Prevotella timonensis bacteria associated with vaginal dysbiosis enhance HIV-1 susceptibility of vaginal CD4+ T cells.

Dysbiosis of the vaginal microbiome poses a serious risk for sexual HIV-1 transmission. Prevotella spp. are abundant during vaginal dysbiosis and associated with enhanced HIV-1 susceptibility; however, underlying mechanisms remain unclear. Here, we investigated the direct effect of vaginal bacteria on HIV-1 susceptibility of vaginal CD4+ T cells. Notably, pre-exposure to Prevotella timonensis enhanced HIV-1 uptake by vaginal T cells, leading to increased viral fusion and enhanced virus production. Pre-exposure to antiretroviral inhibitors abolished Prevotella timonensis-enhanced infection. Hence, our study shows that the vaginal microbiome directly affects mucosal CD4+ T cell susceptibility, emphasising importance of vaginal dysbiosis diagnosis and treatment.

"Hypertension in Pregnancy Intervention Trial At Term" and "Disproportionate Intrauterine Growth Intervention Trial At Term" Studies.

In 2003, in the context of a national research funding program in which obstetric research was prioritized, several perinatal centers took the initiative to jointly submit a number of applications to the subsidy programs of Effectiveness Research and Prevention of ZonMw. This has led to the funding of the Obstetric Consortium with several projects, including the "Hypertension in Pregnancy Intervention Trial At Term" and the "Disproportionate Intrauterine Growth Intervention Trial At Term" studies. The studies showed that induction of labor for hypertension and growth restriction at term was the appropriate management. Subsequent implementation improved maternal and perinatal outcomes.

Does induction of labor at 41 weeks (early, mid or late) improve birth outcomes in low-risk pregnancy? A nationwide propensity score-matched study.

INTRODUCTION: This study aimed to assess whether induction of labor at 41 weeks of gestation improved perinatal outcomes in a low-risk pregnancy compared with expectant management. MATERIAL AND METHODS: Registry-based national cohort study in The Netherlands. The study population comprised 239 971 low-risk singleton pregnancies from 2010 to 2019, with birth occurring from 41+0 to 42+0 weeks. We used propensity score matching to compare induction of labor in three 2-day groups to expectant management, and further conducted separate analyses by parity. The main outcome measures were stillbirth, perinatal mortality, 5-min Apgar <4 and <7, neonatal intensive care unit (NICU) admissions ≥24 h, and emergency cesarean section rate. RESULTS: Compared with expectant management, induction of labor at 41+0 to 41+1 weeks resulted in reduced stillbirths (adjusted odds ratio [aOR] 0.15, 95% confidence interval [CI] 0.05-0.51) in both nulliparous and multiparous women. Induction of labor increased 5-min Apgar score <7 (aOR 1.30, 95% CI 1.09-1.55) and NICU admissions ≥24 h (aOR 2.12, 95% CI 1.53-2.92), particularly in nulliparous women, and increased the cesarean section rate (aOR 1.42, 95% CI 1.34-1.51). At 41+2-41+3 weeks, induction of labor reduced perinatal mortality (aOR 0.13, 95% CI 0.04-0.43) in both nulliparous and multiparous women. The rate of 5-min Apgar score <7 was increased (aOR 1.26, 95% CI 1.06-1.50), reaching significance in multiparous women. The cesarean section rate increased (aOR 1.57, 95% CI 1.48-1.67) in both nulliparous and multiparous women. Induction of labor at 41+4 to 41+5 weeks reduced stillbirths (aOR 0.30, 95% CI 0.10-0.93). Induction of labor increased rates of 5-min Apgar score <4 (aOR 1.61, 95% CI 1.01-2.56) and NICU admissions ≥24 h (aOR 1.52, 95% CI 1.08-2.13) in nulliparous women. Cesarean section rate was increased (aOR 1.47, 95% CI 1.38-1.57) in nulliparous and multiparous women. CONCLUSIONS: At 41+2 to 41+3 weeks, induction of labor reduced perinatal mortality, and in all 2-day groups at 41 weeks, it reduced stillbirths, compared with expectant management. Low 5-min Apgar score (<7 and <4) and NICU admissions ≥24 h occurred more often with induction of labor, especially in nulliparous women. Induction of labor in all 2-day groups coincided with elevated cesarean section rates in nulliparous and multiparous women. These findings pertaining to the choice of induction of labor vs expectant management should be discussed when counseling women at 41 weeks of gestation.

Offspring school performance at age 12 after induction of labor vs non-intervention at term: A linked cohort study.

