Long-term quality of life after obstetric intensive care unit admission: A cross-sectional cohort study.

OBJECTIVE: To assess the long-term quality of life (QoL) after obstetric Intensive Care Unit (ICU) admission. DESIGN: Cross-sectional survey study. SETTING: Tertiary care centre. POPULATION: Women admitted to the level 3 ICU during pregnancy or ≤6 weeks postpartum, between 2000 and 2015. METHODS: Quality of life measures were compared with the population reference values. Associations with baseline ICU parameters were assessed with multivariable linear regression. Patient-reported outcome and experience measures (PROMs/PREMs) were described. MAIN OUTCOME MEASURES: Quality of life according to the Linear Analogous Scale (LAS), the Satisfaction with Life Scale (SWLS) and the SF-36 questionnaire; PROMs/PREMs using the Pregnancy and Childbirth outcome set of the International Consortium for Health Outcomes Measurement. RESULTS: Of all 265 obstetric ICU admissions, 230 were eligible and 94 (41%) were included (median follow-up time 14 years). The LAS (75.7 versus 78.7, p = 0.077) and SWLS (25.2 versus 26, p = 0.176) sum scores were not different from the population reference values. The SF-36 subdomains bodily pain (55.3 versus 73.9), general health (58.2 versus 73.9) and vitality (56.9 versus 69.1) were lower than the reference values (all p < 0.001). PROMs/PREMs were low in 46.2% for pain, 15.1% for depression, 11.8% for satisfaction with care and 52.7% for healthcare responsiveness. An indirect obstetric ICU admission diagnosis was independently associated with a reduced physical health score (B -1.7, 95% confidence interval [CI] -3.4 to -0.1) and severe neonatal morbidity with a reduced mental health score (B -6.6, 95% CI -11.3 to -1.8). CONCLUSION: Obstetric ICU admission is associated with reductions in long-term physical health QoL and in some patients with mental health QoL. We suggest multidisciplinary rehabilitation and long-term psychosocial support.

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.

Perinatal mortality and neonatal and maternal outcome per gestational week in term pregnancies: A registry-based study.

INTRODUCTION: Human pregnancy is considered term from 37+0/7 to 41+6/7 weeks. Within this range, both maternal, fetal and neonatal risks may vary considerably. This study investigates how gestational age per week is related to the components of perinatal mortality and parameters of adverse neonatal and maternal outcome at term. MATERIAL AND METHODS: A registry-based study was made of all singleton term pregnancies in the Netherlands from January 2014 to December 2017. Stillbirth and early neonatal mortality, as components of perinatal mortality, were defined as primary outcomes; adverse neonatal and maternal events as secondary outcomes. Neonatal adverse outcomes included birth trauma, 5-minute Apgar score ≤3, asphyxia, respiratory insufficiency, neonatal intensive care unit admission and composite neonatal outcome. Maternal adverse outcomes included instrumental vaginal birth, emergency cesarean section, obstetric anal sphincter injury, postpartum hemorrhage, hypertensive disorders of pregnancy and composite maternal outcome. The primary outcomes were evaluated by comparing weekly prospective risks of stillbirth and neonatal death using a fetuses-at-risk approach. Secondly, odds ratios (OR) for perinatal mortality, adverse neonatal and maternal outcome using a births-based approach were compared for each gestational week with all births occurring after that week. RESULTS: Data of 581 443 births were analyzed. At 37, 38, 39, 40, 41 and 42 weeks, the respective weekly prospective risks of stillbirth were 0.015%, 0.022%, 0.031%, 0.036%, 0.069% and 0.081%; the respective weekly prospective risks of early neonatal death were 0.051%, 0.047%, 0.032%, 0.031%, 0.039% and 0.035%. The OR for adverse neonatal outcomes were the lowest at 39 and 40 weeks. The OR for adverse maternal outcomes, including operative birth, continuously increased with each gestational week. CONCLUSIONS: The prospective risk of early neonatal death for babies born at 39 weeks is lower than the risk of stillbirth in pregnancies continuing beyond 39+6/7 weeks. Birth at 39 weeks was associated with the best combined neonatal and maternal outcome, fewer operative births and fewer maternal and neonatal adverse outcomes compared with pregnancies continuing beyond 39 weeks. This information with appropriate perspectives should be included when counseling term pregnant women.

