The impact of age and parity on the experience of relief and regret in women who have undergone hysterectomy for benign disease: A cross sectional survey.

OBJECTIVE: To investigate the impact of age and parity on the experience on relief and regret following elective hysterectomy for benign disease, and to explore the factors that impact relief and regret. DESIGN: Retrospective cross-sectional survey of a cohort. SETTING: Single-centre tertiary hospital in Melbourne, Australia. POPULATION: Patients who underwent elective hysterectomy for benign indications from 01 January 2008 - 31 July 2015 (inclusive) with age <51 years at time of admission. METHODS: Eligible participants completed a retrospective survey regarding their experience of relief and regret following hysterectomy. MAIN OUTCOME MEASURES: Regret was defined as a positive response to "Do you regret the decision to have a hysterectomy?". Relief was defined as responding "agree/strongly agree" to "I feel relieved I had a hysterectomy". RESULTS: 268 of 1285 (21%) eligible participants completed the study questionnaire. Of these, 29 were aged <36 years at the time of hysterectomy. Seven percent (n=18/262) reported regretting having a hysterectomy and 88% (n=230/262) reported experiencing relief. We did not observe associations between age at hysterectomy and regret (aOR 0.93; 95% CI 0.85, 1.03), age at hysterectomy and relief (aOR 1.01; 95% CI 0.93, 1.09), nulliparity and regret (aOR 0.32; 95% CI 0.06, 1.59) or nulliparity and relief (aOR 2.37; 95% CI 0.75, 7.51). Desire for future pregnancy at the time of hysterectomy was more frequently reported in those who experienced regret vs no regret (46.7% vs 12.1%, OR: 6.33; 95% CI: 2.12, 18.90; p=0.001). CONCLUSIONS: Age and parity are not associated with relief nor regret following elective hysterectomy for benign disease.

Perineal trauma with vaginal birth after a previous caesarean section: A retrospective cohort study.

BACKGROUND: There is a paucity of information regarding perineal injuries in women who achieve vaginal birth after caesarean section (VBAC). AIMS: To ascertain the rate of severe perineal injuries in women achieving VBAC at a major tertiary obstetric hospital, and to determine if vaginal birth is more likely to be associated with perineal injuries in women with one previous caesarean section compared with nulliparous women. MATERIALS AND METHODS: A retrospective cohort study was undertaken of women with singleton pregnancies at term who delivered vaginally between 2013 and 2016. We compared nulliparous women with women who had undergone one previous caesarean section. The primary outcome analysed was the rate of third and fourth degree tears in each group. Secondary outcomes were major post-partum haemorrhage and instrumental delivery. RESULTS: Totals of 10 663 nulliparous women and 629 VBAC women achieved vaginal birth. Of the VBAC women, 418 achieved their first vaginal birth (first VBAC group). Overall, there was no significant difference in the rate of third and fourth degree tears in the VBAC group compared with the nulliparous group (6.0% vs 5.6%; P = 0.73). There was no significant increase in anal sphincter injuries in the first VBAC group compared with the nulliparous group (6.0% vs 7.4%; P = 0.25). CONCLUSION: No overall difference in the rate of severe perineal injuries between VBAC women and nulliparous women who achieve vaginal birth was observed in this study.

Managing menopausal symptoms after cancer: an evidence-based approach for primary care.

Impaired ovarian function and menopausal symptoms are common after cancer treatment. Menopausal symptoms often occur at an earlier age in women with cancer, and may be more severe than in natural menopause; they may be the most persistent and troubling sequelae of cancer. A third of female patients with cancer report dissatisfaction with the quality and length of physician-patient discussions about reproductive health, including menopause. Systemic menopausal hormone therapy is the most effective treatment for menopausal symptoms, but it is not suitable for all patients after cancer - where it is unsuitable, alternative effective non-hormonal treatments are available. Effective pharmacological agents available to treat vasomotor symptoms include selective serotonin reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors, clonidine and gabapentin. There is increasing evidence supporting cognitive behavioural therapy for the treatment of vasomotor symptoms, in self-help or group settings. Vaginal atrophy can be treated with vaginal (topical) oestrogen with minimal systemic absorption; topical vaginal lubricants may help with vaginal dryness and dyspareunia, with some evidence suggesting that silicone-based products may be more effective than water-based ones. Bone health may be impaired in post-menopausal women with cancer or in cancer survivors, particularly in women with treatment-related menopause or in women receiving anti-oestrogen therapies; this should be managed in addition to menopausal symptoms. Primary care physicians should be aware of the troublesome and ongoing nature of menopausal symptoms after cancer, should discuss them with all patients after cancer treatment, and should consider treatment or referral to a specialist for appropriate management.