INTRODUCTION: The incidence of induction of labor, for both medical reasons and as an elective procedure, has been rising and a further increase in induction of labor following the ARRIVE trial may be expected. The effects of induction of labor at term on childhood neurodevelopment, however, are not well studied. We aimed to study the influence of elective induction of labor for each week of gestation separately from 37 to 42 weeks on offspring school performance at 12 years of age after uncomplicated pregnancies. MATERIAL AND METHODS: We performed a population-based study among 226 684 liveborn children from uncomplicated singleton pregnancies, born from 37+0 to 42+0 weeks of gestation in cephalic presentation in 2003-2008 (no hypertensive disorders, diabetes or birthweight ≤p5) in the Netherlands. Children with congenital anomalies, of non-white mothers and born after planned cesarean section were excluded. Birth records were linked with national data on school achievement. We compared, using a fetus-at-risk approach and per week of gestation, school performance score and secondary school level at age 12 in those born after induction of labor to those born after non-intervention, ie spontaneous onset of labor in the same week plus all those born at later gestations. Education scores were standardized to a mean of 0 and a standard deviation of 1 and adjusted in the regression analyses. RESULTS: For each gestational age up to 41 weeks, induction of labor was associated with decreased school performance scores compared with non-intervention (at 37 weeks -0.05 SD, 95% confidence interval [CI] -0.10 to -0.01 SD; adjusted for confounding factors). After induction of labor, fewer children reached higher secondary school level (at 38 weeks 48% vs 54%; adjusted odds ratio [aOR] 0.88, 95% CI 0.82-0.94). CONCLUSIONS: In women with uncomplicated pregnancies at term, consistently, at every week of gestation from 37 to 41 weeks, induction of labor is associated with lower offspring school performance at age 12 and lower secondary school level compared with non-intervention, although residual confounding may remain. These long-term effects of induction of labor should be incorporated in counseling and decision making.

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.

TBX2, a Novel Regulator of Labour.

Background and Objectives: Therapeutic interventions targeting molecular factors involved in the transition from uterine quiescence to overt labour are not substantially reducing the rate of spontaneous preterm labour. The identification of novel rational therapeutic targets are essential to prevent the most common cause of neonatal mortality. Based on our previous work showing that Tbx2 (T-Box transcription factor 2) is a putative upstream regulator preceding progesterone withdrawal in mouse myometrium, we now investigate the role of TBX2 in human myometrium. Materials and Methods: RNA microarray analysis of (A) preterm human myometrium samples and (B) myometrial cells overexpressing TBX2 in vitro, combined with subsequent analysis of the two publicly available datasets of (C) Chan et al. and (D) Sharp et al. The effect of TBX2 overexpression on cytokines/chemokines secreted to the myometrium cell culture medium were determined by Luminex assay. Results: Analysis shows that overexpression of TBX2 in myometrial cells results in downregulation of TNFα- and interferon signalling. This downregulation is consistent with the decreased expression of cytokines and chemokines of which a subset has been previously associated with the inflammatory pathways relevant for human labour. In contrast, CXCL5 (C-X-C motif chemokine ligand 5), CCL21 and IL-6 (Interleukin 6), previously reported in relation to parturition, do not seem to be under TBX2 control. The combined bioinformatical analysis of the four mRNA datasets identifies a subset of upstream regulators common to both preterm and term labour under control of TBX2. Surprisingly, TBX2 mRNA levels are increased in preterm contractile myometrium. Conclusions: We identified a subset of upstream regulators common to both preterm and term labour that are activated in labour and repressed by TBX2. The increased TBX2 mRNA expression in myometrium collected during a preterm caesarean section while in spontaneous preterm labour compared to tissue harvested during iatrogenic preterm delivery does not fit the bioinformatical model. We can only explain this by speculating that the in vivo activity of TBX2 in human myometrium depends not only on the TBX2 expression levels but also on levels of the accessory proteins necessary for TBX2 activity.

Induction of labour at 41 weeks or expectant management until 42 weeks: A systematic review and an individual participant data meta-analysis of randomised trials.

