Vaginal bacterium Prevotella timonensis turns protective Langerhans cells into HIV-1 reservoirs for virus dissemination.

Dysbiosis of vaginal microbiota is associated with increased HIV-1 acquisition, but the underlying cellular mechanisms remain unclear. Vaginal Langerhans cells (LCs) protect against mucosal HIV-1 infection via autophagy-mediated degradation of HIV-1. As LCs are in continuous contact with bacterial members of the vaginal microbiome, we investigated the impact of commensal and dysbiosis-associated vaginal (an)aerobic bacterial species on the antiviral function of LCs. Most of the tested bacteria did not affect the HIV-1 restrictive function of LCs. However, Prevotella timonensis induced a vast uptake of HIV-1 by vaginal LCs. Internalized virus remained infectious for days and uptake was unaffected by antiretroviral drugs. P. timonensis-exposed LCs efficiently transmitted HIV-1 to target cells both in vitro and ex vivo. Additionally, P. timonensis exposure enhanced uptake and transmission of the HIV-1 variants that establish infection after sexual transmission, the so-called Transmitted Founder variants. Our findings, therefore, suggest that P. timonensis might set the stage for enhanced HIV-1 susceptibility during vaginal dysbiosis and advocate targeted treatment of P. timonensis during bacterial vaginosis to limit HIV-1 infection.

The idiopathic preterm delivery methylation profile in umbilical cord blood DNA.

BACKGROUND: Preterm delivery is the leading cause of neonatal morbidity and mortality. Two-thirds of preterm deliveries are idiopathic. The initiating molecular mechanisms behind spontaneous preterm delivery are unclear. Umbilical cord blood DNA samples are an easy source of material to study the neonatal state at birth. DNA methylation changes can be exploited as markers to identify spontaneous preterm delivery. To identify methylation differences specific to idiopathic preterm delivery, we assessed genome-wide DNA methylation changes in 24 umbilical cord blood samples (UCB) using the 450 K Illumina methylation array. After quality control, conclusions were based on 11 term and 11 idiopathic preterm born neonates. The differentially methylated positions (DMPs) specific for preterm/term delivery, neonatal sex, use of oxytocin and mode of initiation of labor were calculated by controlling the FDR p value at 0.05. RESULTS: The analysis identifies 1855 statistically significant DMPs between preterm and term deliveries of which 508 DMPs are also attributable to clinical variables other than preterm versus term delivery. 1347 DMPs are unique to term vs preterm delivery, of which 196 DMPs do not relate to gestational age as such. Pathway analysis indicated enrichment of genes involved in calcium signalling, myometrial contraction and relaxation pathways. The 1151 DMPs that correlate with advancing gestational age (p < 0.05) include 161 DMPs that match with two previously reported studies on UCB methylation. Additionally, 123 neonatal sex specific DMPs, 97 DMPs specific to the induction of labour and 42 DMPs specific to the mode of initiation of labor were also identified. CONCLUSION: This study identifies 196 DMPs in UCB DNA of neonates which do not relate to gestational age or any other clinical variable recorded and are specific to idiopathic preterm delivery. Furthermore, 161 DMPs from our study overlap with previously reported studies of which a subset is also reported to be differentially methylated at 18 years of age. A DMP on MYL4, encoding myosin light chain 4, is a robust candidate for the identification of idiopathic preterm labour as it is identified by all 3 independent studies.

Elective induction of labour and expectant management in late-term pregnancy: A prospective cohort study alongside the INDEX randomised controlled trial.