Hypertensive disorders of pregnant women with heart disease: the ESC EORP ROPAC Registry.

AIMS: Hypertensive disorders of pregnancy (HDP) occur in 10% of pregnancies in the general population, pre-eclampsia specifically in 3-5%. Hypertensive disorders of pregnancy may have a high prevalence in, and be poorly tolerated by, women with heart disease. METHODS AND RESULTS: The prevalence and outcomes of HDP (chronic hypertension, gestational hypertension or pre-eclampsia) were assessed in the ESC EORP ROPAC (n = 5739), a worldwide prospective registry of pregnancies in women with heart disease.The overall prevalence of HDP was 10.3%, made up of chronic hypertension (5.9%), gestational hypertension (1.3%), and pre-eclampsia (3%), with significant differences between the types of underlying heart disease (P < 0.05). Pre-eclampsia rates were highest in women with pulmonary arterial hypertension (PAH) (11.1%), cardiomyopathy (CMP) (7.1%), and ischaemic heart disease (IHD) (6.3%). Maternal mortality was 1.4 and 0.6% in women with vs. without HDP (P = 0.04), and even 3.5% in those with pre-eclampsia. All pre-eclampsia-related deaths were post-partum and 50% were due to heart failure. Heart failure occurred in 18.5 vs. 10.6% of women with vs. without HDP (P < 0.001) and in 29.1% of those with pre-eclampsia. Perinatal mortality was 3.1 vs. 1.7% in women with vs. without HDP (P = 0.019) and 4.7% in those with pre-eclampsia. CONCLUSION: Hypertensive disorders of pregnancy and pre-eclampsia rates were higher in women with CMP, IHD, and PAH than in the general population. Adverse outcomes were increased in women with HDP, and maternal mortality was strikingly high in women with pre-eclampsia. The combination of HDP and heart disease should prompt close surveillance in a multidisciplinary context and the diagnosis of pre-eclampsia requires hospital admission and continued monitoring during the post-partum period.

Nicardipine for treating severe antepartum hypertension during pregnancy: Nine years of experience in more than 800 women.

INTRODUCTION: Women with severe hypertension during pregnancy require prompt stabilization with a combination of magnesium sulfate and rapidly acting intravenously administered antihypertensives. It remains unknown which antihypertensive is best suited for pregnancy. The present study evaluated the intravenous use of the calcium antagonist, nicardipine. MATERIAL AND METHODS: This multicenter, retrospective case series included all pregnant women beyond 20 weeks of gestation with severe antepartum hypertension that were treated with intravenous nicardipine. PRIMARY OUTCOME MEASURES: successful treatment, time to successful treatment, and maternal safety. Severe hypertension was defined as systolic blood pressure (SBP) of 160 mm Hg or more and/or diastolic blood pressure (DBP) of 110 mm Hg or more. RESULTS: This study included 830 women. After 1 h of treatment, two-thirds of the women had SBP below 160 mm Hg and DBP below 100 mm Hg. In three out of four women, the mean arterial pressure was below 120 mm Hg. Within 2 h of treatment, 77.4% of women achieved successful treatment. In all cases, nicardipine was eventually effective. Within the first 2 h, 42.7% of women experienced temporary low DBP (ie below 70 mm Hg) without clinical consequences for the mother or fetus. In all cases, the low DBP resolved after discontinuing or reducing the dosage of nicardipine. One case of fetal distress was attributable to maternal hypotension, and a cesarean section was performed at more than 2 h after initiating therapy. During treatment, headache, nausea, and vomiting decreased significantly. CONCLUSIONS: To date, this was the largest case-series study on the use of nicardipine for treating severe antepartum hypertension in pregnancy. We found that nicardipine could effectively and safely treat this condition. Based on its high success rate and acceptable safety profile, nicardipine should be considered a first-line treatment in women with severe hypertension in pregnancy.

Nationwide confidential enquiries into maternal deaths because of obstetric hemorrhage in the Netherlands between 2006 and 2019.