BACKGROUND: The risk of perinatal death and severe neonatal morbidity increases gradually after 41 weeks of pregnancy. Several randomised controlled trials (RCTs) have assessed if induction of labour (IOL) in uncomplicated pregnancies at 41 weeks will improve perinatal outcomes. We performed an individual participant data meta-analysis (IPD-MA) on this subject. METHODS AND FINDINGS: We searched PubMed, Excerpta Medica dataBASE (Embase), The Cochrane Library, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and PsycINFO on February 21, 2020 for RCTs comparing IOL at 41 weeks with expectant management until 42 weeks in women with uncomplicated pregnancies. Individual participant data (IPD) were sought from eligible RCTs. Primary outcome was a composite of severe adverse perinatal outcomes: mortality and severe neonatal morbidity. Additional outcomes included neonatal admission, mode of delivery, perineal lacerations, and postpartum haemorrhage. Prespecified subgroup analyses were conducted for parity (nulliparous/multiparous), maternal age (<35/≥35 years), and body mass index (BMI) (<30/≥30). Aggregate data meta-analysis (MA) was performed to include data from RCTs for which IPD was not available. From 89 full-text articles, we identified three eligible RCTs (n = 5,161), and two contributed with IPD (n = 4,561). Baseline characteristics were similar between the groups regarding age, parity, BMI, and higher level of education. IOL resulted overall in a decrease of severe adverse perinatal outcome (0.4% [10/2,281] versus 1.0% [23/2,280]; relative risk [RR] 0.43 [95% confidence interval [CI] 0.21 to 0.91], p-value 0.027, risk difference [RD] -57/10,000 [95% CI -106/10,000 to -8/10,000], I2 0%). The number needed to treat (NNT) was 175 (95% CI 94 to 1,267). Perinatal deaths occurred in one (<0.1%) versus eight (0.4%) pregnancies (Peto odds ratio [OR] 0.21 [95% CI 0.06 to 0.78], p-value 0.019, RD -31/10,000, [95% CI -56/10,000 to -5/10,000], I2 0%, NNT 326, [95% CI 177 to 2,014]) and admission to a neonatal care unit ≥4 days occurred in 1.1% (24/2,280) versus 1.9% (46/2,273), (RR 0.52 [95% CI 0.32 to 0.85], p-value 0.009, RD -97/10,000 [95% CI -169/10,000 to -26/10,000], I2 0%, NNT 103 [95% CI 59 to 385]). There was no difference in the rate of cesarean delivery (10.5% versus 10.7%; RR 0.98, [95% CI 0.83 to 1.16], p-value 0.81) nor in other important perinatal, delivery, and maternal outcomes. MA on aggregate data showed similar results. Prespecified subgroup analyses for the primary outcome showed a significant difference in the treatment effect (p = 0.01 for interaction) for parity, but not for maternal age or BMI. The risk of severe adverse perinatal outcome was decreased for nulliparous women in the IOL group (0.3% [4/1,219] versus 1.6% [20/1,264]; RR 0.20 [95% CI 0.07 to 0.60], p-value 0.004, RD -127/10,000, [95% CI -204/10,000 to -50/10,000], I2 0%, NNT 79 [95% CI 49 to 201]) but not for multiparous women (0.6% [6/1,219] versus 0.3% [3/1,264]; RR 1.59 [95% CI 0.15 to 17.30], p-value 0.35, RD 27/10,000, [95% CI -29/10,000 to 84/10,000], I2 55%). A limitation of this IPD-MA was the risk of overestimation of the effect on perinatal mortality due to early stopping of the largest included trial for safety reasons after the advice of the Data and Safety Monitoring Board. Furthermore, only two RCTs were eligible for the IPD-MA; thus, the possibility to assess severe adverse neonatal outcomes with few events was limited. CONCLUSIONS: In this study, we found that, overall, IOL at 41 weeks improved perinatal outcome compared with expectant management until 42 weeks without increasing the cesarean delivery rate. This benefit is shown only in nulliparous women, whereas for multiparous women, the incidence of mortality and morbidity was too low to demonstrate any effect. The magnitude of risk reduction of perinatal mortality remains uncertain. Women with pregnancies approaching 41 weeks should be informed on the risk differences according to parity so that they are able to make an informed choice for IOL at 41 weeks or expectant management until 42 weeks. Study Registration: PROSPERO CRD42020163174.

Intrapartum epidural analgesia and low Apgar score among singleton infants born at term: A propensity score matched study.

INTRODUCTION: The associations of epidural analgesia and low Apgar score found in the Swedish Registry might be a result of confounding by indication. The objective of this study was to assess the possible effect of intrapartum epidural analgesia on low Apgar score and neonatal intensive care unit (NICU) admission in term born singletons with propensity score matching. MATERIAL AND METHODS: This was a propensity score matched study (n = 257 872) conducted in a national cohort of 715 449 term live born singletons without congenital anomalies in the Netherlands. Mothers with prelabor cesarean section were excluded. Main outcome measures were 5-minute Apgar score <7, 5-minute Apgar score <4 and admission to a NICU for at least 24 hours. First, an analysis of the underlying risk factors for low Apgar score <7 was performed. Multivariable analyses were applied to assess the effect of the main risk factor, intrapartum epidural analgesia, on low Apgar score to adjust the results for confounding factors. Second, a propensity score matched analysis on the main risk factors for epidural analgesia was applied. By propensity score matching the (confounding) characteristics of the women who received epidural analgesia with the characteristics of the control women without epidural analgesia, the effect of possible confounding by indication is minimized. RESULTS: Intrapartum epidural analgesia was performed in 128 936 women (18%). Apgar score <7 was present in 1.0%, Apgar score <4 in .2% and NICU admission in .4% of the deliveries. The strongest risk factor for Apgar score <7 was epidural analgesia (adjusted odds ratio [aOR] 1.9, 95% confidence interval [CI] 1.8-2.0). The propensity score matched adjusted analysis of women with epidural analgesia showed significant adverse neonatal outcomes: aOR 1.8 (95% CI 1.7-1.9) for AS <7, aOR 1.6 (95% CI 1.4-1.9) for AS <4 and aOR 1.7 (95% CI 1.6-1.9) for NICU admission. The results of epidural analgesia on AS <7 were also significantly increased for spontaneous start of labor (aOR 2.0, 95% CI 1.8-2.1) and for spontaneous delivery. CONCLUSIONS: Intrapartum epidural analgesia at term is strongly associated with low Apgar score and more NICU admissions, especially in spontaneous deliveries. This association needs further research and awareness.

