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ObjectiveRevised guidelines for caesarean section (CS) advise maternal antibiotic administration prior to skin incision instead of after umbilical cord clamping, unintentionally exposing the infant to antibiotics antenatally. We aimed to investigate if timing of intrapartum antibiotics contributes to the impairment of microbiota colonisation in CS born infants.DesignIn this randomised controlled trial, women delivering via CS received antibiotics prior to skin incision (n=20) or after umbilical cord clamping (n=20). A third control group of vaginally delivering women (n=23) was included. Faecal microbiota was determined from all infants at 1, 7 and 28 days after birth and at 3 years by 16S rRNA gene sequencing and whole-metagenome shotgun sequencing.ResultsCompared with vaginally born infants, profound differences were found in microbial diversity and composition in both CS groups in the first month of life. A decreased abundance in species belonging to the genera Bacteroides and Bifidobacterium was found with a concurrent increase in members belonging to the phylum Proteobacteria. These differences could not be observed at 3 years of age. No statistically significant differences were observed in taxonomic and functional composition of the microbiome between both CS groups at any of the time points.ConclusionWe confirmed that microbiome colonisation is strongly affected by CS delivery. Our findings suggest that maternal antibiotic administration prior to CS does not result in a second hit on the compromised microbiome. Future, larger studies should confirm that antenatal antibiotic exposure in CS born infants does not aggravate colonisation impairment and impact long-term health.

Objective To evaluate the implementation of low-dose aspirin in pregnancy for the prevention of utero-placental complications among gynecologists in the Netherlands between 2016 and 2021. In this timeframe, a national guideline about aspirin in pregnancy was introduced by the Dutch Society of Obstetrics and Gynecology. Materials and methods A national online survey among Dutch gynecologists and residents was performed. An online questionnaire was distributed among the members of the Dutch Society of Obstetrics and Gynecology in April 2016 and April 2021. Main outcome measure was the proportion of gynecologists indicating prescription of aspirin in pregnancy for high and moderate risk indications. Results In 2016, 133 respondents completed the survey, and in 2021 231. For all indications mentioned in the guideline there was an increase in prescribing aspirin in 2021 in comparison to 2016. More specifically, the percentage of gynecologists prescribing aspirin for a history of preeclampsia before 34 weeks, between 34 and 37 weeks and at term increased from respectively 94% to 100%, 39% to 98%, and 15% to 97%. Consultant obstetricians and respondents working in an university hospital did not more often indicate the prescription of aspirin for tertiary care indications in 2021. Future use of a prediction model was suggested in the narrative comments. Conclusion Implementation of aspirin in pregnancy among Dutch gynecologists substantially improved after a five year timeframe in which the national guideline on aspirin during pregnancy was introduced and trials confirming the effect of aspirin were published.

It is a truth universally acknowledged that states can consent to the military presence of other states on their territory. This is better known as intervention by invitation. Yet many issues surrounding this concept remain unclear or are too easily accepted, e.g. its name and its place within the rules of jus ad bellum. This article seeks to clarify and resolve these issues. First, an analysis is conducted into what the two terms intervention and invitation actually entail. The term intervention is contrasted with the use of force and the entire concept of intervention by invitation is differentiated from collective self-defence. It is concluded that the threshold of force has been met and thus the focus should be placed on the rules regulating this field of law, rather than the rules of non-intervention. The concept would be more aptly labelled as the use of force by invitation. Second, this article examines where intervention by invitation finds its place in relation to the prohibition of the use of force. Alternative perspectives are investigated encompassing the scope of Article 2(4) UN Charter and the circumstances precluding wrongfulness under the rules of state responsibility, of which consent is of particular relevance here. This article concludes that intervention by invitation falls outside the scope of Article 2(4) as the force is not used within international relations. The prohibition of the use of force therefore does not apply to intervention by invitation. Consequently, an action of intervention by invitation is legal.

The coronavirus pandemic and its long-term impact on our working life have been discussed extensively since the first outbreaks of COVID-19: In particular, this included the opportunity of working remotely. Whereas, before the pandemic, only 12% of German employees had ever worked from home, in February 2021 one in two worked remotely at least for a few hours a week. The desire to work from home will have legal relevance if the contracting parties want to derive any claim from mutual protective duties in an exceptional situation such as a worldwide pandemic. Moreover, this wish raises the question of how a legal right to work from home could be implemented by law in compliance with fundamental rights.