Objective: To assess adverse perinatal outcomes and caesarean section of low-risk women receiving elective induction of labour at 41 weeks or expectant management until 42 weeks according to their preferred and actual management strategy. Design: Multicentre prospective cohort study alongside RCT. Setting: 90 midwifery practices and 12 hospitals in the Netherlands. Population: 3642 low-risk women with uncomplicated singleton late-term pregnancy. Main outcome measures: Composite adverse outcome (perinatal death, Apgar score 5' < 7, NICU admission, meconium aspiration syndrome), composite severe adverse perinatal outcome (all above with Apgar score 5' < 4 instead of < 7) and caesarean section. Results: From 2012-2016, 3642 women out of 6088 eligible women for the INDEX RCT, participated in the cohort study for observational data collection (induction of labour n = 372; expectant management n = 2174; unknown preference/management strategy n = 1096).Adverse perinatal outcome occurred in 1.1 % (4/372) in the induction group versus 1.9 % (42/2174) in the expectant group (adjRR 0.56; 95 %CI: 0.17-1.79), with severe adverse perinatal outcome occurring in 0.3 % (1/372) versus 1.0 % (22/2174), respectively (adjRR 0.39; 95 % CI: 0.05-2.88). There were no stillbirths among all 3642 women; one neonatal death occurred in the unknown preference/management group. Caesarean section rates were 10.5 % (39/372) after induction and 8.9 % (193/2174) after expectant management (adjRR 1.32; 95 % CI: 0.95-1.84).A higher incidence of adverse perinatal outcome was observed in nulliparous compared to multiparous women. Nulliparous 1.8 % (3/170) in the induction group versus 2.6 % (30/1134) in the expectant management group (adjRR 0.58; 95 % CI 0.14-2.41), multiparous 0.5 % (1/201) versus 1.1 % (11/1039) (adjRR 0.54; 95 % CI 0.07-24.19). One maternal death due to amniotic fluid embolism occurred after elective induction at 41 weeks + 6 days. Conclusion: In this cohort study among low-risk women receiving the policy of their preference in late-term pregnancy, a non-significant difference was found between induction of labour at 41 weeks and expectant management until 42 weeks in absolute risks of composite adverse (1.1 % versus 1.9 %) and severe adverse (0.3 % versus 1.0 %) perinatal outcome. The risks in this cohort study were lower than in the trial setting. There were no stillbirths among all 3642 women. Caesarean section rates were comparable.

Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks' gestation (HYPITAT): a multicentre, open-label randomised controlled trial.

BACKGROUND: Robust evidence to direct management of pregnant women with mild hypertensive disease at term is scarce. We investigated whether induction of labour in women with a singleton pregnancy complicated by gestational hypertension or mild pre-eclampsia reduces severe maternal morbidity. METHODS: We undertook a multicentre, parallel, open-label randomised controlled trial in six academic and 32 non-academic hospitals in the Netherlands between October, 2005, and March, 2008. We enrolled patients with a singleton pregnancy at 36-41 weeks' gestation, and who had gestational hypertension or mild pre-eclampsia. Participants were randomly allocated in a 1:1 ratio by block randomisation with a web-based application system to receive either induction of labour or expectant monitoring. Masking of intervention allocation was not possible. The primary outcome was a composite measure of poor maternal outcome--maternal mortality, maternal morbidity (eclampsia, HELLP syndrome, pulmonary oedema, thromboembolic disease, and placental abruption), progression to severe hypertension or proteinuria, and major post-partum haemorrhage (>1000 mL blood loss). Analysis was by intention to treat and treatment effect is presented as relative risk. This study is registered, number ISRCTN08132825. FINDINGS: 756 patients were allocated to receive induction of labour (n=377 patients) or expectant monitoring (n=379). 397 patients refused randomisation but authorised use of their medical records. Of women who were randomised, 117 (31%) allocated to induction of labour developed poor maternal outcome compared with 166 (44%) allocated to expectant monitoring (relative risk 0.71, 95% CI 0.59-0.86, p<0.0001). No cases of maternal or neonatal death or eclampsia were recorded. INTERPRETATION: Induction of labour is associated with improved maternal outcome and should be advised for women with mild hypertensive disease beyond 37 weeks' gestation. FUNDING: ZonMw.

Morning versus evening induction of labour for improving outcomes.

