 1 was performed to explore the effects on labor time of subcutaneous administration of tafoxiparin before onset of labor. Study 2 was performed to test the hypothesis that intravenous treatment with tafoxiparin reduces the risk for prolonged labor after spontaneous labor onset in situations requiring oxytocin stimulation because of dystocia. STUDY DESIGN: Both studies were randomized, double-blind, and placebo-controlled. Participants were healthy, nulliparous females aged 18 to 45 years with a normal singleton pregnancy and gestational age confirmed by ultrasound. The primary endpoints were time from onset of established labor (cervical dilation of 4 cm) until delivery (study 1) and time from start of study treatment infusion until delivery (study 2). In study 1, patients at 38 to 40 weeks of gestation received 60 mg tafoxiparin or placebo daily as 0.4 mL subcutaneous injections until labor onset (maximum 28 days). In study 2, patients experiencing slow progression of labor, a prolonged latent phase, or labor arrest received a placebo or 1 of 3 short-term tafoxiparin regimens (initial bolus 7, 21, or 35 mg followed by continuous infusion at 5, 15, or 25 mg/hour until delivery; maximum duration, 36 hours) in conjunction with oxytocin. RESULTS: The number of participants randomized in study 1 was 263, and 361 were randomized in study 2. There were no statistically significant differences in the primary endpoints between those receiving tafoxiparin and those receiving the placebo in both studies. However, in study 1, the risk for having a labor time exceeding 12 hours was significantly reduced by tafoxiparin (tafoxiparin 6/114 [5%] vs placebo 18/101 [18%]; P=.0045). Post hoc analyses showed that women who underwent labor induction had a median (range) labor time of 4.44 (1.2-8.5) hours with tafoxiparin and 7.03 (1.5-14.3) hours with the placebo (P=.0041) and that co-administration of tafoxiparin potentiates the effect of oxytocin and facilitates a shorter labor time among women with a labor time exceeding 6 to 8 hours (P=.016). Among women induced into labor, tafoxiparin had a positive effect on cervical ripening in 11 of 13 cases (85%) compared with 3 of 13 participants (23%) who received the placebo (P=.004). For women requiring oxytocin because of slow progression of labor, the corresponding results were 34 of 51 participants (66%) vs 16 of 40 participants (40%) (P=.004). In study 2, tafoxiparin had no positive effects on the secondary endpoints when compared with the placebo. Except for injection-site reactions in study 1, adverse events were no more common for tafoxiparin than for the placebo among either mothers or infants. There were few serious or treatment-related adverse events. CONCLUSION: Subcutaneous treatment with tafoxiparin before labor onset (study 1) may be effective in reducing the labor time among women undergoing labor induction and among those requiring oxytocin for slow progression of labor. Moreover, tafoxiparin may have a positive effect on cervical ripening. Short-term, intravenous treatment with tafoxiparin as an adjunct to oxytocin in patients with labor arrest (study 2) did not affect labor time or other endpoints. Both studies suggest that tafoxiparin has a favorable safety profile in mothers and their infants.

Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer.

Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1-14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer.

Higher alcohol consumption in early pregnancy or low-to-moderate drinking during pregnancy may affect children's behaviour and development at one year and six months.

AIM: It is unclear whether low-to-moderate alcohol consumption during pregnancy affects child development. This study examined the effects that a mother's self-reported alcohol consumption had on her pregnancy and her child's birth, behaviour and development. METHODS: We asked 291 Swedish women to report their alcohol consumption before and during pregnancy using the Alcohol Use Disorders Identification Test (AUDIT); provide data on their pregnancy, labour and neonatal period; and complete a child behaviour and development questionnaire when their child was one year and six months of age. The mothers were separated into four subgroups based on their AUDIT scores. RESULTS: There were no group differences in gestational length, but children were shorter at birth if their mother drank during pregnancy. Mothers with the highest alcohol consumption before pregnancy were generally younger and more likely to smoke, have unplanned pregnancies and have children who displayed behavioural problems than controls who reported abstinence before and during pregnancy. Mothers who drank more during pregnancy than before were more likely to have had abortions and unplanned pregnancies and less likely to breastfeed for more than six months. CONCLUSION: Our results suggested that low-to-moderate alcohol consumption during pregnancy may negatively influence a child's development and behaviour in several ways.