A review of the mechanisms and evidence for typical and atypical twinning.

The mechanisms responsible for twinning and disorders of twin gestations have been the subject of considerable interest by physicians and scientists, and cases of atypical twinning have called for a reexamination of the fundamental theories invoked to explain twin gestations. This article presents a review of the literature focusing on twinning and atypical twinning with an emphasis on the phenomena of chimeric twins, phenotypically discordant monozygotic twins, mirror-image twins, polar body twins, complete hydatidiform mole with a coexistent twin, vanishing twins, fetus papyraceus, fetus in fetu, superfetation, and superfecundation. The traditional models attributing monozygotic twinning to a fission event, and more recent models describing monozygotic twinning as a fusion event, are critically reviewed. Ethical restrictions on scientific experimentation with human embryos and the rarity of cases of atypical twinning have limited opportunities to elucidate the exact mechanisms by which these phenomena occur. Refinements in the modeling of early embryonic development in twin pregnancies may have significant clinical implications. The article includes a series of figures to illustrate the phenomena described.

Identifying late-onset fetal growth restriction by measuring circulating placental RNA in the maternal blood at 28 weeks' gestation.

BACKGROUND: Late-onset fetal growth restriction (FGR) is often undetected prior to birth, which puts the fetus at increased risk of adverse perinatal outcomes including stillbirth. OBJECTIVE: Measuring RNA circulating in the maternal blood may provide a noninvasive insight into placental function. We examined whether measuring RNA in the maternal blood at 26-30 weeks' gestation can identify pregnancies at risk of late-onset FGR. We focused on RNA highly expressed in placenta, which we termed "placental-specific genes." STUDY DESIGN: This was a case-control study nested within a prospective cohort of 600 women recruited at 26-30 weeks' gestation. The circulating placental transcriptome in maternal blood was compared between women with late-onset FGR (<5th centile at >36+6 weeks) and gestation-matched well-grown controls (20-95th centile) using microarray (n = 12). TaqMan low-density arrays, reverse transcription-polymerase chain reaction (PCR), and digital PCR were used to validate the microarray findings (FGR n = 40, controls n = 80). RESULTS: Forty women developed late-onset FGR (birthweight 2574 ± 338 g, 2nd centile) and were matched to 80 well-grown controls (birthweight 3415 ± 339 g, 53rd centile, P < .05). Operative delivery and neonatal admission were higher in the FGR cohort (45% vs 23%, P < .05). Messenger RNA coding 137 placental-specific genes was detected in the maternal blood and 37 were differentially expressed in late-onset FGR. Seven were significantly dysregulated with PCR validation (P < .05). Activating transcription factor-3 messenger RNA transcripts were the most promising single biomarker at 26-30 weeks: they were increased in fetuses destined to be born FGR at term (2.1-fold vs well grown at term, P < .001) and correlated with the severity of FGR. Combining biomarkers improved prediction of severe late-onset FGR (area under the curve, 0.88; 95% CI 0.80-0.97). A multimarker gene expression score had a sensitivity of 79%, a specificity of 88%, and a positive likelihood ratio of 6.2 for subsequent delivery of a baby <3rd centile at term. CONCLUSION: A unique placental transcriptome is detectable in maternal blood at 26-30 weeks' gestation in pregnancies destined to develop late-onset FGR. Circulating placental RNA may therefore be a promising noninvasive test to identify pregnancies at risk of developing FGR at term.

