Study protocol for two randomised controlled trials evaluating the effects of Cerclage in the reduction of extreme preterm birth and perinatal mortality in twin pregnancies with a short cervix or dilatation: the TWIN Cerclage studies.

INTRODUCTION: Twin pregnancies have a high risk of extreme preterm birth (PTB) at less than 28 weeks of gestation, which is associated with increased risk of neonatal morbidity and mortality. Currently there is a lack of effective treatments for women with a twin pregnancy and a short cervix or cervical dilatation. A possible effective surgical method to reduce extreme PTB in twin pregnancies with an asymptomatic short cervix or dilatation at midpregnancy is the placement of a vaginal cerclage. METHODS AND ANALYSIS: We designed two multicentre randomised trials involving eight hospitals in the Netherlands (sites in other countries may be added at a later date). Women older than 16 years with a twin pregnancy at <24 weeks of gestation and an asymptomatic short cervix of ≤25 mm or cervical dilatation will be randomly allocated (1:1) to both trials on vaginal cerclage and standard treatment according to the current Dutch Society of Obstetrics and Gynaecology guideline (no cerclage). Permuted blocks sized 2 and 4 will be used to minimise the risk of disbalance. The primary outcome measure is PTB of <28 weeks. Analyses will be by intention to treat. The first trial is to demonstrate a risk reduction from 25% to 10% in the short cervix group, for which 194 patients need to be recruited. The second trial is to demonstrate a risk reduction from 80% to 35% in the dilatation group and will recruit 44 women. A cost-effectiveness analysis will be performed from a societal perspective. ETHICS AND DISSEMINATION: This study has been approved by the Research Ethics Committees in the Netherlands on 3/30/2023. Participants will be required to sign an informed consent form. The results will be presented at conferences and published in a peer-reviewed journal. Participants will be informed about the results. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT05968794.

Successful management of fetal hypoxia due to amniotic banding at 26 weeks of pregnancy: A case report of a rare survival.

BACKGROUND: Amniotic banding is a rare condition that can lead to structural limb anomalies, fetal distress and adverse obstetric outcomes. The main hypothesis for its etiology is a rupture of the amniotic membrane in early pregnancy, with the formation of tightly entangling strands around the fetus. These strands can constrict, incise, and subsequently amputate limb parts, the neck or head. More rarely, the amniotic banding can affect the umbilical cord, leading to fetal distress or potential intra-uterine fetal demise. OBJECTIVE: We present a unique case of a 26-week pregnant woman who attended a polyclinical consultation due to reduced fetal movements with concerning cardiotocography (CTG) findings. A review of the literature about amniotic banding of the umbilical cord was conducted as well, identifying diagnostic and interventional options for the obstetrician's practice. STUDY DESIGN: This is a case report, alongside a review of the literature. RESULTS: The CTG indicated fetal distress, prompting an emergency caesarean section (C-section). Upon delivery, the neonate exhibited signs of amniotic band sequence, with distal phalangeal defects on the right hand and severe constriction of the umbilical cord caused by amniotic strands, the latter precipitating fetal hypoxia. Direct ultrasound diagnosis remains a challenge in the absence of limb amputation, yet indirect signs such as distal limb or umbilical doppler flow abnormalities and distal limb edema may be suggestive of amniotic banding. MRI is proposed as an adjuvant diagnostic tool yet does not present a higher detection rate compared to ultrasound. Fetoscopic surgery to perform lysis of the amniotic strands with favorable outcome has been described in literature. CONCLUSION: This case presents the first reported survival of an extremely preterm fetus in hypoxic distress as a cause of amniotic banding of the umbilical cord, with a rare degree of incidental timing. Ultrasound diagnosis remains the gold standard. Obstetrical vigilance is warranted, with fetal rescue proven to be feasible.

Birth outcomes of twins after multifetal pregnancy reduction compared with primary twins.