Alcohol consumption among pregnant women in a Swedish sample and its effects on the newborn outcomes.

BACKGROUND: Little is known about the effects of low levels of maternal alcohol intake on the neuropsychological development of the child. This study is part of an ongoing investigation on maternal drinking and presents data on demographic variables, maternal alcohol use, and birth outcomes from that study. METHODS: The sample comprised 2,264 women from a Swedish antenatal clinic. Retrospective self-report data were collected on alcohol consumption before and during pregnancy, using the Alcohol Use Disorders Identification Test (AUDIT), and on nicotine use. Specific alcohol biomarkers for excessive drinking, carbohydrate-deficient transferrin (CDT) in serum and phosphatidylethanol (PEth) in whole blood, were determined during mid-pregnancy in a subsample of the women. Data on labor and early characteristics of the child were also assessed. RESULTS: Before pregnancy, 89% of the women regularly consumed alcohol and 49% reported occasional or frequent binge drinking. Nicotine was used by 15% before and by 5% during pregnancy. During pregnancy, 12% continued using alcohol and 5% also admitted binge drinking. However, all alcohol biomarker values were below the reporting limits (CDT ≤ 1.7% disialotransferrin; total PEth < 0.1 µmol/L). Self-reported drinking during pregnancy was associated with a higher AUDIT score before pregnancy, nicotine use at the time of the first prenatal visit, older age, and previous legal abortions. CONCLUSIONS: The AUDIT questionnaire and 2 specific alcohol biomarkers were used in routine maternity care to collect information about drinking during pregnancy and thereby to identify children at risk for alcohol-related complications. While the AUDIT results suggested that a significant number of women continued using alcohol during pregnancy, implying a risk for fetal disorders, the biomarkers showed negative test values thus indicating only modest drinking levels.

The expression of syndecan-1, syndecan-4 and decorin in healthy human breast tissue during the menstrual cycle.

BACKGROUND: In order to unravel the interactions between the epithelium and the extra cellular matrix (ECM) in breast tissue progressing to cancer, it is necessary to understand the relevant interactions in healthy tissue under normal physiologic settings. Proteoglycans in the ECM play an important role in the signaling between the different tissue compartments. The proteoglycan decorin is abundant in the breast stroma. Decreased expression in breast cancer tissue is a sign of a poor tumor prognosis. The heparane sulphate proteoglycans syndecan-1 and syndecan-4 promote the integration of cellular adhesion and proliferation. The aim of this study was to investigate the gene expression and location of decorin, syndecan-1 and syndecan-4 in the healthy breast during the menstrual cycle. METHODS: Tissue from healthy women undergoing breast reduction plastic surgery was examined using immunohistochemistry (n = 38) and Real-Time RT-PCR (n = 20). Both parous and nulliparous women were eligible and the mean age of the women was 34(+/- 10 years) with regular menstrual cycles (28 +/- 7 days). None of the women had used hormonal treatment the last three months. The women were randomized to needle biopsy two months before the operation in the follicular or luteal menstrual phase and for another biopsy at the operation in the opposite phase. Serum samples were obtained to characterize the menstrual phase. The Wilcoxon signed rank test and Mann Whitney test were used for statistical analyses. RESULTS: By real time-RT-PCR the gene signal for all three proteoglycans; decorin (p = 0.02) and syndecan-1 (p = 0.03) and syndecan-4 (p = 0.02) was significantly lower among parous women in the luteal phase than in the follicular phase. Immunohistochemistry confirmed the identification of the proteins but no significant difference between menstrual phases was observed. Serum samples verified the menstrual phase. CONCLUSIONS: Our study shows, for the first time in the healthy breast, a significantly lower expression of the genes for the three proteoglycans, decorin, syndecan-1 and syndecan-4 in the luteal phase during the menstrual cycle. These changes were registered under normal physiologic conditions. Since ECM molecules appear to be involved in tumor progression, these findings in the normal breast could constitute a base for further studies in women receiving hormonal therapy or those with breast cancer.