Different treatment regimens of magnesium sulphate for tocolysis in women in preterm labour.

BACKGROUND: Magnesium sulphate has been used to inhibit preterm labour to prevent preterm birth. There is no consensus as to the safety profile of different treatment regimens with respect to dose, duration, route and timing of administration. OBJECTIVES: To assess the efficacy and safety of alternative magnesium sulphate regimens when used as single agent tocolytic therapy during pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2015) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised trials comparing different magnesium sulphate treatment regimens when used as single agent tocolytic therapy during pregnancy in women in preterm labour. Quasi-randomised trials were eligible for inclusion but none were identified. Cross-over and cluster trials were not eligible for inclusion. Health outcomes were considered at the level of the mother, the infant/child and the health service. INTERVENTION: intravenous or oral magnesium sulphate given alone for tocolysis.Comparison: alternative dosing regimens of magnesium sulphate given alone for tocolysis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and quality and extracted data. MAIN RESULTS: Three trials including 360 women and their infants were identified as eligible for inclusion in this review. Two trials were rated as low risk of bias for random sequence generation and concealment of allocation. A third trial was assessed as unclear risk of bias for these domains but did not report data for any of the outcomes examined in this review. No trials were rated to be of high quality overall.Intravenous magnesium sulphate was administered according to low-dose regimens (4 g loading dose followed by 2 g/hour continuous infusion and/or increased by 1 g/hour hourly until successful tocolysis or failure of treatment), or high-dose regimens (4 g loading dose followed by 5 g/hour continuous infusion and increased by 1 g/hour hourly until successful tocolysis or failure of treatment, or 6 g loading dose followed by 2 g/hour continuous infusion and increased by 1 g/hour hourly until successful tocolysis or failure of treatment).There were no differences seen between high-dose magnesium sulphate regimens compared with low-dose magnesium sulphate regimens for the primary outcome of fetal, neonatal and infant death (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.12 to 1.56; one trial, 100 infants). Using the GRADE approach, the evidence for fetal, neonatal and infant death was considered to be VERY LOW quality. No data were reported for any of the other primary maternal and infant health outcomes (birth less than 48 hours after trial entry; composite serious infant outcome; composite serious maternal outcome).There were no clear differences seen between high-dose magnesium sulphate regimens compared with low-dose magnesium sulphate regimens for the secondary infant health outcomes of fetal death; neonatal death; and rate of hypocalcaemia, osteopenia or fracture; and secondary maternal health outcomes of rate of caesarean birth; pulmonary oedema; and maternal self-reported adverse effects. Pulmonary oedema was reported in two women given high-dose magnesium sulphate, but not in any of the women given low-dose magnesium sulphate.In a single trial of high and low doses of magnesium sulphate for tocolysis including 100 infants, the risk of respiratory distress syndrome was lower with use of a high-dose regimen compared with a low-dose regimen (RR 0.31, 95% CI 0.11 to 0.88; one trial, 100 infants). Using the GRADE approach, the evidence for respiratory distress syndrome was judged to be LOW quality. No difference was seen in the rate of admission to the neonatal intensive care unit. However, for those babies admitted, a high-dose regimen was associated with a reduction in the length of stay in the neonatal intensive care unit compared with a low-dose regimen (mean difference -3.10 days, 95% confidence interval -5.48 to -0.72).We found no data for the majority of our secondary outcomes. AUTHORS' CONCLUSIONS: There are limited data available (three studies, with data from only two studies) comparing different dosing regimens of magnesium sulphate given as single agent tocolytic therapy for the prevention of preterm birth. There is no evidence examining duration of therapy, timing of therapy and the role for repeat dosing.Downgrading decisions for our primary outcome of fetal, neonatal and infant death were based on wide confidence intervals (crossing the line of no effect), lack of blinding and a limited number of studies. No data were available for any of our other important outcomes: birth less than 48 hours after trial entry; composite serious infant outcome; composite serious maternal outcome. The data are limited by volume and the outcomes reported. Only eight of our 45 pre-specified primary and secondary maternal and infant health outcomes were reported on in the included studies. No long-term outcomes were reported. Downgrading decisions for the evidence on the risk of respiratory distress were based on wide confidence intervals (crossing the line of no effect) and lack of blinding.There is some evidence from a single study suggesting a reduction in the length of stay in the neonatal intensive care unit and a reduced risk of respiratory distress syndrome where a high-dose regimen of magnesium sulphate has been used compared with a low-dose regimen. However, given that evidence has been drawn from a single study (with a small sample size), these data should be interpreted with caution.Magnesium sulphate has been shown to be of benefit in a wide range of obstetric settings, although it has not been recommended for tocolysis. In clinical settings where health benefits are established, further trials are needed to address the lack of evidence regarding the optimal dose (loading dose and maintenance dose), duration of therapy, timing of therapy and role for repeat dosing in terms of efficacy and safety for mothers and their children. Ongoing examination of different regimens with respect to important health outcomes is required.

