Nasal delivery of an IgM offers broad protection from SARS-CoV-2 variants.

Resistance represents a major challenge for antibody-based therapy for COVID-191-4. Here we engineered an immunoglobulin M (IgM) neutralizing antibody (IgM-14) to overcome the resistance encountered by immunoglobulin G (IgG)-based therapeutics. IgM-14 is over 230-fold more potent than its parental IgG-14 in neutralizing SARS-CoV-2. IgM-14 potently neutralizes the resistant virus raised by its corresponding IgG-14, three variants of concern-B.1.1.7 (Alpha, which first emerged in the UK), P.1 (Gamma, which first emerged in Brazil) and B.1.351 (Beta, which first emerged in South Africa)-and 21 other receptor-binding domain mutants, many of which are resistant to the IgG antibodies that have been authorized for emergency use. Although engineering IgG into IgM enhances antibody potency in general, selection of an optimal epitope is critical for identifying the most effective IgM that can overcome resistance. In mice, a single intranasal dose of IgM-14 at 0.044 mg per kg body weight confers prophylactic efficacy and a single dose at 0.4 mg per kg confers therapeutic efficacy against SARS-CoV-2. IgM-14, but not IgG-14, also confers potent therapeutic protection against the P.1 and B.1.351 variants. IgM-14 exhibits desirable pharmacokinetics and safety profiles when administered intranasally in rodents. Our results show that intranasal administration of an engineered IgM can improve efficacy, reduce resistance and simplify the prophylactic and therapeutic treatment of COVID-19.

Prenatal detection of placenta accreta spectrum using a sonographic checklist.

INTRODUCTION: The European Working Group for Abnormally Invasive Placenta proposed a checklist of ultrasound features for the antenatal detection of placenta accreta spectrum (PAS). This study aims to assess the performance of the checklist in identifying histopathologically confirmed PAS cases in a cohort with a high pre-test probability of PAS, and identify if particular features are associated with PAS. MATERIAL AND METHODS: This is a prospective multi-site cohort study conducted between 2018 and 2023. Consecutive patients who underwent ultrasound assessment for suspicion of PAS were included, and the sonographic checklist was completed at the time of ultrasound. Cases were defined as PAS where they had intraoperative findings as described by the International Federation of Gynecology and Obstetrics (FIGO) grading, and histopathological findings for hysterectomy and myometrial resection cases. All non-PAS cases in this study had placenta previa and at least one prior cesarean delivery. RESULTS: Seventy-eight participants met inclusion criteria, of whom 63 (80.7%) were diagnosed with PAS. Cesarean hysterectomy was performed in 49 cases (62.8%). Overall, third-trimester ultrasound performed at a median gestational age of 32 weeks (IQR 30-34 weeks) had a sensitivity of 0.84 (95% CI 0.73 to 0.92) and specificity of 0.73 (95% CI 0.45 to 0.92) for detecting PAS, with a positive and negative likelihood ratio of 3.15 (95% CI 1.35 to 7.35) and 0.22 (95% CI 0.11 to 0.41), respectively. Features most associated with PAS were abnormal placental lacunae (Odds Ratio [OR] 5.40 [95% CI 1.61 to 18.03] and myometrial thinning OR 6.87 [95% CI 1.93 to 24.4]). While many of the ultrasound features seen in PAS were also present in cases of placenta previa with prior Cesarean section, the median (IQR) number of features present in PAS cases was significantly higher than in the non-PAS placenta previa group (six features [3-8] vs. two features [0-3] p = 0.001). No case of non-PAS placenta previa had more than five features present. CONCLUSIONS: The use of a standardized sonographic checklist had a high sensitivity and good specificity for the detection of PAS in this prospective cohort of well-classified PAS cases.

Severe fetal ventriculomegaly: Fetal morbidity and mortality, caesarean delivery rates and obstetrical challenges in a large prospective cohort.