BACKGROUND: The introduction of assisted reproductive technology and the trend of increasing maternal age at conception have contributed to a significant rise in the incidence of multiple pregnancies. Multiple pregnancies bear several inherent risks for both mother and child. These risks increase with plurality and type of chorionicity. Multifetal pregnancy reduction is the selective abortion of ≥1 fetuses to improve the outcome of the remaining fetus(es) by decreasing the risk of premature birth and other complications. OBJECTIVE: This study aimed to compare birth outcomes of trichorionic triplets reduced to twins with those of trichorionic triplets and primary dichorionic twins. The added value of this study is the comparison with an additional control group, namely primary dichorionic twins. STUDY DESIGN: This was a retrospective cohort study. Data from January 1990 to November 2016 were collected from the East Flanders Prospective Twin Survey, one of the largest European multiple birth registries. A total of 85 trichorionic triplet pregnancies (170 neonates) undergoing multifetal pregnancy reduction to twins were compared with 5093 primary dichorionic twin pregnancies (10,186 neonates) and 104 expectantly managed trichorionic triplet pregnancies (309 neonates). The assessed outcomes were gestational age at delivery, birthweight, and small for gestational age. RESULTS: Pregnancy reduction from triplets to twins was associated with higher birthweight (+365.44 g; 95% confidence interval, 222.75-508.14 g; P<.0001) and higher gestational age (1.7 weeks; 95% confidence interval, 0.93-2.46; P<.0001) compared with ongoing trichorionic triplets after adjustment for sex, parity, method of conception, birth year, and maternal age. A trend toward lower risk of small for gestational age was observed. Reduced triplets had, on average, lower birthweight (-263.12 g; 95% confidence interval, -371.80 to -154.44 g; P<.0001) and lower gestational age (-1.13 weeks; 95% confidence interval, -1.70 to -0.56; P=.0001) compared with primary twins. No statistically significant difference was observed between primary twins and reduced triplets that reached 32 weeks of gestation. CONCLUSION: Multifetal pregnancy reduction from trichorionic triplets to twins significantly improved birth outcomes. This suggests that multifetal pregnancy reduction of trichorionic triplets to twins is medically justifiable. However, the birth outcomes of primary twins before 32 weeks of gestation are still better than those of reduced triplets. The process of multifetal pregnancy reduction includes at least 1 fetal death by definition, and thus prevention of higher-order pregnancies is preferable.

The 2023 Belgian clinical guidance on anticoagulation management in hospitalized and ambulatory COVID-19 patients.

COVID-19 is associated with an increased risk for thrombotic complications. The trials investigating the optimal thromboprophylactic dose are performed in challenging times and seemingly produce conflicting evidence. The burdensome circumstances, divergent endpoints, and different analytical approaches hamper comparison and extrapolation of available evidence. Most importantly, clinicians should provide thromboprophylaxis in hospitalized COVID-19 patients while (re)assessing bleeding and thrombotic risk frequently. The COVID-19 Thromboprophylaxis Working Group of the BSTH updated its guidance document. It aims to summarize the available evidence critically and to guide clinicians in providing the best possible thromboprophylaxis.

On optimal timing of antenatal corticosteroids: time to reformulate the question.