Effects of pre- and postmenopausal use of exogenous hormones on receptor content in normal human breast tissue: a randomized study.

OBJECTIVE: To examine the effects of exposure to endogenous and exogenous hormones on estrogen receptor-alpha (ERalpha) and progesterone receptor (PR) levels in normal human breast tissue. METHODS: In a randomized study of women scheduled for mammary reduction plasty (n = 81), ERalpha and PR content in breast parenchyma was analyzed in premenopausal (n = 49) and postmenopausal (n = 16) women. Premenopausal women were randomized to surgery in the follicular or luteal phase of the menstrual cycle or after oral contraceptive treatment for 2 months. Postmenopausal women were randomized to sequential or estrogen-only therapy for 2 months prior to surgery. RESULTS: ERalpha content was higher in parous than in nulliparous (p = 0.009) premenopausal women and displayed a positive association with age (r(s) = 0.51, p = 0.0002). Compared with premenopausal women in the follicular phase, postmenopausal women had higher ERalpha content (p = 0.040) whereas premenopausal women on oral contraception had lower ERalpha (p = 0.048) and PR (p = 0.007) content. Smokers had lower PR content than non-smokers (p = 0.02). CONCLUSION: In the present study ERalpha content was higher in parous than in non-parous women and associated with premenopausal age. Short-term oral contraceptives yielded lower ERalpha and PR contents. Postmenopausal estrogen/progestogen combined therapy yielded lower PR content than estrogen-only therapy.

Self-reported exposure to severe events on the labour ward among Swedish midwives and obstetricians: A cross-sectional retrospective study.

BACKGROUND: The process of delivery entails potentially traumatic events in which the mother or child becomes injured or dies. Midwives and obstetricians are sometimes responsible for these events and can be negatively affected by them as well as by the resulting investigation or complaints procedure (clinical negligence). OBJECTIVE: To assess the self-reported exposure rate of severe events among midwives and obstetricians on the delivery ward and the cumulative risk by professional years and subsequent investigations and complaints. DESIGN: Cross-sectional survey. PARTICIPANTS: Members of the Swedish Association of Midwives (SFB) and the Swedish Society of Obstetrics and Gynaecology (SFOG). METHODS: A questionnaire covering demographic characteristics, experiences of self-reported severe events on the delivery ward, and complaints of medical negligence was developed. Potential consequences of the complaint was not reported. A severe event was defined as: 1) the death of an infant due to delivery-related causes during childbirth or while on the neonatal ward; 2) an infant being severely asphyxiated or injured at delivery; 3) maternal death; 4) very severe or life threatening maternal morbidity; or 5) other stressful events during delivery, such as exposure to violence or aggression. RESULTS: The response rate was 39.9% (n=1459) for midwives and 47.1% (n=706) for obstetricians. Eighty-four percent of the obstetricians and almost 71% of responding midwives had experienced one or more self-reported severe obstetric event with detrimental consequences for the woman or the new-born. Fourteen percent of the midwives and 22.4% of the obstetricians had faced complaints of medical negligence from the patient or the family of the patient. CONCLUSIONS: A considerable proportion of midwives and obstetricians will, in the course of their working life, experience severe obstetric events in which the mother or the new-born is injured or dies. Preparedness for such exposure should be part of the training, as should managerial and peer support for those in need. This could prevent serious consequences for the health care professionals involved and their subsequent careers.

[Incontinentia pigmenti. A rare disease with many symptoms]. / Incontinentia pigmenti. En ovanlig sjukdom med många symtom.

Incontinentia pigmenti, also known as Bloch-Sulzberger syndrome, is a rare multi-systemic disorder. The disease is characterised by abnormalities in ectodermal tissues including the skin, eyes, central nervous system and dentition. It is inherited as an X-linked dominant trait and is usually fatal for male fetuses. Thirty-eight Swedish patients from 16 families were identified. Thirty patients were examined clinically and their DNA were analysed for deletions in the NEMO-gene. The disease showed a large clinical variability even within families and the common deletion in the NEMO-gene was found present in 70% of the families.