Risk factors for high and low placental weight.

BACKGROUND: Placental weight is an independent predictor of adverse perinatal outcome. However, risk factors for high and low placental weight are poorly understood. The objective of this study was to identify maternal, placental, and umbilical cord determinants of placental weight, before and after accounting for birthweight. METHODS: This cohort study of 87,600 singleton births at the Royal Victoria Hospital in Montreal, Canada assessed the relationship between maternal, placental, and umbilical cord characteristics and placental weight (standardised for sex and gestational age). We separately examined risk factors for high (z-score >+1) and low (z-score <-1) placental weight. Multivariable logistic regression was used to study associations after adjusting for confounders and further adjusting for birthweight. RESULTS: Chronic hypertension was associated with low placental weight {relative risk (RR) 2.1 [95% confidence interval (CI) 1.8, 2.4] and 1.8 [95% CI 1.5, 2.1] before and after accounting for birthweight}, while pre-eclampsia was associated with low placenta weight before, but not after adjustment for birthweight. Anaemia and gestational diabetes were linked with high placental weight (RRs 1.2-1.4, respectively) before and after adjustment for birthweight, while smoking was linked with high placental weight only after adjustment for birthweight (RR 1.4 [95% CI 1.3, 1.5]). Placental and cord determinants of high placental weight included chorioamnionitis, chorangioma/chorangiosis, circumvallate placenta, marginal cord insertion, and other cord abnormalities. CONCLUSIONS: The broad range of risk factors for high placental weight suggests multiple aetiologic pathways. Future work should seek to understand the pathways by which the placenta adapts to unfavourable intrauterine conditions, which may provide insights into potential therapies.

Pain experience with outpatient hysteroscopy: A prospective cohort study.

