Spontaneous haemoperitoneum in pregnancy: Nationwide surveillance and Delphi audit system.

OBJECTIVE: To evaluate the incidence, diagnostic management strategies and clinical outcomes of women with spontaneous haemoperitoneum in pregnancy (SHiP) and reassess the definition of SHiP. DESIGN: A population-based cohort study using the Netherlands Obstetric Surveillance System (NethOSS). SETTING: Nationwide, the Netherlands. POPULATION: All pregnant women between April 2016 and April 2018. METHODS: This is a case study of SHiP using the monthly registry reports of NethOSS. Complete anonymised case files were obtained. A newly introduced online Delphi audit system (DAS) was used to evaluate each case, to make recommendations on improving the management of SHiP and to propose a new definition of SHiP. MAIN OUTCOME MEASURES: Incidence and outcomes, lessons learned about clinical management and the critical appraisal of the current definition of SHiP. RESULTS: In total, 24 cases were reported. After a Delphi procedure, 14 cases were classified as SHiP. The nationwide incidence was 4.9 per 100 000 births. Endometriosis and conceiving after artificial reproductive techniques were identified as risk factors. No maternal and three perinatal deaths occurred. Based on the DAS, adequate imaging of free intra-abdominal fluid, and identifying and treating women with signs of hypovolemic shock could improve the early detection and management of SHiP. A revised definition of SHiP was proposed, excluding the need for surgical or radiological intervention. CONCLUSIONS: SHiP is a rare and easily misdiagnosed condition that is associated with high perinatal mortality. To improve care, better awareness among healthcare workers is needed. The DAS is a sufficient tool to audit maternal morbidity and mortality.

Hyperemesis gravidarum severity, enteral tube feeding and cardiometabolic markers in offspring cord blood.

This study aimed to investigate the association between hyperemesis gravidarum (HG) severity and early enteral tube feeding on cardiometabolic markers in offspring cord blood. We included women admitted for HG, who participated in the MOTHER randomised controlled trial (RCT) and observational cohort. The MOTHER RCT showed that early enteral tube feeding in addition to standard care did not affect symptoms/birth outcomes. Among RCT and cohort participants, we assessed how HG severity affected lipid, c-peptide, glucose and free thyroxine cord blood levels. HG severity measures were severity of vomiting at inclusion and 3 weeks after inclusion, pregnancy weight gain and 24-h energy intake at inclusion, readmissions and duration of hospital admissions. Cord blood measures were also compared between RCT participants allocated to enteral tube feeding and those receiving standard care. Between 2013-2016, 215 women were included: 115 RCT and 100 cohort participants. Eighty-one cord blood samples were available. Univariable not multivariable regression analysis showed that lower maternal weight gain was associated with higher cord blood glucose levels (ß: -0·08, 95% CI -0·16, -0·00). Lower maternal weight gain was associated with higher Apo-B cord blood levels in multivariable regression analysis (ß: -0·01, 95% CI -0·02, -0·01). No associations were found between other HG severity measures or allocation to enteral tube feeding and cord blood cardiometabolic markers. In conclusion, while lower maternal weight gain was associated with higher Apo-B cord blood levels, no other HG severity measures were linked with cord blood cardiometabolic markers, nor were these markers affected by enteral tube feeding.

Recurrence, postponing pregnancy, and termination rates after hyperemesis gravidarum: Follow up of the MOTHER study.