INTRODUCTION: Severe fetal ventriculomegaly (VM) is defined as an enlargement of the atria of the lateral cerebral ventricles (Vp) of greater than 15 mm. While it is well established that it confers significant risk of morbidity and mortality to the neonate, there is limited information pertaining to the caesarean delivery rates and the obstetric management of these complex cases. The aim of this study was twofold: firstly, to determine survival rates in fetuses with severe VM, and secondly to determine the caesarean delivery rates in continuing pregnancies. We explore the obstetric challenges associated with these difficult cases. METHODS: This was a prospective observational study of patients with antenatal severe VM, attending the Department of Fetal Medicine, National Maternity Hospital, Dublin, Ireland, from 1st January 2011 to 31st July 2020. Data were obtained from the hospital database and those with severe VM (Vp > 15 mm) were identified. The rates of chromosomal abnormalities, the survival rates and the caesarean delivery (CD) rates for the overall group were then determined. The data were then further sub-divided into two groups: 1. Vp < 20 mm and 2. Vp > 20 mm, and the results compared. Statistical analysis was performed using the Chi-Square test. RESULTS: A total of N = 95 pregnancies with severe VM were included for analysis, of which additional structural abnormalities on ultrasound were apparent in 67/95 (70.5%) and 28/95 (29.5%) had isolated severe VM. Chromosomal abnormalities were diagnosed in 15/95 (15.8%) of cases, with (2/28) 7.1% in the isolated SVM group versus (13/67) 19.4% in the non-isolated SVM group. The overall survival rate (excluding TOP) was 53/74 (71.6%), with 20/23 (86.9%) in the isolated SVM group. The overall CD rate was 47/72 (65.3%), which was significantly higher than the CD for the hospital during the same time period of 25.4% (P < 0.01). The data were subdivided into Vp < 20 and Vp > 20 and those with a Vp > 20 had higher rates of additional intracranial findings on ultrasound (Vp < 20 13/41 (31.7%) versus Vp > 20 32/54 (59.3%) (P < 0.05)) and macrocrania (Vp < 20 14/41 (34.1%) versus Vp > 20 35/54 (64.8%) (P < 0.05)). No significant difference was observed in the overall survival or CD rates between the two groups. CONCLUSION: In conclusion this study reports significant fetal morbidity and mortality with severe VM with high CD rates observed in this cohort. Significant challenges exist in relation to the obstetric management and counseling of parents regarding an often uncertain neonatal prognosis. In continuing pregnancies with significant macrocrania delivery plans should be individualized to improve neonatal outcomes where possible and minimize harm to the mother.

Face mask leak with nasal cannula during noninvasive positive pressure ventilation: A randomized crossover trial.

BACKGROUND: Nasal cannula can achieve apneic oxygenation during emergency intubation. However, pre-procedure nasal cannula placement may be difficult in patients undergoing non-invasive positive pressure ventilation (NPPV) prior to intubation. Our objective was to compare mask leak during NPPV with versus without simultaneous application of nasal cannula. We hypothesized mask leak would be no worse with concomitant use of nasal cannula (non-inferiority design). METHODS: We performed a randomized crossover non-inferiority study of healthy volunteers. We randomized subjects undergoing 60s trials of NPPV (10cmH2O continuous positive airway pressure) to either NPPV alone (NPPV-a) or NPPV with nasal cannula at 15L/min (NPPV-nc). After a brief rest period, all subjects underwent the alternative intervention. The primary outcome was time averaged mask leak over 60s (L/min). We defined a non-inferiority margin of 5L/min. RESULTS: We enrolled 64 subjects. Mean time-averaged mask leak was 2.2L/min for NPPV-a versus 4.0L/min for NPPV-nc for a difference of 1.7L/min (one-sided 95% CI -∞ to 3.2L/min). NPPV-a resulted in higher mean minute volume received (13.5 versus 12.2L) and higher mean respiratory rates (14.8 versus 13.5 breaths per minute). CONCLUSION: The addition of nasal cannula during NPPV does not significantly increase mask leak. The simultaneous application of nasal cannula with NPPV may be a useful strategy to streamline airway management among patients undergoing NPPV prior to intubation.

End-Tidal Oxygen Saturation with Nasal Cannula During Noninvasive Positive Pressure Ventilation: A Randomized Crossover Trial.

BACKGROUND: Simultaneous use of nasal cannula (NC) with noninvasive positive pressure ventilation (NIPPV) may help streamline the transition from preoxygenation to intubation with apneic oxygenation in patients with deteriorating respiratory status, but may also compromise preoxygenation by impairing NIPPV mask seal. OBJECTIVES: To demonstrate that end-tidal oxygen (EtO2) after NIPPV with NC is noninferior to that of NIPPV without NC. METHODS: We conducted a randomized cross-over noninferiority study using healthy volunteers. All subjects underwent a 3-min trial of NIPPV with or without high-flow NC at 15 L/min of oxygen, followed by a 5-min washout period, and then a second 3-min trial of the opposite intervention. We randomized subjects to order of interventions. The primary outcome was postintervention EtO2 as measured by immediate exhalation into an oxygen analyzer after the 3-min ventilation period. We compared this outcome between the two study arms using an absolute 5% noninferiority margin. RESULTS: We enrolled 37 subjects, each of whom underwent both interventions of NIPPV alone and NIPPV with 15 L/min NC. The paired mean difference in EtO2 between NIPPV with NC measurements vs. NC alone measurements was 0.5% (95% confidence interval -∞ to 2.7%). Analyses stratified by order of intervention yielded similar results. CONCLUSIONS: The mean difference confidence interval did not include the noninferiority margin. Hence, NIPPV with NC seems noninferior to NIPPV alone with regard to EtO2. These results indicate that concomitant use of NC with NIPPV may be an appropriate preoxygenation strategy in anticipation of the potential need for transition to intubation.