Administration of antenatal corticosteroids (ACS) for accelerating foetal lung maturation in threatened preterm birth is one of the cornerstones of prevention of neonatal mortality and morbidity. To identify the optimal timing of ACS administration, most studies have compared subgroups based on treatment-to-delivery intervals. Such subgroup analysis of the first placebo-controlled randomised controlled trial indicated that a one to seven day interval between ACS administration and birth resulted in the lowest rates of neonatal respiratory distress syndrome. This efficacy window was largely confirmed by a series of subgroup analyses of subsequent trials and observational studies and strongly influenced obstetric management. However, these subgroup analyses suffer from a methodological flaw that often seems to be overlooked and potentially has important consequences for drawing valid conclusions. In this commentary, we point out that studies comparing treatment outcomes between subgroups that are retrospectively identified at birth (i.e. after randomisation) may not only be plagued by post-randomisation confounding bias but, more importantly, may not adequately inform decision making before birth, when the projected duration of the interval is still unknown. We suggest two more formal interpretations of these subgroup analyses, using a counterfactual framework for causal inference, and demonstrate that each of these interpretations can be linked to a different hypothetical trial. However, given the infeasibility of these trials, we argue that none of these rescue interpretations are helpful for clinical decision making. As a result, guidelines based on these subgroup analyses may have led to suboptimal clinical practice. As an alternative to these flawed subgroup analyses, we suggest a more principled approach that clearly formulates the question about optimal timing of ACS treatment in terms of the protocol of a future randomised study. Even if this 'target trial' would never be conducted, its protocol may still provide important guidance to avoid repeating common design flaws when conducting observational 'real world' studies using statistical methods for causal inference.

Preterm birth during the COVID-19 pandemic: more, less, or just the same?

OBJECTIVES: Coronavirus disease (COVID-19) and its mitigation measures have been associated with changes in preterm birth (PTB) incidences. The objective of this paper is to summarize and comment on the literature on COVID-19 and PTB and to compare PTB incidence between 2019 (pre-COVID-19) and 2020 (COVID-19) in three Belgian tertiary care hospitals. METHODS: A non-systematic review on COVID-19 and PTB was performed, and literature was summarized in a table. Preterm birth rates at Ghent University Hospital, Ziekenhuis Oost-Limburg, and University Hospital Leuven in 2019 and 2020 were compared. Chi-square and Fisher's exact tests were used to compare PTB rates between 2019 and 2020, and Kaplan Meier survival analysis was used to compare pregnancy duration. The mean outcome measure was PTB incidence in 2020 (COVID-19) compared with PTB incidence in 2019 (pre-COVID-19). RESULTS: Some (parts of) countries report decreases in PTB rates, others report no differences in incidence, and a minority of countries report an increased incidence of PTB. Almost all studies only consider live-births. In three tertiary care hospitals in Flanders, there were no differences in PTB rates before and during the COVID-19 pandemic. CONCLUSION: The impact of the (mitigation measures during the) COVID-19 pandemic on PTB incidence is unclear and difficult to explore. To enable a correct interpretation, all conceptions before and during the pandemic should be taken into consideration, as well as all births, still or alive.

Neonatal magnesium levels are safe after maternal MgSO4 administration: a comparison between unexposed preterm neonates and neonates exposed for fetal neuroprotection or maternal eclampsia prevention-a cohort study.

To objective of this study was to compare neonatal magnesemia in the first 15 days of neonatal life between three groups: a control group not exposed to MgSO4, a neuroprotection group, and an eclampsia prevention group, and to explore its associations with child outcomes. A retrospective single-centre cohort study was performed in a tertiary care setting. Infants admitted at the neonatal intensive care unit born between 24 and 32 weeks' gestation, regardless of etiology of preterm birth, were included. The mean outcome measure was neonatal magnesemia (mmol/L). Linear mixed regression of neonatal magnesemia on exposure group and day of life was done. Generalised estimating equation models of child outcomes on neonatal magnesemia according to exposure group and day of life were made. The analyses showed that in neonatal magnesemia is significantly higher in the preeclampsia group compared to the control and neuroprotection groups. On the day of birth, this is irrespective of maternal magnesemia (preeclampsia vs control groups), and the maternal total dose or duration of MgSO4 administration (preeclampsia vs neuroprotection group). No differences were found in short-term composite outcome between the three groups. CONCLUSION: We found mean differences in neonatal magnesemia between children not exposed to MgSO4 antenatally, children exposed for fetal neuroprotection, and children exposed for maternal eclampsia prevention. A 4-g loading and 1-g/h maintenance doses, for fetal neuroprotection and eclampsia prevention, appear to be safe on the short term for the neonate. WHAT IS KNOWN: • Magnesium sulphate is a valuable medicine in obstetrics. The main indications are prevention of eclampsia and fetal neuroprotection. The most used dosage is a 4- or 6-g loading dose and a 1- or 2-g per h maintenance dose. It reduces neuromotor disabilities in extreme-to-moderate preterm born children. WHAT IS NEW: • Maternal concentrations are supraphysiological and the maternal total dose can be high. Concentrations in neonates appear to remain in safe ranges. A dosage of 4-g loading and 1 g/h seems safe for the preterm neonate on the short term.