INTRODUCTION: Hyperemesis gravidarum (HG) complicates 1% of pregnancies and has a major impact on maternal quality of life and well-being. We know very little about HG's long-term impact after an affected pregnancy, including recurrence rates in future pregnancies, which is essential information for women considering subsequent pregnancies. In this study, we aimed to prospectively measure the recurrence rate of HG and the number of postponed and terminated subsequent pregnancies due to HG. We also aimed to evaluate if there were predictive factors that could identify women at increased risk for HG recurrence, and postponing and terminating subsequent pregnancies. MATERIAL AND METHODS: We conducted a prospective cohort study. A total of 215 women admitted for HG to public hospitals in the Netherlands were enrolled in the original MOTHER randomized controlled trial and associated observational cohort. Seventy-three women were included in this follow-up study. Data were collected through an online questionnaire. Recurrent HG was defined as vomiting symptoms accompanied by any of the following: multiple medication use, weight loss, admission, tube feeding or if nausea and vomiting symptoms were severe enough to affect life and/or work. Outcome measures were recurrence, postponing, and termination rates due to HG. Univariable logistic regression analysis was used to identify predictive factors associated with HG recurrence, and postponing and terminating subsequent pregnancies. RESULTS: Thirty-five women (48%) became pregnant again of whom 40% had postponed their pregnancy due to HG. HG recurred in 89% of pregnancies. One woman terminated and eight women (23%) considered terminating their pregnancy because of recurrent HG. Twenty-four out of 38 women did not get pregnant again because of HG in the past. Univariable logistic regression analysis identifying possible predictive factors found that having a western background was associated with having weight loss due to recurrent HG in subsequent pregnancies (odds ratio 12.9, 95% CI 1.3-130.5, p = 0.03). CONCLUSIONS: High rates of HG recurrence and a high number of postponed pregnancies due to HG were observed. Women can be informed of a high chance of recurrence to enable informed family planning.

Thyroid-stimulating hormone and free thyroxine fail to predict the severity and clinical course of hyperemesis gravidarum: A prospective cohort study.

INTRODUCTION: Little is known about the pathophysiology of hyperemesis gravidarum (HG). Proposed underlying causes are multifactorial and thyroid function is hypothesized to be causally involved. In this study, we aimed to assess the utility of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) as a marker and predictor for the severity and clinical course of HG. MATERIAL AND METHODS: We conducted a prospective cohort study including women admitted for HG between 5 and 20 weeks of gestation in 19 hospitals in the Netherlands. Women with a medical history of thyroid disease were excluded. TSH and FT4 were measured at study entry. To adjust for gestational age, we calculated TSH multiples of the median (MoM). We assessed HG severity at study entry as severity of nausea and vomiting (by the Pregnancy Unique Quantification of Emesis and nausea score), weight change compared with prepregnancy weight, and quality of life. We assessed the clinical course of HG as severity of nausea and vomiting and quality of life 1 week after inclusion, duration of hospital admissions, and readmissions. We performed multivariable regression analysis with absolute TSH, TSH MoMs, and FT4. RESULTS: Between 2013 and 2016, 215 women participated in the cohort. TSH, TSH MoM, and FT4 were available for, respectively, 150, 126, and 106 of these women. Multivariable linear regression analysis showed that lower TSH MoM was significantly associated with increased weight loss or lower weight gain at study entry (ΔKg; ß = 2.00, 95% CI 0.47-3.53), whereas absolute TSH and FT4 were not. Lower TSH, not lower TSH MoM or FT4, was significantly associated with lower nausea and vomiting scores 1 week after inclusion (ß = 1.74, 95% CI 0.36-3.11). TSH and FT4 showed no association with any of the other markers of the severity or clinical course of HG. Twenty-one out of 215 (9.8%) women had gestational transient thyrotoxicosis. Women with gestational transient thyrotoxicosis had a lower quality of life 1 week after inclusion than women with no gestational transient thyrotoxicosis (p = 0.03). CONCLUSIONS: Our findings show an inconsistent role for TSH, TSH MoM, or FT4 at time of admission and provide little guidance on the severity and clinical course of HG.

Association of Maternal Prepregnancy Body Mass Index With Placental Histopathological Characteristics in Uncomplicated Term Pregnancies.