Intrapartum and neonatal mortality in low-risk term women in midwife-led care and obstetrician-led care at the onset of labor: A national matched cohort study.

INTRODUCTION: Midwife-led models of care have been the subject of debate for many years. We conducted a study to compare intrapartum and neonatal mortality rates in midwife-led (primary) vs obstetrician-led (secondary) care at the onset of labor in low-risk term women. MATERIAL AND METHODS: We performed an unmatched and a propensity score matched cohort study using data from the national perinatal audit registry (PAN) and from the national perinatal registry (PERINED) of the Netherlands. We included women with singleton pregnancies (without congenital anomalies or antepartum fetal death) who gave birth at term between 2010 and 2012. We excluded the following major risk factors: non-vertex position of the fetus, previous cesarean birth, hypertension, diabetes mellitus, prolonged rupture of membranes (≥24 hours), vaginal bleeding in the second half of pregnancy, nonspontaneous start of labor and post-term pregnancy (≥42 weeks). The primary outcome was intrapartum or neonatal mortality up to 28 days after birth. Secondary outcome measures were mode of delivery and a 5-minute Apgar score <7. RESULTS: We included 259 211 women. There were 100/206 642 (0.48‰) intrapartum and neonatal deaths in the midwife group and 23/52 569 (0.44‰) in the obstetrician group (odds ratio [OR] 1.11, 95% CI 0.70-1.74). Propensity score matched analysis showed mortality rates of 0.49‰ (26/52 569) among women in midwife-led care and 0.44‰ (23/52 569) for women in obstetrician-led care (OR 1.13, 95% CI 0.65-1.98). In the midwife group there were significantly lower rates of vaginal instrumental deliveries (8.4% vs 13.0%; matched OR 0.65, 95% CI 0.62-0.67) and intrapartum cesarean sections (2.6% vs 8.2%; matched OR 0.32, 95% CI 0.30-0.34), and fewer neonates with low Apgar scores (<7 after 5 minutes) (0.69% vs 1.11%; matched OR 0.61, 95% CI 0.53-0.69). CONCLUSIONS: Among low-risk term women, there were comparable intrapartum and neonatal mortality rates for women starting labor in midwife-led vs obstetrician-led care, with lower intervention rates and fewer low Apgar scores in the midwife group.

Decreasing trend in preterm birth and perinatal mortality, do disparities also decline?

BACKGROUND: In the Netherlands, several initiatives started after the publication of the PERISTAT findings that showed the perinatal mortality risk was higher than in other European countries. The objective of this study is 1) to report recent trends in perinatal mortality and in intermediate risk groups (preterm birth, congenital anomalies and small for gestational age (SGA)), 2) describing perinatal mortality risk among children born preterm, with congenital anomalies or SGA, and born in maternal high risk groups (parity, age, ethnicity and socio-economic status (SES)). METHODS: A nationwide cohort study in the Netherlands among 996,423 singleton births in 2010-2015 with a gestational age between 24.0 and 42.6 weeks. Trend tests, univariate and multivariable logistic regression analyses were used. We did separate analyses for gestational age subgroups and line of care. RESULTS: The perinatal mortality rate was 5.0 per 1000 and it decreased significantly from 5.6 in 2010 to 4.6 per 1000 in 2015. Preterm birth significantly declined (6.1% in 2010 to 5.6% in 2015). Analysis by gestational age groups showed that the largest decline in perinatal mortality of 32% was seen at 24-27 weeks of gestation where the risk declined from 497 to 339 per 1000. At term, the decline was 23% from 2.2 to 1.7 per 1000. The smallest decline was 3% between 32 and 36 weeks. In children with preterm birth, congenital anomalies or SGA, the perinatal mortality risk significantly declined. Main risk factors for perinatal mortality were African ethnicity (adjusted odds ratio (aOR) 2.1 95%CI [1.9-2.4]), maternal age ≥ 40 years (aOR1.9 95%CI [1.7-2.2]) and parity 2+ (aOR 1.4 95%CI [1.3-1.5]). Among the (post)term born neonates, there was no significant decline in perinatal mortality in women with low age, low or high SES, non-Western ethnicity and among women who started or delivered under primary care. CONCLUSIONS: There is a decline in preterm birth and in perinatal mortality between 2010 and 2015. The decline in perinatal mortality is both in stillbirths and in neonatal mortality, most prominently among 24-27 weeks and among (post)term births. A possible future target could be deliveries among 32-36 weeks, women with high maternal age or non-Western ethnicity.