INTRODUCTION: Obstetric hemorrhage-related deaths are rare in high income countries. Yet, with increasing incidences of obstetric hemorrhage in these countries, it is of utmost importance to learn lessons from each obstetric hemorrhage-related death to improve maternity care. Our objective was to calculate the obstetric hemorrhage-related maternal mortality ratio (MMR), assess causes of obstetric hemorrhage-related deaths, and identify lessons learned. MATERIAL AND METHODS: Nationwide mixed-methods prospective case-series with confidential enquiries into maternal deaths due to obstetric hemorrhage in the Netherlands from January 1, 2006 to December 31, 2019. RESULTS: The obstetric hemorrhage-related MMR in the Netherlands in 2006-2019 was 0.7 per 100 000 livebirths and was not statistically significantly different compared with the previous MMR of 1.0 per 100 000 livebirths in 1993-2005 (odds ratio 0.70, 95% confidence interval 0.38-1.30). Leading underlying cause of hemorrhage was retained placenta. Early recognition of persistent bleeding, prompt involvement of a senior clinician and timely management tailored to the cause of hemorrhage with attention to coagulopathy were prominent lessons learned. Also, timely recourse to surgical interventions, including hysterectomy, in case other management options fail to stop bleeding came up as an important lesson in several obstetric hemorrhage-related deaths. CONCLUSIONS: The obstetric hemorrhage-related MMR in the Netherlands in 2006-2019 has not substantially changed compared to the MMR of the previous enquiry in 1993-2005. Although obstetric hemorrhage is commonly encountered by maternity care professionals, it is important to remain vigilant for possible adverse maternal outcomes and act upon an ongoing bleeding following birth in a more timely and adequate manner. Our confidential enquiries still led to important lessons learned with clinical advice to professionals as how to improve maternity care and avoid maternal deaths. Drawing lessons from maternal deaths should remain a qualitative and moral imperative.

Confidential enquiry into maternal deaths in the Netherlands, 2006-2018.

INTRODUCTION: To calculate the maternal mortality ratio (MMR) for 2006-2018 in the Netherlands and compare this with 1993-2005, and to describe women's characteristics, causes of death and improvable factors. MATERIAL AND METHODS: We performed a nationwide, cohort study of all maternal deaths between January 1, 2006 and December 31, 2018 reported to the Audit Committee Maternal Mortality and Morbidity. Main outcome measures were the national MMR and causes of death. RESULTS: Overall MMR was 6.2 per 100 000 live births, a decrease from 12.1 in 1993-2005 (risk ratio [RR] 0.5). Women with a non-western ethnic background had an increased MMR compared with Dutch women (MMR 6.5 vs. 5.0, RR 1.3). The MMR was increased among women with a background from Surinam/Dutch Antilles (MMR 14.7, RR 2.9). Half of all women had an uncomplicated medical history (79/161, 49.1%). Of 171 pregnancy-related deaths within 1 year postpartum, 102 (60%) had a direct and 69 (40%) an indirect cause of death. Leading causes within 42 days postpartum were cardiac disease (n = 21, 14.9%), hypertensive disorders (n = 20, 14.2%) and thrombosis (n = 19, 13.5%). Up to 1 year postpartum, the most common cause of death was cardiac disease (n = 32, 18.7%). Improvable care factors were identified in 76 (47.5%) of all deaths. CONCLUSIONS: Maternal mortality halved in 2006-2018 compared with 1993-2005. Cardiac disease became the main cause. In almost half of all deaths, improvable factors were identified and women with a background from Surinam/Dutch Antilles had a threefold increased risk of death compared with Dutch women without a background of migration.

Women of reproductive age in a tertiary intensive care unit: indications, outcome and the impact of pregnancy-a retrospective cohort study.