INTRODUCTION: Prepregnancy obesity is a growing global health problem and has several risks for mother and child. The aim of this study was to systematically examine the effect of increased maternal body mass index (BMI) on placental pathology in otherwise uneventful term pregnancies. METHODS: In this analysis, we studied data of the Netherlands Amniotic Fluid study, a prospective study of women delivering in Utrecht, the Netherlands, between 2006 and 2007. We included women with uncomplicated pregnancies, vaginal delivery, and data on prepregnancy weight and height (n = 382). Placental histopathology was compared between women of normal BMI (≤24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (≥30 kg/m2). RESULTS: Increasing prepregnancy BMI was associated with heavier placentas and higher mean infant's birth weight. In addition, obesity was positively associated with high-grade chronic villitis (odds ratio [OR]: 18.1, 95% confidence interval [CI]: 1.6-205.2), accelerated villous maturation (OR: 1.1, 95% CI: 1.0-1.2), and lower incidence of placental weight below the 10th percentile for gestational age (OR: 0.5, 95% CI: 0.3-1.0). There was a substantial effect of parity on maternal, placental, and neonatal weights. CONCLUSIONS: Even in uncomplicated pregnancies, maternal obesity is associated with characteristic changes in placental pathology. Further research is needed to evaluate these changes in view of later-life health of infants born to obese mothers.

Prevalence of placental bed spiral artery pathology in preeclampsia and fetal growth restriction: A prospective cohort study.

BACKGROUND: Preeclampsia and fetal growth restriction (PE/FGR) are pregnancy complications known to be associated with poor utero-placental function due to abnormal "physiological" remodeling of spiral arteries and unfavorable maternal cardiovascular health. However, the prevalence and degree of impaired spiral artery remodeling has not been clearly established. METHOD: Prospective, multi-center observational cohort study to assess the prevalence of lesions associated with abnormal development of spiral arteries in placental bed biopsies systematically obtained from 121 women undergoing Caesarian section for PE/FGR compared with a reference group of 149 healthy controls. RESULTS: PE/FGR was associated with a high prevalence of impaired spiral artery remodeling compared with controls (63.6 vs 10.1 %, p < 0.001), and a higher prevalence of non-remodeled spiral arteries without the presence of intramural trophoblast (45.5 vs 6.7 %, p < 0.001), despite abundant interstitial trophoblast invasion in surrounding decidua and myometrium. Normal remodeling was associated with circumferential presence of intramural trophoblast and hardly any trophoblast in surrounding tissue. Acute atherosis (28.9 vs 3.4 %, p < 0.001) and thrombosis (16.5 vs 5.4 %, p = 0.003) lesions were significantly more prevalent in PE/FGR. Impaired remodeling, acute atherosis and thrombosis lesions were equally present in both decidual and myometrial segments of the spiral arteries in both groups. Impaired remodeling was most prominent in the groups with FGR (with or without PE) and thrombosis was most often seen in the group with PE and FGR. CONCLUSION: PE/FGR is associated with a high prevalence of impaired physiological remodeling and vascular lesions of the uterine spiral arteries in the placental bed.

Costs and effects of screening and treating low risk women with a singleton pregnancy for asymptomatic bacteriuria, the ASB study.

BACKGROUND: The prevalence of asymptomatic bacteriuria (ASB) in pregnancy is 2-10% and is associated with both maternal and neonatal adverse outcomes as pyelonephritis and preterm delivery. Antibiotic treatment is reported to decrease these adverse outcomes although the existing evidence is of poor quality. METHODS/DESIGN: We plan a combined screen and treat study in women with a singleton pregnancy. We will screen women between 16 and 22 weeks of gestation for ASB using the urine dipslide technique. The dipslide is considered positive when colony concentration ≥105 colony forming units (CFU)/mL of a single microorganism or two different colonies but one ≥105 CFU/mL is found, or when Group B Streptococcus bacteriuria is found in any colony concentration. Women with a positive dipslide will be randomly allocated to receive nitrofurantoin or placebo 100 mg twice a day for 5 consecutive days (double blind). Primary outcomes of this trial are maternal pyelonephritis and/or preterm delivery before 34 weeks. Secondary outcomes are neonatal and maternal morbidity, neonatal weight, time to delivery, preterm delivery rate before 32 and 37 weeks, days of admission in neonatal intensive care unit, maternal admission days and costs. DISCUSSION: This trial will provide evidence for the benefit and cost-effectiveness of dipslide screening for ASB among low risk women at 16-22 weeks of pregnancy and subsequent nitrofurantoin treatment. TRIAL REGISTRATION: Dutch trial registry: NTR-3068.

Mode of delivery in non-cephalic presenting twins: a systematic review.