Predicting seizures in pregnant women with epilepsy: Development and external validation of a prognostic model.

BACKGROUND: Seizures are the main cause of maternal death in women with epilepsy, but there are no tools for predicting seizures in pregnancy. We set out to develop and validate a prognostic model, using information collected during the antenatal booking visit, to predict seizure risk at any time in pregnancy and until 6 weeks postpartum in women with epilepsy on antiepileptic drugs. METHODS AND FINDINGS: We used datasets of a prospective cohort study (EMPiRE) of 527 pregnant women with epilepsy on medication recruited from 50 hospitals in the UK (4 November 2011-17 August 2014). The model development cohort comprised 399 women whose antiepileptic drug doses were adjusted based on clinical features only; the validation cohort comprised 128 women whose drug dose adjustments were informed by serum drug levels. The outcome was epileptic (non-eclamptic) seizure captured using diary records. We fitted the model using LASSO (least absolute shrinkage and selection operator) regression, and reported the performance using C-statistic (scale 0-1, values > 0.5 show discrimination) and calibration slope (scale 0-1, values near 1 show accuracy) with 95% confidence intervals (CIs). We determined the net benefit (a weighted sum of true positive and false positive classifications) of using the model, with various probability thresholds, to aid clinicians in making individualised decisions regarding, for example, referral to tertiary care, frequency and intensity of monitoring, and changes in antiepileptic medication. Seizures occurred in 183 women (46%, 183/399) in the model development cohort and in 57 women (45%, 57/128) in the validation cohort. The model included age at first seizure, baseline seizure classification, history of mental health disorder or learning difficulty, occurrence of tonic-clonic and non-tonic-clonic seizures in the 3 months before pregnancy, previous admission to hospital for seizures during pregnancy, and baseline dose of lamotrigine and levetiracetam. The C-statistic was 0.79 (95% CI 0.75, 0.84). On external validation, the model showed good performance (C-statistic 0.76, 95% CI 0.66, 0.85; calibration slope 0.93, 95% CI 0.44, 1.41) but with imprecise estimates. The EMPiRE model showed the highest net proportional benefit for predicted probability thresholds between 12% and 99%. Limitations of this study include the varied gestational ages of women at recruitment, retrospective patient recall of seizure history, potential variations in seizure classification, the small number of events in the validation cohort, and the clinical utility restricted to decision-making thresholds above 12%. The model findings may not be generalisable to low- and middle-income countries, or when information on all predictors is not available. CONCLUSIONS: The EMPiRE model showed good performance in predicting the risk of seizures in pregnant women with epilepsy who are prescribed antiepileptic drugs. Integration of the tool within the antenatal booking visit, deployed as a simple nomogram, can help to optimise care in women with epilepsy.

CONDISOX- continued versus discontinued oxytocin stimulation of induced labour in a double-blind randomised controlled trial.

BACKGROUND: Oxytocin is an effective drug for induction of labour, but is associated with serious adverse effects of which uterine tachysystole, fetal distress and the need of immediate delivery are the most common. Discontinuation of oxytocin once the active phase of labour is established could reduce the adverse effects. The objective is to investigate how the caesarean section rate is affected when oxytocin stimulation is discontinued in the active phase of labour compared to labours where oxytocin is continued. METHODS: CONDISOX is a double-blind multicentre randomised controlled trial conducted at Danish and Dutch Departments of Obstetrics and Gynaecology. The first participant was recruited on April 8 2016. Based on a clinically relevant relative reduction in caesarean section rate of 7%, an alpha of 0.05, a beta of 80%, we aim for 1200 participating women (600 in each arm). The CONDISOX trial includes women at a gestational age of 37-42 complete weeks of pregnancy, who have uterine activity stimulated with oxytocin infusion for the induction of labour. Women are randomised when the active phase of labour becomes established, to study medication containing either oxytocin (continuous group) or placebo (discontinued group) infusion. Women are stratified by birth site, indication for oxytocin stimulation (induction of labour, prelabour rupture of membranes) and parity (nulliparous, parous +/- previous caesarean section). We will compare the primary outcome, caesarean section rate, in the two groups using a chi-square test with a p-value of 0.05. If superiority is not demonstrated, we have a pre-defined post hoc non-inferiority boundary (margin, delta) at 1.09. Secondary outcomes include duration of the active phase of labour, incidence of uterine tachysystole, postpartum haemorrhage, admission to the neonatal intensive care unit, Apgar score, umbilical arterial blood pH, and birth experience. DISCUSSION: The high frequency of oxytocin use and the potential risks of both maternal and fetal adverse effects of oxytocin emphasise the need to determine the optimal oxytocin regime for induction of labour. TRIAL REGISTRATION: NCT02553226 (registered September 17, 2015). Eudra-CT number: 2015-002942-30.