OBJECTIVE: Determine the risk of hypertensive disorders of pregnancy (HD) in women with a history of spontaneous preterm birth (SPTB).STUDY DESIGN: Longitudinal linked national cohort study within the Dutch Perinatal Registry (1999-2009) on linked data among 349,291 women with a first and second singleton pregnancy in the Netherlands.MAIN OUTCOME MEASURES: The incidence of HD, small for gestational age (SGA) and placental abruption in the second pregnancy.RESULTS: Out of 349,291 women with a singleton first pregnancy, 19,991 (5.7%) had a SPTB. The incidence of HD in the second pregnancy was 8.1% in women with a previous SPTB, as compared to 5.6% in women with a previous term birth (aOR 1.49 (CI 1.41-1.57)). Also after excluding HD, SGA and/or placental abruption in the first pregnancy, women with a history of SPTB had a higher risk of HD in their second pregnancy compared to women with a previous term birth (4.6% versus 2.7%, aOR 1.77 (CI 1.64-191)). Similarly, the incidence of SGA and placental abruption was higher in the second pregnancy in women with a history of SPTB compared to term birth in the first pregnancy.CONCLUSIONS: Women with a history of SPTB are at elevated risk of HD in the subsequent pregnancy. These results support shared pathophysiology between SPTB and HD.

Background: To reduce the risk of maternal infections, revised guidelines for caesarean section (CS) now advise maternal antibiotic administration prior to skin incision instead of after cord clamping. Unintentionally, this results in perinatal exposure to antibiotics in all CS born neonates. Aim of this study is to investigate the effect of timing of maternally administered antibiotics during CS on the infant microbiome. Methods: In this randomized controlled trial, women scheduled for an elective CS received antibiotics prior to skin incision (group A: intrauterine antibiotic exposed infants) or after clamping of the umbilical cord (group B: intrauterine unexposed infants). Women delivering vaginally were included as controls (group C). Faecal microbiota was determined from all infants at one, seven and twenty-eight days and three years after birth by means of whole-metagenome shotgun sequencing and 16S rRNA gene sequencing. The trial is registered with https://www.trialregister.nl/, NTR6000. Findings: Differences between intrauterine antibiotic exposed infants (n=20) and non-exposed infants (n=20) born via CS were limited at day one and seven. However, at twenty-eight days, the whole metagenome based microbiome of infants from the former group consisted of a lower abundance of bifidobacteria compared to the latter (p

intervention by invitation and collective self-defence are often dealt with as two distinct justifications to the prohibition of the use of force, thus two separate reasons for states to use force lawfully. Upon closer scrutiny, however, the two concepts appear to be quite similar as both deal with a situation where a state invites/requests the military assistance of another state. This article analyses both concepts and their criteria. It subsequently determines whether they are substantially different or in fact two sides of the same coin.

Introduction: Spontaneous preterm birth (SPTB) has several causes and its pathophysiology remains unclear. In a significant proportion of SPTB, placental histology shows signs of maternal vascular malperfusion (MVM); commonly associated with hypertensive disorders of pregnancy (HD), fetal growth restriction (FGR) and placental abruption, together referred to as clinical ischemic placental diseases (IPD). We hypothesized that women with SPTB and placental MVM are at elevated risk for IPD in a subsequent pregnancy. Methods: We included women with SPTB in our cohort and followed the subsequent ongoing pregnancy (n = 110). Histological placental characteristics in the index were reported according to new international guidelines, and related to the clinical outcome of the subsequent pregnancy. Results: In the SPTB placentas, we observed MVM in 61.8% (n = 68). In the subsequent pregnancies in 19.1% (n = 21) at least one clinical sign of IPD was present (HD (12.7%), FGR (5.5%) or placental abruption (0.9%)). There was no significant difference in the prevalence of clinical IPD or recurrence of SPTB in the subsequent pregnancy between women with and without placental MVM in the index pregnancy, although our study was not powered to detect small differences. Discussion: Women with a history of SPTB have an elevated risk of IPD in the subsequent pregnancy. MVM is present in a large proportion of SPTB placentas. The presence of placental MVM in the index pregnancy does not predict clinical IPD or recurrent SPTB in a subsequent pregnancy.

Introduction Preterm birth (PTB) is one of the greatest challenges in obstetric and children’s healthcare. PTB remains the most important cause of perinatal morbidity and mortality worldwide. We studied the number of publications concerning PTB over the last two decades using advanced bibliometric visualization methodology. We put the number of publications in perspective of growing awareness of PTB as a major health problem. Methods We analyzed publications over time and performed bibliometric analysis of publications on PTB in the Web of Science from 1997 to 2016. The subjects of publications were visualized using a term map showing the relevant terms occurring in titles and abstracts. Results We identified 47,811 publications. The annual number of publications on PTB increased significantly by 443% in 2016 (n = 5027) compared to 1997 (n = 1135). Obstetrics & Gynecology is the leading research field (with 10.4% on the subject PTB in 2016) followed closely by Pediatrics (7.6% on the subject PTB in 2016), within the field Public, Environmental & Occupational Health minimal increase was observed (only 1% was published on the subject PTB in 2016). The publications on PTB have increased at higher rates than the overall increase of publications. In recent years we found more publications on PTB describing epidemiology and clinical characteristics/outcomes whereas in earlier years publications focused more on translational, basic research. Conclusion A significant increase in research concerning PTB was observed over the last two decades. This increase of publications is in line with the growing global awareness of the need to reduce PTB by clinical research. Electronic supplementary material The online version of this article (10.1007/s10995-019-02772-x) contains supplementary material, which is available to authorized users.