PURPOSE: This systematic review aims to determine if there are evidence-based recommendations for the optimal mode of delivery for non-cephalic presenting first- and/or second twins. We investigated the impact of the mode of delivery on neonatal outcome for twin deliveries with (1) the first twin (twin A) in non-cephalic presentation, (2) the second (twin B) in non-cephalic presentation and (3) both twins in non-cephalic presentation. METHODS: A computer-aided search of Medline, Embase, Cinahl and Cochrane databases was carried out and quality of the studies was assessed with the Cochrane Collaboration's tool for assessing risk of bias and the GRADE approach. RESULTS: One high-quality clinical trial (60 twin pairs) and 16 moderate/low-quality observational studies (3,167 twin pairs) showed no difference in neonatal outcome between vaginal and caesarean delivery in twin A and/or B. CONCLUSION: Our results do not suggest benefit of caesarean over vaginal delivery for selected twin gestations with twin A and/or twin B in non-cephalic presentation. However, no final conclusion can be drawn due to the small sample sizes and statistic limitations of the included studies. Randomized studies with sufficient power are required to make a strong recommendation.

Depression, anxiety, and post-traumatic stress disorder symptoms after hyperemesis gravidarum: a prospective cohort study.

OBJECTIVE: To determine the prevalence of depression, anxiety, and posttraumatic stress disorder (PTSD) years after hyperemesis gravidarum (HG) and its association with HG severity. MATERIAL AND METHODS: This prospective cohort study consisted of a follow-up of 215 women admitted for HG, who were eligible to participate in a randomized controlled trial and either declined or agreed to be randomized between 2013 and 2016 in 19 hospitals in the Netherlands. Participants completed the Hospital Anxiety and Depression Scale (HADS) six weeks postpartum and during follow-up and the PTSD checklist for DSM-5 (PCL-5) during follow-up. An anxiety or depression score ≥8 is indicative of an anxiety or depression disorder and a PCL-5 ≥ 31 indicative of PTSD. Measures of HG severity were symptom severity (PUQE-24: Pregnancy Unique Quantification of Emesis), weight change, duration of admissions, readmissions, and admissions after the first trimester. RESULTS: About 54/215 participants completed the HADS six weeks postpartum and 73/215 participants completed the follow-up questionnaire, on average 4.5 years later. Six weeks postpartum, 13 participants (24.1%) had an anxiety score ≥8 and 11 participants (20.4%) a depression score ≥8. During follow-up, 29 participants (39.7%) had an anxiety score ≥8, 20 participants (27.4%) a depression score ≥8, and 16 participants (21.9%) a PCL-5 ≥ 31.Multivariable logistic regression analysis showed that for every additional point of the mean PUQE-24 three weeks after inclusion, the likelihood of having an anxiety score ≥8 and PCL-5 ≥ 31 at follow-up increased with OR 1.41 (95% CI: 1.10;1.79) and OR 1.49 (95% CI: 1.06;2.10) respectively. CONCLUSION: Depression, anxiety, and PTSD symptoms are common years after HG occurred.

Invasive placentation and uterus preserving treatment modalities: a systematic review.

PURPOSE: We present a systematic review to evaluate failure rates (secondary hysterectomy or maternal mortality) and success rates (subsequent menstruation or pregnancy) after different uterus preserving treatment modalities in women with invasive placentation. METHODS: A review of English, German or Dutch language-published research, using Medline and Embase databases, was performed. Studies of any design were included. RESULTS: Ten cohort studies and 50 case series or case reports were included. Expectant management reported a secondary hysterectomy in 55/287 (19%), maternal mortality in 1/295 (0.3%), a subsequent menstruation in 44/49 (90%) and a subsequent pregnancy in 24/36 (67%). Embolization of the uterine arteries described a secondary hysterectomy in 8/45 (18%), a subsequent menstruation in 8/13 (62%) and a subsequent pregnancy in 5/33 (15%). Methotrexate therapy presented a secondary hysterectomy in 1/16 (6%), a subsequent menstruation in 4/5 (80%) and a subsequent pregnancy in 1/2 (50%). Uterus preserving surgery showed a secondary hysterectomy in 24/77 (31%), maternal mortality in 2/55 (4%), a subsequent menstruation in 28/34 (82%) and a subsequent pregnancy in 19/26 (73%). CONCLUSIONS: This review indicates that different uterus preserving treatment modalities may be effective in managing invasive placentation. Despite the extensive review of the literature, no conclusions about the superiority of any modality can be drawn.