This is the protocol for a review and there is no abstract. The objectives are as follows: To assess whether induction of labour starting in the evening, coinciding with the endogenous circadian rhythm, improves the outcome of labour compared to induction of labour starting in the early morning, organised to coincide with office hours.

Pessaries in multiple pregnancy as a prevention of preterm birth: the ProTwin Trial.

BACKGROUND: Multiple pregnancies are at high risk for preterm birth, and therefore an important cause of infant mortality and morbidity. A pessary is a simple and potentially effective measure for the prevention of preterm birth. Small studies have indicated its effectiveness, but large studies with sufficient power on the subject are lacking. Despite this lack of evidence, the treatment is at present applied by some gynaecologists in The Netherlands. METHODS/DESIGN: We aim to investigate the hypothesis that prophylactic use of a cervical pessary will be effective in the prevention of preterm delivery and the neonatal mortality and morbidity resulting from preterm delivery in multiple pregnancy. We will evaluate the costs and effects of this intervention. At study entry, cervical length will be measured. Eligible women will be randomly allocated to receive either a cervical pessary or no intervention. The cervical pessary will be placed in situ at 16 to 20 weeks, and will stay in situ up to 36 weeks gestation or until delivery, whatever comes first.The primary outcome is composite bad neonatal condition (perinatal death or severe morbidity). Secondary outcome measures are time to delivery, preterm birth rate before 32 and 37 weeks, days of admission in neonatal intensive care unit, maternal morbidity, maternal admission days for preterm labour and costs. We need to include 660 women to indicate a reduction in bad neonatal outcome from 7.2% without to 3.9% with a cervical pessary, using a two-sided test with an alpha of 0.05 and a power of 0.80. DISCUSSION: This trial will provide evidence on whether a cervical pessary will decrease the incidence of early preterm birth and its concomitant bad neonatal outcome in multiple pregnancies. TRIAL REGISTRATION: Current Controlled Trials: NTR 1858.

Assessment of perinatal outcome after sustained tocolysis in early labour (APOSTEL-II trial).

BACKGROUND: Preterm labour is the main cause of perinatal morbidity and mortality in the Western world. At present, there is evidence that tocolysis for 48 hours is useful in women with threatened preterm labour at least before 32 weeks. This allows transfer of the patient to a perinatal centre, and maximizes the effect of corticosteroids for improved neonatal survival. It is questionable whether treatment with tocolytics should be maintained after 48 hours. METHODS/DESIGN: The APOSTEL II trial is a multicentre placebo-controlled study. Pregnant women admitted for threatened preterm labour who have been treated with 48 hours corticosteroids and tocolysis will be eligible to participate in the trial between 26+0 and 32+2 weeks gestational age. They will be randomly allocated to nifedipine (intervention) or placebo (control) for twelve days or until delivery, whatever comes first.Primary outcome is a composite of perinatal death, and severe neonatal morbidity up to evaluation at 6 months after birth. Secondary outcomes are gestational age at delivery, number of days in neonatal intensive care and total days of the first 6 months out of hospital. In addition a cost-effectiveness analysis will be performed. Analysis will be by intention to treat. The power calculation is based on an expected 11% difference in adverse neonatal outcome. This implies that 406 women have to be randomised (two sided test, beta 0.2 at alpha 0.05). DISCUSSION: This trial will provide evidence as to whether maintenance tocolysis reduces severe perinatal morbidity and mortality in women with threatened preterm labour before 32 weeks. CLINICAL TRIAL REGISTRATION: http://www.trialregister.nl, NTR 1336, date of registration: June 3rd 2008.

Induction of labour at 41 weeks versus expectant management until 42 weeks (INDEX): multicentre, randomised non-inferiority trial.