BACKGROUND: Abnormal uterine bleeding (AUB) affects women of all ages and is one of the most common reasons for referral to a gynaecological clinic. Operative hysteroscopic procedures allow for a see-and-treat approach to AUB, and these techniques have been shown to be feasible and acceptable in the outpatient setting. OBJECTIVE: To assess if there is an increase in pain scores for women who are undergoing an operative hysteroscopic procedure with Myosure LITE® (Hologic; mechanical hysteroscopic tissue removal system) compared to outpatient diagnostic hysteroscopy alone. STUDY DESIGN: A prospective cohort study was performed. All participants attending the outpatient hysteroscopy clinic at Mercy Hospital for Women completed a pre-and post-procedure questionnaire. This included a visual analogue scale (VAS) for any pre-existing pain, anticipated pain, and actual pain experienced during procedure. Factors influencing overall satisfaction and willingness to attend again were also assessed. Data was entered into RedCap® for analysis. A difference in VAS of 10 mm or more was considered clinically significant. An alpha of p < 0.05 was assigned for statistical significance. RESULTS: Between February 2020 and November 2022, 208 women underwent outpatient diagnostic hysteroscopy followed by an operative hysteroscopy with MyoSure®. To allow for standardisation of analgesia, only participants who had a cervical block before their Myosure® procedure were included for analysis (n = 111). There was statistical evidence (t(111) = 2.36, p = 0.02) of a lower mean VAS pain score for operative Myosure (36.5 mm, 95 % CI: 31.1-41.8 mm) compared to outpatient diagnostic hysteroscopy (44.1 mm, 95 % CI: 39.0-49.2 mm). The mean difference in VAS pain score was estimated as 7.7 mm (95 % CI: 1.2-14.1 mm) lower for Myosure compared to hysteroscopy. Given the threshold for clinical significance was considered as 10 mm difference in VAS, the variance in pain scores is under the likely clinically significant range. There was no significant difference in pain scores for diagnostic hysteroscopy with or without paracervical block (mean difference = 1.42; 95 % CI: -6.35 to 9.20). There was no association between pre-existing pain, and actual pain for hysteroscopy, or Myosure (p = 0.997 and p = 0.065 respectively). The anticipated pain score was weakly associated with actual pain during the operative Myosure procedure (p = 0.02), and with outpatient diagnostic hysteroscopy (p = 0.019). CONCLUSION: Outpatient hysteroscopy procedures are generally well tolerated. The pain experience with operative Myosure was less than that reported during the diagnostic hysteroscopy by the same patient although this is unlikely of clinical significance. Importantly, Myosure was not more painful than the initial diagnostic procedure, and most patients were satisfied with the outcome and would choose to have the procedure again in an outpatient setting. This is in keeping with other studies which have shown a high degree of patient tolerance and satisfaction with this approach.

Smoking in preeclamptic women is associated with higher birthweight for gestational age and lower soluble fms-like tyrosine kinase-1 levels: a nested case control study.

BACKGROUND: Smoking paradoxically increases the risk of small-for-gestational-age (SGA) birth but protects against preeclampsia. Some studies have reported a "U-shaped" distribution of fetal growth in preeclamptic pregnancies, but reasons for this are unknown. We investigated whether cigarette smoking interacts with preeclampsia to affect fetal growth, and compared levels of soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating anti-angiogenic protein, in preeclamptic smokers and non-smokers. METHODS: From a multicenter cohort of 5337 pregnant women, we prospectively identified 113 women who developed preeclampsia (cases) and 443 controls. Smoking exposure was assessed by self-report and maternal hair nicotine levels. Fetal growth was assessed as z-score of birthweight for gestational age (BWGA). sFlt-1 was measured in plasma samples collected at the 24-26-week visit. RESULTS: In linear regression, smoking and preeclampsia were each associated with lower BWGA z-scores (ß = -0.29; p = 0.008, and ß = -0.67; p < 0.0001), but positive interaction was observed between smoking and preeclampsia (ß = +0.86; p = 0.0008) such that smoking decreased z-score by -0.29 in controls but increased it by +0.57 in preeclampsia cases. Results were robust to substituting log hair nicotine for self-reported smoking and after adjustment for confounding variables. Mean sFlt-1 levels were lower in cases with hair nicotine levels above vs. below the median (660.4 pg/ml vs. 903.5 pg/ml; p = 0.0054). CONCLUSIONS: Maternal smoking seems to protect against preeclampsia-associated fetal growth restriction and may account, at least partly, for the U-shaped pattern of fetal growth described in preeclamptic pregnancies. Smoking may exert this effect by reducing levels of the anti-angiogenic protein sFlt-1.

Peripheral, Central, and Cross Sensitization in Endometriosis-Associated Pain and Comorbid Pain Syndromes.