Determinants of disease course and severity in hyperemesis gravidarum.

OBJECTIVE: We aimed to identify determinants that predict hyperemesis gravidarum (HG) disease course and severity. STUDY DESIGN: For this study, we combined data of the Maternal and Offspring outcomes after Treatment of HyperEmesis by Refeeding (MOTHER) randomized controlled trial (RCT) and its associated observational cohort with non-randomised patients. Between October 2013 and March 2016, in 19 hospitals in the Netherlands, women hospitalised for HG were approached for study participation. In total, 215 pregnant women provided consent for participation. We excluded women enrolled during a readmission (n = 24). Determinants were defined as patient characteristics and clinical features, available to clinicians at first hospital admission. Patient characteristics included i.e. age, ethnicity, socio-economic status, history of mental health disease and HG and gravidity. Clinical features included weight loss compared to pre-pregnancy weight and symptom severity measured with Pregnancy Unique Quantification of Emesis (PUQE-24) questionnaire and the Nausea and Vomiting in Pregnancy specific Quality of Life questionnaire (NVPQoL). Outcome measures were measures of HG disease severity present at 1 week after hospital admission, including weight change, PUQE-24 and NVPQoL scores. Total days of admission hospital admission and readmission were also considered outcome measures. RESULTS: We found that high PUQE-24 and NVPQoL scores at hospital admission were associated with those 1 week after hospital admission (difference (ß) 0.36, 95 %CI 0.16 to 0.57 and 0.70,95 %CI 0.45-1.1). PUQE-24 and NVPQoL scores were not associated with other outcome measures. None of the patient characteristics were associated with any of the outcome measures. CONCLUSION: Our findings suggest that the PUQE-24 and NVPQoL questionnaires can identify women that maintain high symptom scores a week after admission, but that patient characteristics cannot be used as determinants of HG disease course and severity.

SUGAR-DIP trial: oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial.

INTRODUCTION: In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. METHODS: The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NTR6134; Pre-results.

Effects on asymmetric dimethylarginine of HMR 3339, a novel selective estrogen receptor modulator: a 12-week, randomized, placebo-controlled, double-blind, dose-ranging study in healthy postmenopausal women.

OBJECTIVE: To investigate the short-term effects of three different doses of the selective estrogen receptor modulator HMR 3339 in comparison with placebo and raloxifene on asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor. DESIGN: This study was a multicenter, randomized, placebo-controlled, double-blind, dose-ranging study. Ninety-four healthy postmenopausal women received daily doses of either placebo (n=16), HMR 3339 2.5 mg (n=20), HMR 3339 10 mg (n=19), HMR 3339 50 mg (n=20), or raloxifene 60 mg (n=19) for 12 weeks. Fasting plasma concentrations of ADMA, arginine, and symmetric dimethylarginine (SDMA) were measured at baseline and after 4 and 12 weeks by high-performance liquid chromatography. RESULTS: HMR 3339 induced a dose-dependent reduction of ADMA and SDMA concentrations, with the largest effects (P<0.01 for both) in the HMR 3339 50 mg group compared with baseline and placebo (at 12 weeks: -7.0% [95% CI, -14.2% to 0.2%] for ADMA and -16.2% [95% CI, -22.4% to -10.0%] for SDMA). Twelve weeks of raloxifene 60 mg significantly reduced SDMA (P=0.03) but not ADMA concentrations. Arginine concentrations were not altered by any treatment. CONCLUSIONS: The reduction of the nitric oxide synthase inhibitor ADMA by HMR 3339 may potentially have a beneficial effect on the cardiovascular system in postmenopausal women.

Early enteral tube feeding in optimizing treatment of hyperemesis gravidarum: the Maternal and Offspring outcomes after Treatment of HyperEmesis by Refeeding (MOTHER) randomized controlled trial.