OBJECTIVE: To compare induction of labour at 41 weeks with expectant management until 42 weeks in low risk women. DESIGN: Open label, randomised controlled non-inferiority trial. SETTING: 123 primary care midwifery practices and 45 hospitals (secondary care) in the Netherlands, 2012-16. PARTICIPANTS: 1801 low risk women with an uncomplicated singleton pregnancy: randomised to induction (n=900) or to expectant management until 42 weeks (n=901). INTERVENTIONS: Induction at 41 weeks or expectant management until 42 weeks with induction if necessary. PRIMARY OUTCOME MEASURES: Primary outcome was a composite of perinatal mortality and neonatal morbidity (Apgar score <7 at five minutes, arterial pH <7.05, meconium aspiration syndrome, plexus brachialis injury, intracranial haemorrhage, and admission to a neonatal intensive care unit (NICU). Secondary outcomes included maternal outcomes and mode of delivery. The null hypothesis that expectant management is inferior to induction was tested with a non-inferiority margin of 2%. RESULTS: Median gestational age at delivery was 41 weeks+0 days (interquartile range 41 weeks+0 days-41 weeks+1 day) for the induction group and 41 weeks+2 days (41 weeks+0 days-41 weeks+5 days) for the expectant management group. The primary outcome was analysed for both the intention-to-treat population and the per protocol population. In the induction group, 15/900 (1.7%) women had an adverse perinatal outcome versus 28/901 (3.1%) in the expectant management group (absolute risk difference -1.4%, 95% confidence interval -2.9% to 0.0%, P=0.22 for non-inferiority). 11 (1.2%) infants in the induction group and 23 (2.6%) in the expectant management group had an Apgar score <7 at five minutes (relative risk (RR) 0.48, 95% CI 0.23 to 0.98). No infants in the induction group and three (0.3%) in the expectant management group had an Apgar score <4 at five minutes. One fetal death (0.1%) occurred in the induction group and two (0.2%) in the expectant management group. No neonatal deaths occurred. 3 (0.3%) neonates in the induction group versus 8 (0.9%) in the expectant management group were admitted to an NICU (RR 0.38, 95% CI 0.10 to 1.41). No significant difference was found in composite adverse maternal outcomes (induction n=122 (13.6%) v expectant management n=102 (11.3%)) or in caesarean section rate (both groups n=97 (10.8%)). CONCLUSIONS: This study could not show non-inferiority of expectant management compared with induction of labour in women with uncomplicated pregnancies at 41 weeks; instead a significant difference of 1.4% was found for risk of adverse perinatal outcomes in favour of induction, although the chances of a good perinatal outcome were high with both strategies and the incidence of perinatal mortality, Apgar score <4 at five minutes, and NICU admission low. TRIAL REGISTRATION: Netherlands Trial Register NTR3431.

Barriers and Facilitators for the Use of a Medical Mobile App to Prevent Work-Related Risks in Pregnancy: A Qualitative Analysis.

BACKGROUND: The number of women participating in the labor market in Europe has increased over the last several decades. At the same time, there is growing evidence that certain conditions of employment during pregnancy may have a negative influence on pregnancy outcomes. In order to better inform pregnant women, we aim to develop an app to help assess the health risk as a result of personal and work-related factors and provide personal advice for these women and their health care providers. OBJECTIVE: The aim of this study was to compose a thematic overview of the perceived facilitators and barriers according to pregnant women, medical professionals, and employers for the use of a mobile app in obstetrical care to prevent occupational-related pregnancy complications. METHODS: Two multidisciplinary focus group meetings with in total 14 participants were conducted with pregnant women, occupational physicians, general practitioners, midwives, obstetricians, and representatives of trade unions and employer organizations. Transcripts were analyzed by qualitatively coding procedures and constant comparative methods. RESULTS: We identified 24 potential facilitators and 12 potential barriers for the use of the app in 4 categories: content of the app, the app as a mean to provide information, ease of use, and external factors. The 3 main facilitators identified were the need for a good interaction between the app and the user, apps were viewed as a more practical source of information, and the information should be understandable, according to the existing guidelines, and well-dosed. The 2 main barriers for use were extensive battery and memory use of the smartphone and sending frequent push notifications. CONCLUSIONS: The results of this study are important considerations in the developing process of a medical app implementing a guideline or evidence-based information in practice.

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.