Comparison of clean intermittent and transurethral indwelling catheterization for the treatment of overt urinary retention after vaginal delivery: a multicentre randomized controlled clinical trial.

INTRODUCTION AND HYPOTHESIS: Overt postpartum urinary retention (PUR) is the inability to void after delivery and affects up to 7% of patients. Clean intermittent catheterization (CIC) and transurethral indwelling catheterization (TIC) are both standard treatments, but have not previously been compared. Clinical guidelines on postpartum bladder management are lacking. METHODS: A total of 85 patients were randomised for TIC (n=45) and CIC (n=40). In total 68 patients (34 patients with TIC and 34 patients with CIC) completed the UDI-6 questionnaire 3 months after delivery.. Patients allocated to TIC received an indwelling catheter for 24 h and if necessary, another catheter for 48 h. Patients with CIC were intermittently catheterized or taught to self-catheterize until adequate voiding with a postvoid residual volume (PVRV) of <150 mL was achieved. The primary outcome was the presence of bothersome micturition symptoms as measured using the Dutch-validated Urogenital Distress Inventory (UDI-6). RESULTS: Only seven patients (10%) reported bothersome micturition problems 3 months after delivery. No significant differences in the occurrence of micturition symptoms were found. Median PVRV was 800 mL in the CIC group and 650 mL in the TIC group. PVRV was ≥1,000 mL in 24% of the patients. The median duration of catheterization was significantly shorter in the CIC group than in the TIC group (12 h vs. 24 h, p < 0,01). In patients with CIC, 35% required only one catheterization before complete bladder emptying occurred. The duration of treatment was not related to the initial PVRV. Both treatments were equally well accepted by the patients. CONCLUSIONS: In patients with overt PUR, CIC is the preferred treatment as a considerable percentage of patients appear to be over-treated when the standard duration of TIC is 24 h. The occurrence of micturition symptoms is not associated with the catheterization method used. CIC is well tolerated in patients with overt PUR.

Long-term micturition problems of asymptomatic postpartum urinary retention: a prospective case-control study.

INTRODUCTION AND HYPOTHESIS: Covert (asymptomatic) postpartum urinary retention (PUR) is defined as post-void residual volume (PVRV) ≥150 mL. Although often supposed to be a common and harmless phenomenon, no data are available on the potential long-term micturition problems of increased PVRV after vaginal delivery. METHODS: After the first spontaneous void post-vaginal delivery, PVRV was measured using a portable scanning device. Micturition symptoms were compared using validated questionnaires between women with PVRV < 150 mL and those with PVRV ≥150 mL until 1 year after delivery. Women with PVRV ≥ 150 mL were followed until complete bladder emptying was achieved. RESULTS: Data of 105 patients with PVRV < 150 mL and 119 with PVRV ≥ 150 mL were available for analysis. 75% of all patients included had PVRV ≥ 250 mL. More primiparous patients had PVRV ≥ 150 mL (p < 0.02). 92% of women with PVRV ≥ 150 mL after delivery were able to adequately empty their bladder within 4 days. One year after delivery, no statistically significant differences were found. CONCLUSIONS: Covert PUR according to the definition of PVRV ≥ 150 mL, is a common and transient phenomenon that does not result in more lower urinary tract symptoms 1 year after delivery. Although the current definition is not useful in identifying postpartum women with a pathological condition, we suggest that the definition of covert PUR should be change to: "PVRV≥500 mL after the first spontaneous void after (vaginal) delivery." This cut-off value is the value at which some women do need more time to normalise emptying of the bladder. The exact clinical implications of covert PUR need to be further studied in this subcategory of women.

Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial.