BACKGROUND: To evaluate the indications for admission and mortality rates of women of reproductive age admitted to a tertiary Intensive Care Unit (ICU) and to compare the outcomes of obstetric and non-obstetric admissions. METHODS: A retrospective cohort study was performed, including all women aged 17-41 years admitted to a level 3 ICU in the Netherlands, between January 1, 2000 and January 1, 2016. Primary outcome was indication for admission and mortality. Mortality, length of stay (LOS), need for mechanical ventilation and APACHE II score were compared between obstetric and non-obstetric admissions. The obstetric group was further analyzed for maternal and perinatal outcomes. RESULTS: 3461 women (median age 32 years) were included, with an overall mortality rate of 13.3%. The obstetric group consisted of 265 women (7.7%). The non-obstetric group (n = 3196) was admitted most often for cardiovascular disease (19.6%), followed by oncologic disease (15%). Mortality was the highest in women with oncologic disease (23.9%). The obstetric group had lower mortality compared to the non-obstetric group (4.9% vs. 14%, p < 0.001), despite higher APACHE II score (14 vs. 11, p < 0.001) and a higher ventilation rate (47.9% vs. 39%, p = 0.004). Major surgical or endovascular interventions, besides caesarean section, were performed in 46% of the obstetric group. Perinatal death occurred in 17.2% and of the surviving infants, 63.2% were born preterm and 45.1% required Neonatal Intensive Care Unit admission. CONCLUSIONS: Cardiovascular disease is the most important indication for admission and oncologic disease is associated with highest mortality in women of reproductive age. Obstetric patients constitute a small percentage of all ICU admissions in a tertiary ICU center. They have lower mortality rates than non-obstetric young female patients, despite a more severe initial presentation. Nevertheless lasting maternal morbidity and perinatal mortality and morbidity is frequent.

Oxidative stress and endothelial function in normal pregnancy versus pre-eclampsia, a combined longitudinal and case control study.

BACKGROUND: Pre-eclampsia (PE) is related to an impaired endothelial function. Endothelial dysfunction accounts for altered vascular reactivity, activation of the coagulation cascade and loss of vascular integrity. Impaired endothelial function originates from production of inflammatory and cytotoxic factors by the ischemic placenta and results in systemic oxidative stress (OS) and an altered bioavailability of nitric oxide (•NO). The free radical •NO, is an endogenous endothelium-derived relaxing factor influencing endothelial function. In placental circulation, endothelial release of •NO dilates the fetal placental vascular bed, ensuring feto-maternal exchange. The Endopreg study was designed to evaluate in vivo endothelial function and to quantify in vitro OS in normal and pre-eclamptic pregnancies. METHODS/DESIGN: The study is divided into two arms, a prospective longitudinal study and a matched case control study. In the longitudinal study, pregnant patients ≥18 years old with a singleton pregnancy will be followed throughout pregnancy and until 6 months post-partum. In the case control study, cases with PE will be compared to matched normotensive pregnant women. Maternal blood concentration of superoxide (O2•) and placental concentration of •NO will be determined using EPR (electron paramagnetic resonance). Endothelial function and arterial stiffness will be evaluated using respectively Peripheral Arterial Tonometry (PAT), Flow-Mediated Dilatation (FMD) and applanation tonometry. Placental expression of eNOS (endothelial NOS) will be determined using immune-histochemical staining. Target recruitment will be 110 patients for the longitudinal study and 90 patients in the case-control study. DISCUSSION: The results of Endopreg will provide longitudinal information on in vivo endothelial function and in vitro OS during normal pregnancy and PE. Adoption of these vascular tests in clinical practice potentially predicts patients at risk to develop cardiovascular events later in life after PE pregnancies. •NO, O2•- and eNOS measurements provide further inside in the pathophysiology of PE. TRIAL REGISTRATION: This trial has been registered on clinicaltrials.gov. ClinicalTrials.gov Identifier: NCT02603913 . Registered October 2015.

Flow-mediated dilation and peripheral arterial tonometry are disturbed in preeclampsia and reflect different aspects of endothelial function.

Endothelial function and arterial stiffness are known to be altered in preeclamptic pregnancies. Previous studies have shown conflicting results regarding the best technique for assessing vascular function in pregnancy. In this study, we made a comprehensive evaluation of in vivo vascular function [including flow-mediated dilatation (FMD), peripheral arterial tonometry (PAT), and arterial stiffness] in preeclamptic patients and compared them with normal pregnancies. In addition, we assessed the relation between vascular function and systemic inflammation. Fourteen patients with preeclampsia (PE) and 14 healthy pregnant controls were included. Endothelial function was determined by FMD and PAT and arterial stiffness by carotid-femoral pulse-wave velocity and augmentation index. Systemic inflammation was assessed using mean platelet volume (MPV) and neutrophil-lymphocyte ratio (NLR). The reactive hyperemia index, assessed using PAT, is decreased at the third trimester compared with the first trimester in a normal, uncomplicated pregnancy (P = 0.001). Arterial stiffness is significantly higher in PE versus normal pregnancy (P < 0.001). Endothelial function, obtained by FMD, is deteriorated in PE versus normal pregnancy (P = 0.015), whereas endothelial function assessment by PAT is improved in PE versus normal pregnancy (P = 0.001). Systemic inflammation (MPV and NLR) increases during normal pregnancy. FMD and PAT are disturbed in PE. Endothelial function, assessed by FMD and PAT, shows distinct results. This may indicate that measurements with FMD and PAT reflect different aspects of endothelial function and that PAT should not be used as a substitute for FMD as a measure of endothelial function in pregnancy.