The web-based application "QUiPP v.2" for the prediction of preterm birth in symptomatic women is not yet ready for worldwide clinical use: ten reflections on development, validation and use.

PURPOSE: In this correspondence, we highlight general and domain-specific caveats in the development and validation of prediction models. METHODS: Development and use of the "QUiPP" application, a tool for preterm birth prediction which is supported by the United Kingdom National Health Service, is scrutinised and commented on. RESULTS: We highlight and elaborate ten points which may be perceived to be unclear or potentially misleading. CONCLUSION: While the QUiPP application has high potential, it lacks transparency (on certain aspects related to model development) and proper validation. This precludes transportability to settings with other treatment policies and to other countries where the app has been made publicly available.

Placental Tissue Destruction and Insufficiency From COVID-19 Causes Stillbirth and Neonatal Death From Hypoxic-Ischemic Injury.

CONTEXT.­: Perinatal death is an increasingly important problem as the coronavirus disease 2019 (COVID-19) pandemic continues, but the mechanism of death has been unclear. OBJECTIVE.­: To evaluate the role of the placenta in causing stillbirth and neonatal death following maternal infection with COVID-19 and confirmed placental positivity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). DESIGN.­: Case-based retrospective clinicopathologic analysis by a multinational group of 44 perinatal specialists from 12 countries of placental and autopsy pathology findings from 64 stillborns and 4 neonatal deaths having placentas testing positive for SARS-CoV-2 following delivery to mothers with COVID-19. RESULTS.­: Of the 3 findings constituting SARS-CoV-2 placentitis, all 68 placentas had increased fibrin deposition and villous trophoblast necrosis and 66 had chronic histiocytic intervillositis. Sixty-three placentas had massive perivillous fibrin deposition. Severe destructive placental disease from SARS-CoV-2 placentitis averaged 77.7% tissue involvement. Other findings included multiple intervillous thrombi (37%; 25 of 68) and chronic villitis (32%; 22 of 68). The majority (19; 63%) of the 30 autopsies revealed no significant fetal abnormalities except for intrauterine hypoxia and asphyxia. Among all 68 cases, SARS-CoV-2 was detected from a body specimen in 16 of 28 cases tested, most frequently from nasopharyngeal swabs. Four autopsied stillborns had SARS-CoV-2 identified in internal organs. CONCLUSIONS.­: The pathology abnormalities composing SARS-CoV-2 placentitis cause widespread and severe placental destruction resulting in placental malperfusion and insufficiency. In these cases, intrauterine and perinatal death likely results directly from placental insufficiency and fetal hypoxic-ischemic injury. There was no evidence that SARS-CoV-2 involvement of the fetus had a role in causing these deaths.

Relevance of the antenatal corticosteroids-to-delivery interval in the prevention of neonatal respiratory distress syndrome through the eyes of causal inference: a review and target trial.