BACKGROUND: In women with threatened preterm birth, delay of delivery by 48 h allows antenatal corticosteroids to improve neonatal outcomes. For this reason, tocolytics are often administered for 48 h; however, there is no consensus about which drug results in the best maternal and neonatal outcomes. In the APOSTEL III trial we aimed to compare the effectiveness and safety of the calcium-channel blocker nifedipine and the oxytocin inhibitor atosiban in women with threatened preterm birth. METHODS: We did this multicentre, randomised controlled trial in ten tertiary and nine teaching hospitals in the Netherlands and Belgium. Women with threatened preterm birth (gestational age 25-34 weeks) were randomly assigned (1:1) to either oral nifedipine or intravenous atosiban for 48 h. An independent data manager used a web-based computerised programme to randomly assign women in permuted block sizes of four, with groups stratified by centre. Clinicians, outcome assessors, and women were not masked to treatment group. The primary outcome was a composite of adverse perinatal outcomes, which included perinatal mortality, bronchopulmonary dysplasia, sepsis, intraventricular haemorrhage, periventricular leukomalacia, and necrotising enterocolitis. Analysis was done in all women and babies with follow-up data. The study is registered at the Dutch Clinical Trial Registry, number NTR2947. FINDINGS: Between July 6, 2011, and July 7, 2014, we randomly assigned 254 women to nifedipine and 256 to atosiban. Primary outcome data were available for 248 women and 297 babies in the nifedipine group and 255 women and 294 babies in the atosiban group. The primary outcome occurred in 42 babies (14%) in the nifedipine group and in 45 (15%) in the atosiban group (relative risk [RR] 0·91, 95% CI 0·61-1·37). 16 (5%) babies died in the nifedipine group and seven (2%) died in the atosiban group (RR 2·20, 95% CI 0·91-5·33); all deaths were deemed unlikely to be related to the study drug. Maternal adverse events did not differ between groups. INTERPRETATION: In women with threatened preterm birth, 48 h of tocolysis with nifedipine or atosiban results in similar perinatal outcomes. Future clinical research should focus on large placebo-controlled trials, powered for perinatal outcomes. FUNDING: ZonMw (the Netherlands Organisation for Health Research and Development).

Low dose aspirin in the prevention of recurrent spontaneous preterm labour - the APRIL study: a multicenter randomized placebo controlled trial.

BACKGROUND: Preterm birth (birth before 37 weeks of gestation) is a major problem in obstetrics and affects an estimated 15 million pregnancies worldwide annually. A history of previous preterm birth is the strongest risk factor for preterm birth, and recurrent spontaneous preterm birth affects more than 2.5 million pregnancies each year. A recent meta-analysis showed possible benefits of the use of low dose aspirin in the prevention of recurrent spontaneous preterm birth. We will assess the (cost-)effectiveness of low dose aspirin in comparison with placebo in the prevention of recurrent spontaneous preterm birth in a randomized clinical trial. METHODS/DESIGN: Women with a singleton pregnancy and a history of spontaneous preterm birth in a singleton pregnancy (22-37 weeks of gestation) will be asked to participate in a multicenter, randomized, double blinded, placebo controlled trial. Women will be randomized to low dose aspirin (80 mg once daily) or placebo, initiated from 8 to 16 weeks up to maximal 36 weeks of gestation. The primary outcome measure will be preterm birth, defined as birth at a gestational age (GA) < 37 weeks. Secondary outcomes will be a composite of adverse neonatal outcome and maternal outcomes, including subgroups of prematurity, as well as intrauterine growth restriction (IUGR) and costs from a healthcare perspective. Preterm birth will be analyzed as a group, as well as separately for spontaneous or indicated onset. Analysis will be performed by intention to treat. In total, 406 pregnant women have to be randomized to show a reduction of 35% in preterm birth from 36 to 23%. If aspirin is effective in preventing preterm birth, we expect that there will be cost savings, because of the low costs of aspirin. To evaluate this, a cost-effectiveness analysis will be performed comparing preventive treatment with aspirin with placebo. DISCUSSION: This trial will provide evidence as to whether or not low dose aspirin is (cost-) effective in reducing recurrence of spontaneous preterm birth. TRIAL REGISTRATION: Clinical trial registration number of the Dutch Trial Register: NTR 5675 . EudraCT-registration number: 2015-003220-31.

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.

Delivery-related risk factors for covert postpartum urinary retention after vaginal delivery.