Prenatal influence of congenital heart defects on trajectories of cortical folding of the fetal brain using three-dimensional ultrasound.

OBJECTIVE: The objective of the study is to investigate the prenatal influence of congenital heart defects (CHD) on trajectories of fetal cortical folding using three-dimensional ultrasound (3D US). METHOD: We included 20 CHD fetuses and 193 controls for studying the fetal brain at 22, 26 and 32 weeks' gestational age (GA). The Sylvian, insula and parieto-occipital fissure (POF) depths were measured using 3D US, and reliability was evaluated. Doppler indices of the umbilical artery and middle cerebral artery were measured to calculate the cerebro-placental ratio. Associations between CHD and cortical folding were estimated using linear mixed models. RESULTS: Brain fissure measurements were successful in over 80% of 3D US scans, except for the POF at 32 weeks' GA (65%). All measurements showed a good reliability (intraclass correlation coefficients > 0.84). Growth trajectories of the left insula depth (ß = -2.753, 95% CI = -5.375; -0.130, p = 0.040) and right POF (ß = -3.762, 95% CI = -7.178; -0.346, p = 0.031) were decreased in CHD compared with controls, whereas growth rates were increased (ß = 0.014, 95% CI = 0.001; 0.027, p = 0.036 and ß = 0.024, 95% CI = 0.007; 0.041, p = 0.006). In contrast to controls, we found no associations between cerebro-placental ratio and cortical folding in CHD. CONCLUSION: Fetal cortical folding can be evaluated reliably by measuring brain fissure depths. Trajectories of cortical folding between 22 and 32 weeks' GA seem to be influenced by CHD. © 2017 John Wiley & Sons, Ltd.

Which Factors Contribute to False-Positive, False-Negative, and Invalid Results in Fetal Fibronectin Testing in Women with Symptoms of Preterm Labor?

Objective We assessed the influence of external factors on false-positive, false-negative, and invalid fibronectin results in the prediction of spontaneous delivery within 7 days. Methods We studied symptomatic women between 24 and 34 weeks' gestational age. We performed uni- and multivariable logistic regression to estimate the effect of external factors (vaginal soap, digital examination, transvaginal sonography, sexual intercourse, vaginal bleeding) on the risk of false-positive, false-negative, and invalid results, using spontaneous delivery within 7 days as the outcome. Results Out of 708 women, 237 (33%) had a false-positive result; none of the factors showed a significant association. Vaginal bleeding increased the proportion of positive fetal fibronectin (fFN) results, but was significantly associated with a lower risk of false-positive test results (odds ratio [OR], 0.22; 95% confidence intervals [CI], 0.12-0.39). Ten women (1%) had a false-negative result. None of the investigated factors was significantly associated with a significantly higher risk of false-negative results. Twenty-one tests (3%) were invalid; only vaginal bleeding showed a significant association (OR, 4.5; 95% CI, 1.7-12). Conclusion The effect of external factors on the performance of qualitative fFN testing is limited, with vaginal bleeding as the only factor that reduces its validity.

Contraception and cardiovascular disease.

Contraceptive counselling should begin early in females with heart disease, preferably directly after the start of menstruation. In coming to a decision about the method of contraception, the following issues should be considered: (i) the risk of pregnancy for the mother and the consequences of an unplanned pregnancy; (ii) the risks of the contraceptive method; (iii) failure rates; (iv) the non-contraceptive benefits; (v) the availability; (vi) the individual's preferences; (vii) protection against infection; and (viii) costs. In some women with heart disease, the issues may be complex and require the input of both a cardiologist and an obstetrician (or other feto-maternal expert) to identify the optimal approach. No studies have been performed in women with heart disease to investigate the relative risks and benefits of different contraceptive methods.