Background: Hyperemesis gravidarum (HG) leads to dehydration, poor nutritional intake, and weight loss. HG has been associated with adverse pregnancy outcomes such as low birth weight. Information about the potential effectiveness of treatments for HG is limited.Objective: We hypothesized that in women with HG, early enteral tube feeding in addition to standard care improves birth weight.Design: We performed a multicenter, open-label randomized controlled trial [Maternal and Offspring outcomes after Treatment of HyperEmesis by Refeeding (MOTHER)] in 19 hospitals in the Netherlands. A total of 116 women hospitalized for HG between 5 and 20 wk of gestation were randomly allocated to enteral tube feeding for ≥7 d in addition to standard care with intravenous rehydration and antiemetic treatment or to standard care alone. Women were encouraged to continue tube feeding at home. On the basis of our power calculation, a sample size of 120 women was anticipated. Analyses were performed according to the intention-to-treat principle.Results: Between October 2014 and March 2016 we randomly allocated 59 women to enteral tube feeding and 57 women to standard care. The mean ± SD birth weight was 3160 ± 770 g in the enteral tube feeding group compared with 3200 ± 680 g in the standard care group (mean difference: -40 g, 95% CI: -230, 310 g). Secondary outcomes, including maternal weight gain, duration of hospital stay, readmission rate, nausea and vomiting symptoms, decrease in quality of life, psychological distress, prematurity, and small-for-gestational-age, also were comparable. Of the women allocated to enteral tube feeding, 28 (47%) were treated according to protocol. Enteral tube feeding was discontinued within 7 d of placement in the remaining women, primarily because of its adverse effects (34%).Conclusions: In women with HG, early enteral tube feeding does not improve birth weight or secondary outcomes. Many women discontinued tube feeding because of discomfort, suggesting that it is poorly tolerated as an early routine treatment of HG. This trial was registered at www.trialregister.nl as NTR4197.

Emerging selective estrogen receptor modulators: special focus on effects on coronary heart disease in postmenopausal women.

Menopause, regardless of age at onset, is associated with a marked increase in coronary heart disease (CHD) risk. On the basis of epidemiological studies that demonstrated mainly positive effects of postmenopausal hormone therapy on CHD as well as on risk markers of CHD, it has been suggested that CHD could be prevented in postmenopausal women with long-term hormone therapy. However, since the publications of the Heart and Estrogen/progestin Replacement Study and the Women's Health Initiative trial, prescription of hormone therapy for the prevention of CHD has become controversial. Major efforts have been made to identify alternatives for hormone therapy. Compounds suggested have included selective estrogen receptor modulators (SERMs), which represent a class with a growing number of compounds that act as either estrogen receptor agonists or antagonists in a tissue-specific manner. This pharmacological profile may offer the opportunity to dissociate favourable estrogenic effects on the bone and cardiovascular system from unfavourable stimulatory effects on the breast and endometrium. Two SERMs presently on the market are tamoxifen and raloxifene. The only data available regarding the effects of tamoxifen on cardiovascular events in postmenopausal women are from breast cancer trials. These trials found fewer fatal myocardial events in women randomly assigned to tamoxifen compared with women assigned to placebo. Raloxifene is a second-generation SERM that has been shown to prevent osteoporotic fractures, is safe for the endometrium and holds high promise for the prevention of breast cancer. The effect of raloxifene on CHD is still uncertain. On the basis of the MORE (Multiple Outcomes of Raloxifene Evaluation) trial, raloxifene may offer some protection to women with CHD or to those who are at high risk of CHD. Proof that raloxifene reduces the risk of CHD requires a clinical trial with hard clinical endpoints. Such a study is currently underway. Next-generation SERMs taken into clinical development include idoxifene, droloxifene, ospemifene, arzoxifene, acolbifene/EM-800, levormeloxifene, lasofoxifene, bazedoxifene and HMR 3339. The aim is to find a compound with the ideal profile, that is, alleviation of climacteric symptoms and prevention of osteoporotic fractures, but without an adverse effect on the breast and endometrium, and no negative effect or even a beneficial effect on the cardiovascular system and the brain. Currently, limited data are available with regard to these next-generation SERMs and CHD. Nevertheless, some of these novel agents provide arguments for continuing the search for an ideal SERM.