Improved Perinatal Mortality in Twins--Changing Practice and Technologies.

OBJECTIVE: We set out to examine rates of perinatal mortality in twin pregnancies over a 17-year study period. Changes in mode of delivery were also examined as well as causes of death in twin mortalities. STUDY DESIGN: This retrospective cohort study was performed at three large tertiary referral centers from 1996 to 2012. It included all normally formed twin infants with a birth weight more than 500 g. All cases of perinatal mortality in twin pregnancies (infants more than 500 g who suffered an intrauterine or early neonatal (≤ 7 days of age) death were recorded. The changing rate of cesarean delivery as well as varying causes of death in twins over the course of the study were also examined. RESULTS: During the study period, there were 395,830 pregnancies across the three institutions, this included 6,727 twin gestations. The perinatal mortality rate was 21.5/1,000 twin infants. The perinatal mortality rate in twins decreased over the study period (p = 0.0006; R (2) = 0.55; slope = -1.2). Rates of cesarean delivery in twin gestations were found to have increased over the course of the study (p < 0.0001; R (2) = 0.84; slope = 1.7). There were 288 intrauterine and early neonatal deaths in twin infants, 50% (147/288) occurred in twins born extremely premature (< 26 weeks). Prematurity was the leading cause of mortality in twins, followed by twin-to-twin transfusion syndrome (TTTS). TTTS was found to have a decreasing contribution to perinatal mortality during the study (p = 0.008; R (2) = 0.38; slope = -1.5). CONCLUSION: The perinatal mortality rate in twins improved during the study. The rate of cesarean delivery increased by 1.7% for each year of the study, culminating in a cesarean delivery rate of 62% in 2012. TTTS made a decreasing contribution to the mortality rate in twins during the study.

Determination of in Vivo Enzyme Occupancy Utilizing Inhibitor Dissociation Kinetics.

During drug discovery, assessment of in vivo target occupancy by therapeutic candidates is often required for predicting clinical efficacy. Current strategies for determining target occupancy include using radiolabeled or irreversible surrogates, which can be technically challenging, and the results are often not sufficiently quantitative. We developed a straightforward method by applying slow-dissociation kinetics to quantitatively determine enzyme occupancy without using specialized reagents. We applied this method to determine occupancy of Cathepsin K inhibitors in bone tissues harvested from rabbit femurs. Tissues from dosed animals were harvested, flash frozen, lysed, then analyzed by a jump-dilution assay with substrate. The rate of substrate turnover was monitored continuously until reaching steady state and progress curves were fit with the equation [product] = vst + ((vi - vs)/kobs)(1 - exp(-kobst)). The initial rate vi represents the residual activity of the enzyme before inhibitor dissociation; vs is the reaction rate after dissociation of the inhibitor. Occupancy is derived from the ratio of vi/vs. A significant benefit of the method is that data from both the occupied and unoccupied states are obtained in the same assay under identical conditions, which provides greater consistency between studies. The Cat K inhibitor MK-0674 (in vitro IC50 1 nM) was tested in young rabbits (<6 month old) and showed a dose-dependent increase in occupancy, reaching essentially complete occupancy at 1.0 mg/kg. In addition the method enables measurement of the total Cat K in the target tissue. Results confirmed complete occupancy even as the osteoclasts responded to higher doses with increased enzyme production.

Prenatal detection of structural cardiac defects and presence of associated anomalies: a retrospective observational study of 1262 fetal echocardiograms.

OBJECTIVE: The aim of this study is to document the detection of fetal congenital heart defect (CHD) in relation to the following: (1) indication for referral, (2) chromosomal and (3) extracardiac abnormalities. METHOD: All fetal echocardiograms performed in our institution from 2007 to 2011 were reviewed retrospectively. Indication for referral, cardiac diagnosis based on the World Health Organization International Classification of Diseases tenth revision criteria and the presence of chromosomal and extracardiac defects were recorded. RESULTS: Of 1262 echocardiograms, 287 (22.7%) had CHD. Abnormal anatomy scan in pregnancies originally considered to be at low risk of CHD was the best indicator for detecting CHD (91.2% of positive cardiac diagnoses), compared with other indications of family history (5.6%) or maternal medical disorder (3.1%). Congenital anomalies of the cardiac septa comprised the largest category (n = 89), within which atrioventricular septal defects were the most common anomaly (n = 36). Invasive prenatal testing was performed for 126 of 287 cases, of which 44% (n = 55) had a chromosomal abnormality. Of 232 fetuses without chromosomal abnormalities, 31% had an extracardiac defect (n = 76). CONCLUSIONS: Most CHDs occur in pregnancies regarded to be at low risk, highlighting the importance of a routine midtrimester fetal anatomy scan. Frequent association of fetal CHD and chromosomal and extracardiac pathology emphasises the importance of thorough evaluation of any fetus with CHD.