Risk stratification with cervical length and fetal fibronectin in women with threatened preterm labor before 34 weeks and not delivering within 7 days.

OBJECTIVE: To stratify the risk of spontaneous preterm delivery using cervical length (CL) and fetal fibronectin (fFN) in women with threatened preterm labor who remained pregnant after 7 days. DESIGN: Prospective observational study. SETTING: Nationwide cohort of women with threatened preterm labor from the Netherlands. POPULATION: Women with threatened preterm labor between 24 and 34 weeks with a valid CL and fFN measurement and remaining pregnant 7 days after admission. METHODS: Kaplan-Meier and Cox proportional hazards models were used to estimate cumulative percentages and hazard ratios (HR) for spontaneous delivery. MAIN OUTCOME MEASURES: Spontaneous delivery between 7 and 14 days after initial presentation and spontaneous preterm delivery before 34 weeks. RESULTS: The risk of delivery between 7 and 14 days was significantly increased for women with a CL < 15 mm or a CL ≥15 to <30 mm and a positive fFN, compared with women with a CL ≥30 mm: HR 22.3 [95% confidence interval (CI) 2.6-191] and 14 (95% CI 1.8-118), respectively. For spontaneous preterm delivery before 34 weeks the risk was increased for women with a CL < 15 mm [HR 6.3 (95% CI 2.6-15)] or with a CL ≥15 to <30 mm with either positive fFN [HR 3.6 (95% CI 1.5-8.7)] or negative fFN [HR 3.0 (95% CI 1.2-7.1)] compared with women with a CL ≥ 30 mm. CONCLUSIONS: In women remaining pregnant 7 days after threatened preterm labor, CL and fFN results can be used in risk stratification for spontaneous delivery.

Randomized comparison of nifedipine and placebo in fibronectin-negative women with symptoms of preterm labor and a short cervix (APOSTEL-I Trial).

OBJECTIVE: To evaluate whether tocolysis with nifedipine can be omitted in women with symptoms of preterm labor, a shortened cervix, and negative fetal fibronectin test. STUDY DESIGN: A randomized noninferiority trial was performed in all Dutch perinatal centers. Women with symptoms of preterm labor between 24 and 34 weeks, intact membranes, cervical length between 10 and 30 mm, and negative fibronectin test were randomly allocated to nifedipine (80 mg/day) or placebo. The primary outcome was delivery within 7 days. Secondary outcomes were severe neonatal morbidity and mortality. We also followed all eligible nonrandomized women. RESULTS: We allocated 37 women to nifedipine and 36 women to placebo. In the nifedipine group, three women (8.1%) delivered within 7 days, compared with one woman (2.8%) in the placebo group (difference -5.3%; one-sided 95% confidence limit 4.5%). Median gestational age at delivery were respectively 37 + 0 (interquartile range [IQR] 34 + 6 to 38 + 5) and 38 + 2 (IQR 37 + 0 to 39 + 6) weeks (p = 0.008). In the nifedipine group, three pregnancies (8.1%) had a poor outcome; there were no poor outcomes in the placebo group. We observed similar trends in eligible nonrandomized women. CONCLUSION: In symptomatic women with preterm labor, a shortened cervix, and negative fibronectin test, placebo treatment is not inferior to tocolysis with nifedipine.

Uteroplacental blood flow, cardiac function, and pregnancy outcome in women with congenital heart disease.

BACKGROUND: Pregnant women with congenital heart disease (CHD) are susceptible to cardiovascular, obstetric, and offspring complications. In women with CHD, cardiac dysfunction may compromise uteroplacental flow and contribute to the increased incidence of obstetric and offspring events. METHODS AND RESULTS: We performed a prospective multicenter cohort study of pregnant women with CHD and healthy pregnant women. We compared clinical, laboratory, echocardiographic, and uteroplacental Doppler flow (UDF) parameters at 20 and 32 weeks gestation, and pregnancy outcome. We related cardiovascular parameters to UDF parameters and pregnancy outcome in women with CHD. We included 209 women with CHD and 70 healthy women. Cardiovascular parameters (N-terminal pro-B-type natriuretic peptide, left and right ventricular function) differed between both groups. UDF parameters were impaired in CHD women (umbilical artery pulsatility and resistance index at 32 weeks in CHD versus healthy women, P=0.0085 and P=0.017). The following cardiovascular parameters prepregnancy and at 20 weeks gestation were associated with UDF (umbilical artery resistance index) at 32 weeks at multivariable analysis: (1) right ventricular function (tricuspid annular plane systolic excursion) (P=0.002), (2) high N-terminal pro-B-type natriuretic peptide (P=0.085), (3) systemic (P=0.001), and (4) pulmonary (P=0.045) atrioventricular valve regurgitation. Women with CHD had more obstetric (58.9% versus 32.9%, P<0.0001) and offspring events (35.4% versus 18.6%, P=0.008) than healthy women. Impaired UDF was associated with adverse obstetric and offspring outcome. CONCLUSIONS: UDF parameters are abnormal in pregnant women with CHD. Cardiovascular function is associated with an abnormal pattern of UDF. Compromised UDF may be a key factor in the high incidence of offspring and obstetric complications in this population.