PURPOSE: To critically analyse the literature on the antenatal corticosteroids (ACS)-to-birth interval from a causal point of view and to present a solution to the problem of bias caused by post hoc analysis. METHODS: Due to the post hoc nature of the ACS-to-birth interval, a randomised controlled trial (RCT) of ACS versus placebo is not able to examine the importance of the interval. When an RCT is not feasible, for whatsoever reason, a target trial can be set up and an attempt can be made to answer the causal question of interest using observational data. An attempt was made to set up a target trial which could enable to examine the causal effect of the ACS-to-birth interval on neonatal outcomes. An analysis of current literature on the ACS-to-birth interval was done. RESULTS: The majority of studies aimed to examine the causal effect of the interval, but their study design only permitted to find associations between the interval and neonatal outcomes. Barriers for setting up a target trial are highlighted. CONCLUSION: Evidence on the superiority of any ACS-to-birth interval is lacking and the question can only be addressed causally and become clinically relevant if baseline randomisation to ACS-to-birth intervals is made possible.

Belgian clinical guidance on anticoagulation management in hospitalised and ambulatory patients with COVID-19.

OBJECTIVES: COVID-19 predisposes patients to thrombotic disease. The aim of this guidance document is to provide Belgian health-care workers with recommendations on anticoagulation management in COVID-19 positive patients. METHODS: These recommendations were based on current knowledge and a limited level of evidence. RESULTS: We formulated recommendations for the prophylaxis and treatment of COVID-related venous thromboembolism in ambulatory and hospitalised patients, as well as recommendations for the use of antithrombotic drugs in patients with prior indication for anticoagulation who develop COVID-19. CONCLUSIONS: These recommendations represent an easy-to-use practical guidance that can be implemented in every Belgian hospital and be used by primary care physicians and gynaecologists. Of note, they are likely to evolve with increased knowledge of the disease and availability of data from ongoing clinical trials.

Prevalence and clinical relevance of colonization with methicillin-resistant Staphylococcus aureus in the obstetric population.

BACKGROUND AND AIMS: Routine screening for Methicillin-Resistant Staphylococcus aureus (MRSA) in pregnant women is common practice in many hospitals. However, little is known on its prevalence and clinical relevance in this population. In this prospective longitudinal study, we aimed to investigate the MRSA prevalence in our obstetric population, the rate of vertical transmission of MRSA and the potential clinical relevance of MRSA colonization for both mother and child. A possible correlation between GBS and MRSA colonization was also investigated. MATERIALS AND METHODS: MRSA screening samples were collected at 35-37 weeks of gestation (from mother), at delivery and at discharge (from mother and newborn). All samples were analyzed by conventional microbiological methods and MRSA strains were subjected to spa-typing to investigate genetic similarity. The medical records of all positive mother-child pairs were analyzed to detect the occurrence of clinical infection in the postpartum period. RESULTS: 679 mother-child pairs were included between June 2014 and July 2016. Maternal MRSA positivity rate was 1.3% at 35-37 weeks (vaginal/anorectal), 3.1% at delivery (nose/throat) and 3.6% at discharge (nose/throat). MRSA positivity in neonates was 0.3% at delivery and increased to 3% at discharge (nose/umbilicus). Almost all MRSA positive children were born to MRSA positive mothers (OR 120.40, 95% CI: 38.42-377.32). Genetic similarity of the MRSA strains found in mother and child was illustrated for all but one case. 57.7% of the cases of MRSA colonization in our cohort were associated with livestock exposure. 31% of the MRSA positive mothers developed an infectious complication in the postpartum period. No neonatal infectious complications were observed. GBS positivity was not a predictive factor for MRSA colonization in our cohort. CONCLUSION: The rate of MRSA colonization (overall 4.3%) in our obstetric population is similar to that described in the literature and that of the general population admitted to our hospital in the same period. Maternal MRSA colonization appeared to be an important risk factor for neonatal colonization. Whereas mothers were at higher risk of developing infectious morbidity in the postpartum period, no neonatal infectious complications were observed. We observed no correlation between GBS and MRSA colonization.

Differences in clinical practice regarding screening and treatment of infections associated with spontaneous preterm birth: An international survey.