The effects of 12 weeks of HMR 3339, a novel selective estrogen receptor modulator, on markers of coagulation and fibrinolysis: a randomized, placebo-controlled, double-blind, dose-ranging study in healthy postmenopausal women.

OBJECTIVE: To investigate the short-term effects of HMR 3339, a novel selective estrogen receptor modulator, on markers of coagulation and fibrinolysis. STUDY DESIGN: In a multicenter, 14-week, randomized, placebo-controlled, double-blind, dose-ranging study, healthy postmenopausal women received daily placebo (n = 22), HMR 3339 2.5 mg (n = 25), HMR 3339 10 mg (n = 24), HMR 3339 50 mg (n = 24), or raloxifene 60 mg (n = 23). Statistical analysis was performed using standard parametric tests. RESULTS: After 12 weeks, compared with placebo, HMR 3339 50 mg induced the largest mean percentage changes in antithrombin (-14.6%, P < .001), protein C (-12.9%, P = .029), and fibrinogen (-26.3%, P = .001). Decreases were observed in the HMR 3339 2.5 mg group, compared with placebo, in tissue-type plasminogen activator (-55.0%, P = .026 after 4 weeks), plasmin-alpha2-antiplasmin complex (-85%, P = .031 and -63.3%, P = .008, respectively, after 4 and 12 weeks), and D-dimer (-91.4%, P = .018 after 12 weeks). Compared with placebo, raloxifene 60 mg decreased total protein S (-8.2%, P = .009) after 4 weeks and antithrombin (-6.0%, P = .034) and fibrinogen (-18.1%, P = .007) after 12 weeks. CONCLUSION: HMR 3339 and raloxifene decreased fibrinogen levels. In the low dosage, HMR 3339 showed potentially beneficial effects on some markers of fibrinolysis. Both drugs impaired the anticoagulatory potential.

Effect of raloxifene and hormone therapy on serum markers of brain and whole-body cholesterol metabolism in postmenopausal women.

OBJECTIVE: To compare the 2-year effects of raloxifene (Rlx) with oral postmenopausal hormone therapy (HT) on serum markers of brain and whole-body cholesterol metabolism. METHODS: In a randomized, double-blind, placebo-controlled trial, 95 healthy, non-hysterectomized, early postmenopausal women received either daily Rlx 60 mg (n = 24), Rlx 150 mg (n = 23), HT (conjugated equine estrogens 0.625 mg/medroxyprogesterone acetate 2.5 mg; n = 24), or placebo (n = 24). Fasting blood samples were collected at baseline and after 6, 12, and 24 months of treatment for measurement of serum concentrations of cholesterol by means of gas-liquid chromatography; 24S-hydroxycholesterol (cerebrosterol), lathosterol, and the plant sterol campesterol by means of gas-liquid chromatography-mass spectrometry. The analyses were performed retrospectively from serum samples stored at -70 degrees C for 5 years. RESULTS: Twenty-four months of treatment with raloxifene 150 mg was associated with a significant reduction in serum cholesterol concentrations (-10%, P = 0.007). The ratio of 24S-hydroxycholesterol to cholesterol, a serum marker of brain cholesterol metabolism, showed a significant increase after 6 and 12 months with raloxifene 150 mg but not after 24 months (P = 0.001). The ratio of lathosterol to cholesterol, a marker of whole-body cholesterol synthesis, increased with raloxifene 60 mg (P = 0.163), raloxifene 150 mg (P < 0.001), as well as with HT (P = 0.005). The ratio of campesterol to cholesterol, a marker of cholesterol absorption rate, was significantly reduced with HT (P = 0.002). CONCLUSION: Two-year treatment with raloxifene or HT had no influence on brain cholesterol metabolism, while whole-body cholesterol synthesis, assessed by the ratio of lathosterol to cholesterol, increased during raloxifene and HT.

Maternal and neonatal consequences of treated and untreated asymptomatic bacteriuria in pregnancy: a prospective cohort study with an embedded randomised controlled trial.