Effects of antiplatelet therapy on menstrual blood loss in reproductive-aged women: a systematic review.

Background: The effects of antiplatelet therapy on menstrual bleeding have not been well characterized. Objectives: To systematically review the effects of antiplatelet therapy on menstrual bleeding. Methods: A literature search was performed for studies of reproductive-aged women who received antiplatelet therapy. Characteristics of menstrual bleeding both before and after initiation of antiplatelet therapy and from comparison groups were collected. Two reviewers independently assessed the risk of bias in individual studies. Results: Thirteen studies with a total of 611 women who received antiplatelet therapy were included. Types of antiplatelet drugs used were aspirin (n = 8), aspirin and/or clopidogrel (n = 2), prasugrel (n = 1), and not specified (n = 2). Risk of bias was assessed at moderate (n = 1), serious (n = 8), critical (n = 2), and no information (n = 2). Three studies reported changes in menstrual blood loss volume. One of these showed no increase during antiplatelet therapy; the other 2 studies suggested that aspirin may increase menstrual blood loss volume. In 3 studies that assessed the duration of menstrual bleeding, up to 13% of women reported an increased duration of menstruation. In 5 studies that reported the intensity of menstrual flow, 13% to 38% of women experienced an increase in the intensity of flow. Five studies reported the prevalence of heavy menstrual bleeding in women who received antiplatelet therapy, with estimates ranging from 7% to 38%. Conclusion: There is lack of high-quality data on the effects of antiplatelet therapy on menstrual bleeding. Aspirin may increase menstrual blood loss, at least in a minority of women, whereas the effects of P2Y12 inhibitors are unknown.

Functional Analysis of TRPA1, TRPM3, and TRPV1 Channels in Human Dermal Arteries and Their Role in Vascular Modulation.

Transient receptor potential (TRP) channels are pivotal in modulating vascular functions. In fact, topical application of cinnamaldehyde or capsaicin (TRPA1 and TRPV1 channel agonists, respectively) induces "local" changes in blood flow by releasing vasodilator neuropeptides. We investigated TRP channels' contributions and the pharmacological mechanisms driving vasodilation in human isolated dermal arteries. Ex vivo studies assessed the vascular function of artery segments and analyzed the effects of different compounds. Concentration-response curves to cinnamaldehyde, pregnenolone sulfate (PregS, TRPM3 agonist), and capsaicin were constructed to evaluate the effect of the antagonists HC030031 (TRPA1); isosakuranetin (TRPM3); and capsazepine (TRPV1). Additionally, the antagonists/inhibitors olcegepant (CGRP receptor); L-NAME (nitric oxide synthase); indomethacin (cyclooxygenase); TRAM-34 plus apamin (K+ channels); and MK-801 (NMDA receptors, only for PregS) were used. Moreover, CGRP release was assessed in the organ bath fluid post-agonist-exposure. In dermal arteries, cinnamaldehyde- and capsaicin-induced relaxation remained unchanged after the aforementioned antagonists, while PregS-induced relaxation was significantly inhibited by isosakuranetin, L-NAME and MK-801. Furthermore, there was a significant increase in CGRP levels post-agonist-exposure. In our experimental model, TRPA1 and TRPV1 channels seem not to be involved in cinnamaldehyde- or capsaicin-induced relaxation, respectively, whereas TRPM3 channels contribute to PregS-induced relaxation, possibly via CGRP-independent mechanisms.