Endometriosis-associated pain and the mechanisms responsible for its initiation and persistence are complex and difficult to treat. Endometriosis-associated pain is experienced as dysmenorrhea, cyclical pain related to organ function including dysuria, dyschezia and dyspareunia, and persistent pelvic pain. Pain symptomatology correlates poorly with the extent of macroscopic disease. In addition to the local effects of disease, endometriosis-associated pain develops as a product of peripheral sensitization, central sensitization and cross sensitization. Endometriosis-associated pain is further contributed to by comorbid pain conditions, such as bladder pain syndrome, irritable bowel syndrome, abdomino-pelvic myalgia and vulvodynia. This article will review endometriosis-associated pain, its mechanisms, and its comorbid pain syndromes with a view to aiding the clinician in navigating the literature and terminology of pain and pain syndromes. Limitations of our current understanding of endometriosis-associated pain will be acknowledged. Where possible, commonalities in pain mechanisms between endometriosis-associated pain and comorbid pain syndromes will be highlighted.

Mid-trimester maternal plasma cytokines and CRP as predictors of spontaneous preterm birth.

Most previous studies of maternal cytokines and preterm birth have analyzed immunologic biomarkers after the onset of labor or membrane rupture; fewer have examined the systemic (blood) immune response prior to labor onset. We carried out a case-control study nested in a large (n=5337) prospective, multi-center cohort. Cohort women had an interview, examination, and venipuncture at 24-26 weeks. Frozen plasma samples in women with spontaneous preterm birth (n=207) and approximately 2 term controls per case (n=444) were analyzed using Luminex multianalyte profiling technology. Fresh placentas were fixed, stained, and blindly assessed for histologic evidence of infection/inflammation, decidual vasculopathy, and infarction, and vaginal swabs were analyzed for bacterial vaginosis and fetal fibronectin concentration. High maternal matrix metalloproteinase-9 (MMP-9) concentration, but none of the other cytokines or C-reactive protein (CRP), was significantly associated with spontaneous preterm birth [adjusted OR=1.7 (1.1-2.4)] and showed a dose-response relation across quartiles. No association was observed, however, between maternal MMP-9 and placental infection/inflammation, bacterial vaginosis, or vaginal fetal fibronectin concentration. Our results require confirmation in future studies but suggest that a systemic immune response implicating MMP-9 may have an etiologic role in spontaneous preterm birth.

Non-stress-related factors associated with maternal corticotrophin-releasing hormone (CRH) concentration.

During pregnancy, most maternal corticotrophin-releasing hormone (CRH) is secreted by the placenta, not the hypothalamus. Second trimester maternal CRH concentration is robustly associated with the subsequent risk of preterm birth, and it is often assumed that physiological and/or psychological stress stimulates placental CRH release. Evidence supporting the latter assumption is weak, however, and other factors affecting maternal CRH have received little attention from investigators. We carried out a case-control study nested within a large, multicentre prospective cohort of pregnant women to examine potential 'upstream' factors associated with maternal CRH concentration measured at 24-26 weeks of gestation. The predictors studied included maternal age, parity, birthplace (as a proxy for ethnic origin), pre-pregnancy body mass index, height, smoking, bacterial vaginosis and vaginal fetal fibronectin (FFN) concentration. Women with high (above the median) plasma CRH concentration were significantly less likely to have been born in Sub-Saharan Africa or the Caribbean, less likely to be overweight or obese, and more likely to be smokers. Associations with maternal birthplace and BMI persisted in logistic regression analyses controlling for potential confounding variables and when restricted to term controls. A strong (but imprecise and statistically non-significant) association was also observed with high vaginal FFN concentration. Further studies are indicated both in animal models and human populations to better understand the biochemical and physiological pathways to CRH secretion and their aetiological role, if any, in preterm birth.

Vaginal douching, bacterial vaginosis, and spontaneous preterm birth.