OBJECTIVE: An association between infections in pregnancy and increased risk of preterm birth (PTB) is described in the literature. We anticipated that differences may exist in screening and treatment approaches for infections associated with PTB, within and between European countries. The aim of this study was to examine and analyse these differences in clinical practice in greater detail. STUDY DESIGN: We created a descriptive survey examining the screening and treatment of infections in pregnancy. The survey was sent to European representatives of the International Spontaneous Preterm Birth Young Investigators (I-SPY) group in Europe, who sent it to their network. Finally, we had 50 respondents from ten European countries. RESULTS: We found substantial differences in screening for bacterial vaginosis and asymptomatic bacteriuria, administration of antibiotics to women with preterm prelabour rupture of membranes (PPROM), and timing of induction of labour after PPROM. These differences in clinical practice were present both within, and between countries. CONCLUSIONS: Approaches for screening and treatment of infections associated with PTB differ between European countries. There is a lack of robust evidence, which is reflected in a lack of uniformity in international guidelines. International collaboration is paramount to enlarge sample sizes in obstetric studies and to facilitate the process of developing, updating, and implementing consistent guidelines across Europe and beyond.

Overly optimistic prediction results on imbalanced data: a case study of flaws and benefits when applying over-sampling.

Information extracted from electrohysterography recordings could potentially prove to be an interesting additional source of information to estimate the risk on preterm birth. Recently, a large number of studies have reported near-perfect results to distinguish between recordings of patients that will deliver term or preterm using a public resource, called the Term/Preterm Electrohysterogram database. However, we argue that these results are overly optimistic due to a methodological flaw being made. In this work, we focus on one specific type of methodological flaw: applying over-sampling before partitioning the data into mutually exclusive training and testing sets. We show how this causes the results to be biased using two artificial datasets and reproduce results of studies in which this flaw was identified. Moreover, we evaluate the actual impact of over-sampling on predictive performance, when applied prior to data partitioning, using the same methodologies of related studies, to provide a realistic view of these methodologies' generalization capabilities. We make our research reproducible by providing all the code under an open license.

Recurrent uterine artery pseudo-aneurysm requiring repeat embolization during pregnancy - A case report.

BACKGROUND: Uterine artery pseudo-aneurysms (UAP) mainly occur after traumatic delivery or traumatic pregnancy termination. A UAP can be either asymptomatic or present with symptoms such as vaginal bleeding, abdominal pain, hypovolemic shock, or fever when infected. We describe a patient diagnosed with a uterine artery pseudo-aneurysm in pregnancy that required repeat embolization. The patient had no risk factors in her recent medical history. She did, however, undergo in-vitro fertilization with oocyte retrieval performed under transvaginal ultrasonographic guidance. We suggest the hypothesis of formation of the pseudo-aneurysm secondary to vascular injury during oocyte retrieval. CASE REPORT: A 35-year-old primigravida, who conceived by in-vitro fertilization, presenting with severe abdominal pain at 19 2/7 weeks of gestation. Ultrasound examination with color doppler imaging revealed a hypo-echoic lesion with turbulent arterial flow pattern on the lower left side of the uterus. Selective catheterization and subtraction angiography permitted diagnosis of a large pseudo-aneurysm of the left uterine artery. A selective embolization was performed. Recanalization of the embolized artery was confirmed 11 weeks after initial presentation, requiring repeat embolization. A planned caesarean section was performed at 34 weeks of gestation and a healthy boy was born with a birth weight of 2065 g. CONCLUSION: Uterine artery pseudo-aneurysm is a rare but potentially life-threatening condition. It can be diagnosed using (doppler) ultrasound, revealing a hypoechoic mass with swirling blood flow. Angiography is the standard reference in diagnosing UAP and may provide definitive treatment. Management with selective unilateral uterine artery embolization appears to be safe in hemodynamically stable patients. It does not compromise uteroplacental circulation and may help to prolong the pregnancy, reducing morbidity associated with preterm birth.