Diuretics in pregnancy: Data from the ESC Registry of Pregnancy and Cardiac disease (ROPAC).

AIMS: Data on diuretic use in pregnancy are limited and inconsistent, and consequently it remains unclear whether they can be used safely. Our study aims to evaluate the perinatal outcomes after in-utero diuretic exposure. METHODS AND RESULTS: The Registry Of Pregnancy And Cardiac disease (ROPAC) is a prospective, global registry of pregnancies in women with heart disease. Outcomes were compared between women who used diuretics during pregnancy versus those who did not. Multivariable regression analysis was used to assess the impact of diuretic use on the occurrence of congenital anomalies and foetal growth. Diuretics were used in 382 (6.7%) of the 5739 ROPAC pregnancies, most often furosemide (86%). Age >35 years (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2-2.0), other cardiac medication use (OR 5.4, 95% CI 4.2-6.9), signs of heart failure (OR 1.7, 95% CI 1.2-2.2), estimated left ventricular ejection fraction <40% (OR 2.9, 95% CI 2.0-4.2), New York Heart Association class >II (OR 3.4, 95% CI 2.3-5.1), valvular heart disease (OR 6.3, 95% CI 4.7-8.3) and cardiomyopathy (OR 3.9, 95% CI 2.6-5.7) were associated with diuretic use during pregnancy. In multivariable analysis, diuretic use during the first trimester was not significantly associated with foetal or neonatal congenital anomalies (OR 1.3, 95% CI 0.7-2.6), and diuretic use during pregnancy was also not significantly associated with small for gestational age (OR 1.4, 95% CI 1.0-1.9). CONCLUSIONS: Our study does not conclusively establish an association between diuretic use during pregnancy and adverse foetal outcomes. Given these findings, it is essential to assess the risk-benefit ratio on an individual basis to guide clinical decisions.

Effect of maintenance tocolysis with nifedipine in threatened preterm labor on perinatal outcomes: a randomized controlled trial.

IMPORTANCE: In threatened preterm labor, maintenance tocolysis with nifedipine, after an initial course of tocolysis and corticosteroids for 48 hours, may improve perinatal outcome. OBJECTIVE: To determine whether maintenance tocolysis with nifedipine will reduce adverse perinatal outcomes due to premature birth. DESIGN, SETTING, AND PARTICIPANTS: APOSTEL-II (Assessment of Perinatal Outcome with Sustained Tocolysis in Early Labor) is a double-blind, placebo-controlled trial performed in 11 perinatal units including all tertiary centers in The Netherlands. From June 2008 to February 2010, women with threatened preterm labor between 26 weeks (plus 0 days) and 32 weeks (plus 2 days) gestation, who had not delivered after 48 hours of tocolysis and a completed course of corticosteroids, were enrolled. Surviving infants were followed up until 6 months after birth (ended August 2010). INTERVENTION: Randomization assigned 406 women to maintenance tocolysis with nifedipine orally (80 mg/d; n = 201) or placebo (n = 205) for 12 days. Assigned treatment was masked from investigators, participants, clinicians, and research nurses. MAIN OUTCOME MEASURES: Primary outcome was a composite of adverse perinatal outcomes (perinatal death, chronic lung disease, neonatal sepsis, intraventricular hemorrhage >grade 2, periventricular leukomalacia >grade 1, or necrotizing enterocolitis). Analyses were completed on an intention-to-treat basis. RESULTS: Mean (SD) gestational age at randomization was 29.2 (1.7) weeks for both groups. Adverse perinatal outcome was not significantly different between groups: 11.9% (24/201; 95% CI, 7.5%-16.4%) for nifedipine vs 13.7% (28/205; 95% CI, 9.0%-18.4%) for placebo (relative risk, 0.87; 95% CI, 0.53-1.45). CONCLUSIONS AND RELEVANCE: In patients with threatened preterm labor, nifedipine-maintained tocolysis did not result in a statistically significant reduction in adverse perinatal outcomes when compared with placebo. Although the lower than anticipated rate of adverse perinatal outcomes in the control group indicates that a benefit of nifedipine cannot completely be excluded, its use for maintenance tocolysis does not appear beneficial at this time. TRIAL REGISTRATION: trialregister.nl Identifier: NTR1336.