OBJECTIVE: Vaginal douching and bacterial vaginosis (BV) are independently associated with spontaneous preterm birth. Because the interrelationships among these variables remain unclear, we sought to examine the associations in a prospective study. METHODS: We conducted a nested case-control study within a prospectively recruited cohort of pregnant women. We prospectively collected demographic and health status data, data on pre-pregnancy vaginal douching, vaginal smears for bacterial vaginosis as defined by Nugent's criteria, fetal fibronectin at 26 weeks of pregnancy, and placental pathology at delivery. Spontaneous preterm births before 37 weeks' gestation were selected as cases. All spontaneous births occurring after 37 weeks were potential control subjects. To limit costs, some tests were performed only in selected control subjects. RESULTS: Preterm birth occurred in 207 of 5092 women (4.1%). In bivariate analysis, BV was not associated with preterm birth (OR 1.2; 95% CI 0.5 to 2.4). Vaginal douching was significantly associated with bacterial vaginosis (P < 0.05) and preterm birth (P < 0.05). On multivariate analysis, vaginal douching was no longer associated with preterm birth, but a significant association with early preterm birth < 34 weeks (OR, 6.9; 95% CI 1.7 to 28.2) and preterm birth due to preterm labour (OR 3.0; 95% CI 1.1 to 8.5) persisted after controlling for the presence of bacterial vaginosis and placental inflammation. CONCLUSION: Vaginal douching and bacterial vaginosis were not associated with spontaneous preterm birth overall. However, vaginal douching appears to be an independent and potentially modifiable risk factor for early preterm birth (32-34 weeks), although the mechanism remains unclear.

Stress pathways to spontaneous preterm birth: the role of stressors, psychological distress, and stress hormones.

The authors investigated a large number of stressors and measures of psychological distress in a multicenter, prospective cohort study of spontaneous preterm birth among 5,337 Montreal (Canada)-area women who delivered from October 1999 to April 2004. In addition, a nested case-control analysis (207 cases, 444 controls) was used to explore potential biologic pathways by analyzing maternal plasma corticotrophin-releasing hormone (CRH), placental histopathology, and (in a subset) maternal hair cortisol. Among the large number of stress and distress measures studied, only pregnancy-related anxiety was consistently and independently associated with spontaneous preterm birth (for values above the median, adjusted odds ratio = 1.8 (95% confidence interval: 1.3, 2.4)), with a dose-response relation across quartiles. The maternal plasma CRH concentration was significantly higher in cases than in controls in crude analyses but not after adjustment (for concentrations above the median, adjusted odds ratio = 1.1 (95% confidence interval: 0.8, 1.6)). In the subgroup (n = 117) of participants with a sufficient maternal hair sample, hair cortisol was positively associated with gestational age. Neither maternal plasma CRH, hair cortisol, nor placental histopathologic features of infection/inflammation, infarction, or maternal vasculopathy were significantly associated with pregnancy-related anxiety or any other stress or distress measure. The biologic pathways underlying stress-induced preterm birth remain poorly understood.

Antioxidant vitamins, long-chain fatty acids, and spontaneous preterm birth.

BACKGROUND: Neither macro- nor micronutrient supplements have been clearly demonstrated to reduce the risk of preterm birth. However, there has been little attention to carotenoids, tocopherols, and long-chain fatty acids other than n-3 polyunsaturates. METHODS: We conducted a case-control study nested in a large (n = 5337) prospective, multicenter cohort. All cohort women had an interview, examination, and venipuncture at 24-26 weeks' gestation. Frozen plasma samples in spontaneous preterm births (n = 207) and approximately 2-term controls per case (n = 443) were analyzed for carotenoids, retinol, tocopherols, and long-chain fatty acids. Fresh placentas were fixed, stained, and assessed (without knowledge of pregnancy outcome) for histologic evidence of infection or inflammation, decidual vasculopathy, and infarction. RESULTS: High (above the median) plasma concentrations of alpha- and beta-carotene, alpha- and beta-cryptoxanthin, and lycopene were all associated with reductions in risk of spontaneous preterm birth, with evidence of dose-response effects across quartiles. Modest increases in risk were observed with elevated total monounsaturated, total polyunsaturated, and total n-6 polyunsaturated long-chain fatty acids concentrations. Paradoxically, a high gamma-tocopherol concentration was associated with increased preterm birth risk (adjusted odds ratio = 1.8 [95% confidence interval = 1.2-2.6]). Only one of the studied micronutrients (lutein) was independently associated with a reduced risk of decidual vasculopathy (0.5 [0.3-0.9]). CONCLUSIONS: Carotenoids and long-chain fatty acids warrant further investigation in in vitro, animal, and human studies of preterm birth.