INTRODUCTION AND HYPOTHESIS: Postpartum urinary retention (PUR) is a common consequence of bladder dysfunction after vaginal delivery. Patients with covert PUR are able to void spontaneously but have a postvoid residual bladder volume (PVRV) of ≥150 mL. Incomplete bladder emptying may predispose to bladder dysfunction at a later stage of life. The aim of this cross-sectional study was to identify independent delivery-related risk factors for covert PUR after vaginal delivery in order to identify women with an increased risk of covert PUR. METHODS: The PVRV of women who delivered vaginally was measured after the first spontaneous micturition with a portable bladder-scanning device. A PVRV of 150 mL or more was defined as covert PUR. Independent risk factors for covert PUR were identified in multivariate regression analysis. RESULTS: Of 745 included women, 347 (47%) were diagnosed with covert PUR (PVRV ≥150 mL), of whom 197 (26%) had a PVRV ≥250 mL (75th percentile) and 50 (7%) a PVRV ≥500 mL (95th percentile). In multivariate regression analysis, episiotomy (OR 1.7, 95% CI 1.02 - 2.71), epidural analgesia (OR 2.08, 95% CI 1.36 - 3.19) and birth weight (OR 1.03, 95% CI 1.01 - 1.06) were independent risk factors for covert PUR. Opioid analgesia during labour (OR 3.19, 95% CI 1.46 - 6.98), epidural analgesia (OR 3.54, 95% CI 1.64 - 7.64) and episiotomy (OR 3.72, 95% CI 1.71 - 8.08) were risk factors for PVRV ≥500 mL. CONCLUSIONS: Episiotomy, epidural analgesia and birth weight are risk factors for covert PUR. We suggest that the current cut-off values for covert PUR should be reevaluated when data on the clinical consequences of abnormal PVRV become available.

Impact of fetal gender on the risk of preterm birth, a national cohort study.

INTRODUCTION: Fetal gender is associated with preterm birth; however, a proper subdivision by onset of labor and corresponding neonatal outcome by week of gestation is lacking. MATERIAL AND METHODS: Data from the Netherlands Perinatal Registry (1999-2010) were used to calculate relative risk ratios for gender by week of gestation and gender-related risk on adverse neonatal outcomes using a moving average technique. White European women with an alive fetus at onset of labor were included. Adverse neonatal outcomes were defined as neonatal mortality and a composite of neonatal morbidity. Onset of labor was categorized as spontaneous onset with intact membranes, premature rupture of membranes, and induction or elective cesarean section. RESULTS: The study population comprised 1 736 615 singleton deliveries (25(+0) -42(+6) weeks). Male fetuses were at increased risk of spontaneous preterm birth with intact membranes compared with a female fetus with a peak between 27 and 31 weeks [relative risk (RR) 1.5; 95% CI 1.4-1.6]. Male fetuses were also at increased risk of preterm premature rupture of membranes between 27 and 37 weeks (RR 1.2; 95% CI 1.16-1.23). No gender effect was seen for medically indicated preterm birth. No significant differences were seen for neonatal mortality. Males were at significantly increased risk of composite neonatal morbidity from 29 weeks onwards (RR 1.3; 95% CI 1.3-1.4). CONCLUSIONS: Male fetal gender is a relevant risk factor for spontaneous preterm birth, both for intact membranes and for preterm premature rupture of membranes in white European women. In addition, male infants are at increased risk of neonatal morbidity.

Early nasogastric tube feeding in optimising treatment for hyperemesis gravidarum: the MOTHER randomised controlled trial (Maternal and Offspring outcomes after Treatment of HyperEmesis by Refeeding).

BACKGROUND: Hyperemesis gravidarum (HG), or intractable vomiting during pregnancy, is the single most frequent cause of hospital admission in early pregnancy. HG has a major impact on maternal quality of life and has repeatedly been associated with poor pregnancy outcome such as low birth weight. Currently, women with HG are admitted to hospital for intravenous fluid replacement, without receiving specific nutritional attention. Nasogastric tube feeding is sometimes used as last resort treatment. At present no randomised trials on dietary or rehydration interventions have been performed. Small observational studies indicate that enteral tube feeding may have the ability to effectively treat dehydration and malnutrition and alleviate nausea and vomiting symptoms. We aim to evaluate the effectiveness of early enteral tube feeding in addition to standard care on nausea and vomiting symptoms and pregnancy outcomes in HG patients. METHODS/DESIGN: The MOTHER trial is a multicentre open label randomised controlled trial ( www.studies-obsgyn.nl/mother ). Women ≥ 18 years hospitalised for HG between 5 + 0 and 19 + 6 weeks gestation are eligible for participation. After informed consent participants are randomly allocated to standard care with intravenous rehydration or early enteral tube feeding in addition to standard care. All women keep a weekly diary to record symptoms and dietary intake until 20 weeks gestation. The primary outcome will be neonatal birth weight. Secondary outcomes will be the 24-h Pregnancy Unique Quantification of Emesis and nausea score (PUQE-24), maternal weight gain, dietary intake, duration of hospital stay, number of readmissions, quality of life and side-effects. Also gestational age at birth, placental weight, umbilical cord plasma lipid concentration and neonatal morbidity will be evaluated. Analysis will be according to the intention to treat principle. DISCUSSION: With this trial we aim to clarify whether early enteral tube feeding is more effective in treating HG than intravenous rehydration alone and improves pregnancy outcome. TRIAL REGISTRATION NUMBER: NTR4197 . Date of registration: October 2(nd) 2013.