Background A disturbance in the early colonisation of the gut by microorganisms is associated with an aberrant innate immune system and a variety of clinical conditions later in life. Several factors are considered to influence this initial colonisation, including maternally administered antibiotics during pregnancy and delivery. Recent revisions to international obstetric guidelines have resulted in the exposure of all infants born by caesarean section (CS) to broad-spectrum antibiotics perinatally. To date, the consequences of these new guidelines on neonatal gut colonisation and the associated short- and long-term health implications have not yet been addressed. The aim of this study is to investigate the influence of the timing of antibiotic administration during CS to the mother on the course of neonatal intestinal colonisation up to 2 years of age. Methods/design This single-centre randomised controlled trial will recruit 40 women scheduled for an elective CS. The subjects will be randomised to receive 1500 mg of cefuroxime intravenously either prior to the skin incision (n = 20) or after clamping of the umbilical cord (n = 20). Levels of cefuroxime in cord blood will be determined for exposed neonates. Faecal samples from the children will be collected on days 1, 7 and 28 days and at 2 years old and analysed by 16S sequencing. Shannon-diversity indices, absolute and relative abundances, and unsupervised and supervised classification methods will be used to evaluate the effect of the timing of intrapartum cefuroxime administration on the composition of the microbiota. The outcomes for both study groups will be compared to the intestinal microbiota of vaginally born infants (n = 20). To detect possible effects on health state, a questionnaire on health-related issues will be taken at the age of 2 years. Discussion In the proposed study, changes in the intestinal microbiota of 40 children born by CS will be followed until the age of 2 years. Research on this topic is necessary since significant effects relating to the timing of antibiotic administration on microbial colonisation may conflict with the current guidelines, as this may have health consequences later in life. Trial registration Netherlands Clinical Trial Registry, NTR6000. Retrospectively registered on 25 July 2016. Electronic supplementary material The online version of this article (10.1186/s13063-019-3552-8) contains supplementary material, which is available to authorized users.

Contains fulltext : 177805.pdf (Publisher’s version ) (Open Access) 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.

Introduction Spontaneous preterm birth (SPTB) common complicates pregnancy. It has several causes and its pathophysiology has not yet been elucidated. In a significant proportion of SPTB, placental histology shows signs of maternal vascular malperfusion; these signs are commonly associated with hypertensive disorders of pregnancy (HD) or fetal growth restriction (FGR). Therefore, we hypothesized that women with a SPTB and signs of maternal vascular malperfusion in the placenta are at risk for HD and FGR in a subsequent pregnancy. Objective The objective of this study was to describe the association between placental histology of SPTB and the incidence of HD and FGR in the subsequent pregnancy. Materials and methods We included women with a history of SPTB, and a subsequent ongoing pregnancy (n = 110). Histological placental characteristics in the pregnancy complicated by SPTB were described according to new international guidelines, and related to the outcome of the subsequent pregnancy. Results Delivery in the index pregnancy had a median gestational age of 27.7 weeks. In 61.8% (n = 68) of the placentas signs of vascular malperfusion were observed. Maternal and respectively fetal inflammatory response was observed in 51.8 %(n = 57) and 46.4% (n = 51) and was observed as a secondary finding in 42.6% (n = 29) and 36.8% (n = 25) of the placentas with maternal vascular malperfusion. In the index pregnancy HD was present in 8.2% (n = 9), and FGR in 10.9% (n = 12). In the subsequent pregnancy HD was present in 12.7% (n = 14) and FGR in 5.5 % (n = 6). The incidence of HD or FGR in the subsequent pregnancy was not associated with histological signs of maternal vascular malperfusion in the index pregnancy. Conclusion Women with a history of SPTB have an elevated risk on hypertensive diseases in the subsequent pregnancy, when compared to epidemiologic data on the incidence of HD in women with a prior term birth. The incidence of HD was not associated with of the presence of placental maternal vascular malperfusion in the index pregnancy. This data suggest that signs of maternal vascular malperfusion by placental histology in SPTB cannot be used as a marker for adverse outcome in a subsequent pregnancy.