Inherited thrombophilia and preeclampsia within a multicenter cohort: the Montreal Preeclampsia Study.

OBJECTIVE: We sought to evaluate the association between inherited thrombophilia and preeclampsia. STUDY DESIGN: From a multicenter cohort of 5337 pregnant women, we prospectively identified 113 women who developed preeclampsia and selected 443 control subjects who did not have preeclampsia or nonproteinuric gestational hypertension. Blood samples were tested for DNA polymorphisms affecting thrombophilia (factor V Leiden mutation, prothrombin G20210A mutation, methylenetetrahydrofolate reductase C677T polymorphism), homocysteine, and folate levels, and placentae underwent pathological evaluation. RESULTS: Thrombophilia was present in 14% of patients and 21% of control subjects (adjusted logistic regression odds ratio, 0.6; 95% confidence interval, 0.3-1.3). Placental underperfusion was present in 63% of patients vs 46% of control subjects (P < .001) and was more frequent in women with folate levels in the lowest quartile (P = .04), but was not associated with thrombophilia. CONCLUSION: We did not find evidence to support an association between inherited thrombophilia and increased risk of preeclampsia. Placental underperfusion is associated with preeclampsia, but this does not appear to be consequent to thrombophilia.

Investigating socio-economic disparities in preterm birth: evidence for selective study participation and selection bias.

Selective study participation can theoretically lead to selection bias. We explored this issue in the context of a multicentre cohort study of socio-economic disparities in preterm birth. Women with singleton pregnancies were recruited from four large Montreal maternity hospitals and invited to return for an interview, vaginal examination and venepuncture at 24-26 weeks of gestation. We compared the observed preterm birth rate (ultrasound confirmed) among the 5146 cohort women to that expected based on all 108 724 Montreal Census Metropolitan Area (CMA) singleton births for 1998-2000. The observed preterm birth rate in the study cohort was 5.1%, compared with 6.3% in the CMA (P < 0.001) (unadjusted morbidity ratio [95% CI] = 0.80 [0.71, 0.90]). Within each stratum of maternal education and neighbourhood income (the latter based on postal code matched links to the 2001 Canadian census), cohort women had substantially lower rates of preterm birth than women from the CMA. No significant association between socio-economic status (SES) and preterm birth was observed in the study cohort, except among 'indicated' (non-spontaneous) cases. The association between neighbourhood income and preterm birth was biased to the null in the study cohort, with adjusted odds ratios in the poorest vs. richest quintiles of 1.01 [0.63, 1.64] in the cohort vs. 1.28 [1.18, 1.39] in the CMA, although no such bias was observed for the association with maternal education assessed at the individual level. We speculate that the lower-than-expected preterm birth rate and attenuated association between neighbourhood income and preterm birth may be related to selective participation by women more psychologically invested in their pregnancies. Investigators should consider the potential for biased associations in pregnancy/birth cohort studies, especially associations based on SES or race/ethnicity, and carry out sensitivity analyses to gauge their effects.

Managing coagulopathy following PPH.

The prothrombotic state during pregnancy protects against coagulopathy. Fibrinogen is of key importance with concentrations of 4-6 g/l in parturients preventing the majority of women with postpartum haemorrhage developing hypofibrinogenaemia. However, plasma levels below 2 g/l are strongly predictive of bleed progression and should be maintained above this. Laboratory tests of coagulation have a low sensitivity in major haemorrhage, and results are not quickly available. Viscoelastometry provides rapid results, and the FIBTEM A5 test correlates with fibrinogen levels in PPH. Fibrinogen concentrate or cryoprecipitate is more suitable for fibrinogen replacement in pregnancy than fresh frozen plasma. Formulaic blood product administration results in unnecessary treatment for the majority. Reduced morbidity with viscoelastometry-guided blood product administration has been demonstrated with observational studies but not with randomised controlled trials. Further studies are needed to assess the optimal treatment threshold and outcome benefits from targeted fibrinogen replacement.