BACKGROUND: Existing approaches for the screening and treatment of asymptomatic bacteriuria in pregnancy are based on trials that were done more than 30 years ago. In this study, we reassessed the consequences of treated and untreated asymptomatic bacteriuria in pregnancy. METHODS: In this multicentre prospective cohort study with an embedded randomised controlled trial, we screened women (aged ≥18 years) at eight hospitals and five ultrasound centres in the Netherlands with a singleton pregnancy between 16 and 22 weeks' gestation for asymptomatic bacteriuria. Screening was done with a single dipslide and two culture media. Dipslides were judged positive when the colony concentration was at least 1×10(5) colony-forming units (CFU) per mL of a single microorganism or when two different colony types were present but one had a concentration of at least 1×10(5) CFU per mL. Asymptomatic bacteriuria-positive women were eligible to participate in the randomised controlled trial comparing nitrofurantoin with placebo treatment. In this trial, participants were randomly assigned 1:1 to receive either nitrofurantoin 100 mg or identical placebo tablets, and were instructed to self-administer these tablets twice daily for 5 consecutive days. Randomisation was done by a web-based application with a computer-generated list with random block sizes of two, four, or six participants rendered by an independent data manager. 1 week after the end of treatment, they provided us with a follow-up dipslide. Women, treating physicians, and researchers all remained unaware of the bacteriuria status and treatment allocation. Women who refused to participate in the randomised controlled trial did not receive any antibiotics, but their outcomes were collected for analysis in the cohort study. We compared untreated and placebo-treated asymptomatic bacteriuria-positive women with asymptomatic bacteriuria-negative women and nitrofurantoin-treated asymptomatic bacteriuria-positive women. The primary endpoint was a composite of pyelonephritis with or without preterm birth at less than 34 weeks, analysed by intention to treat at 6 weeks post-partum. This trial is registered with the Dutch Trial Registry, number NTR3068. FINDINGS: Between Oct 11, 2011, and June 10, 2013, we enrolled 5621 women into our screening cohort, of whom 5132 were eligible for screening. After exclusions for contaminated dipslides and patients lost to follow-up, in our final cohort of 4283 women, 248 were asymptomatic bacteriuria positive, of whom 40 were randomly assigned to nitrofurantoin and 45 to placebo for the randomised controlled trial, whereas the other 163 asymptomatic bacteriuria-positive women were followed without treatment. The proportion of women with pyelonephritis, preterm birth, or both did not differ between untreated or placebo-treated asymptomatic bacteriuria-positive women and asymptomatic bacteriuria-negative women (6 [2·9%] of 208 vs 77 [1·9%] of 4035; adjusted odds ratio [OR] 1·5, 95% CI 0·6-3·5) nor between asymptomatic bacteriuria-positive women treated with nitrofurantoin versus those who were untreated or received placebo (1 [2·5%] of 40 vs 6 [2·9%] of 208; risk difference -0·4, 95% CI -3·6 to 9·4). Untreated or placebo-treated asymptomatic bacteriuria-positive women developed pyelonephritis in five [2·4%] of 208 cases, compared with 24 [0·6%] of 4035 asymptomatic bacteriuria-negative women (adjusted OR 3·9, 95% CI 1·4-11·4). INTERPRETATION: In women with an uncomplicated singleton pregnancy, asymptomatic bacteriuria is not associated with preterm birth. Asymptomatic bacteriuria showed a significant association with pyelonephritis, but the absolute risk of pyelonephritis in untreated asymptomatic bacteriuria is low. These findings question a routine screen-treat-policy for asymptomatic bacteriuria in pregnancy. FUNDING: ZonMw (the Netherlands Organisation for Health Research and Development).

Effect of HMR 3339, a novel selective estrogen receptor modulator, on C-reactive protein levels in healthy postmenopausal women.

We investigated the 12-week effects of 3 doses of HMR 3339, a novel selective estrogen receptor modulator, in comparison with raloxifene and placebo, on plasma concentrations of C-reactive protein in 96 healthy postmenopausal women. A dose-dependent reduction in C-reactive protein was observed, the largest reduction with HMR 3339 50 mg.