Estimating fetal weight in gastroschisis: A 10 year audit of outcomes at the National Maternity Hospital.

OBJECTIVE: To identify whether conventional methods of estimating fetal growth (Hadlock's formula), which relies heavily on abdominal circumference measurements, are accurate in fetuses with gastroschisis. METHODS: A retrospective cohort study was performed between the period January 1, 2011 and December 31, 2021 in a tertiary referral maternity hospital identifying all pregnancies with a diagnosis of gastroschisis. Projected fetal weight was obtained using the formula (EFW [Hadlock's formula] + 185 g × [X/7]) where X was the number of days to delivery. RESULTS: During the study period 41 cases were identified. The median maternal age was 25. The median BMI was 25 and 63% were primiparous women (n = 26). Median gestation at diagnosis was 21 weeks. Median gestation at delivery was 36 weeks. A total of 4.8% of mothers had a history of drug use (n = 2). The rate of maternal tobacco use was 21.9% (n = 9). A total of 4.8% of fetuses had additional congenital anomalies including amniotic band syndrome and myelomeningocele (n = 2). Estimated fetal weight (EFW) and birth weight data were available for 34 cases. A Wilcoxon signed-rank test showed projected EFW using Hadlock's formula did not result in a statistically significant different birth weight (Z = -1.3, P = 0.169). Median projected weight and actual birth weight were 2241.35 and 2415 g respectively. Median difference was 0.64 g (95% CI: -148 to -28.5). CONCLUSION: Our data showed accuracy using standard formulae for EFW in fetuses with gastroschisis.

Cesarean scar niche: An evolving concern in clinical practice.

Increasing cesarean section rates have led to an increased awareness of associated complications such as the formation of cesarean scar niche, defined as an indentation at the site of the cesarean scar with a depth of at least 2 mm, diagnosed by ultrasound or magnetic resonance imaging. The precise prevalence of cesarean scar niche is unclear. The cause of a cesarean scar niche appears to be multifactorial and likely a combination of technical factors (low incision location), anatomical factors (uterine retroflexion), and patient factors, which might impair healing (body mass index, smoking, maternal age). Most patients with cesarean scar niche are asymptomatic; however, women can present with postmenstrual bleeding, pelvic pain, and subfertility. In pregnancy, cesarean scar niches have been associated with placenta accreta spectrum disorder and uterine rupture. Treatment should be reserved for symptomatic women. Hormonal treatment using either the combined oral contraceptive pill or a progesterone-containing intrauterine device may address irregular vaginal bleeding. Surgical management should be reserved for those in whom hormonal manipulation has failed or is contraindicated. The aim of this review was to summarize current literature pertaining to the cause, prevalence, diagnosis, and symptoms of cesarean scar niche and to make recommendations for managing this relatively new condition.

Placenta accreta spectrum ultrasound stage and fetal growth.

OBJECTIVE: to evaluate fetal growth in pregnancies complicated by placenta accreta spectrum (PAS) and to compare fetal growth between cases stratified by ultrasound stage of PAS. METHODS: This was a prospective multicenter cohort study of women diagnosed with PAS between January 2018 and December 2021. We grouped participants into cases by ultrasound stage (PAS stage 1-3) and controls (PAS0). Fetal growth centiles at three timepoints with median gestational ages of 21 ± 1 weeks (interquartile range [IQR], 20 ± 1-22 ± 0 weeks), 28 ± 0 weeks (IQR, 27 ± 0-28 ± 5 weeks), and 33 ± 0 weeks (IQR, 32 ± 1-34 ± 0 weeks) and birth weight centiles were compared between cases and controls and between those with PAS stratified by ultrasound stage. RESULTS: A total of 53 women met inclusion criteria, with a mean age of 37 years (standard deviation, ±4.0 years) and body mass index of 27 kg/m2 (standard deviation, ±5.8 kg/m2 ). Median (IQR) fetal weight centiles were around the 50th centile at each timepoint, with no difference between groups. The incidence of small for gestational age (birth weight ≤ 10th percentile) and large for gestational age (birth weight ≥ 90th percentile) was 11.3% (n = 6) and 15.1% (n = 8), respectively, with no differences by ultrasound stage. The median birth weight centile was 64 (IQR, 26-85), with no differences between cases and controls or by ultrasound stage. CONCLUSIONS: In our cohort, a diagnosis of PAS was not associated with fetal growth restriction.

An ACE2 decamer viral trap as a durable intervention solution for current and future SARS-CoV.

The capacity of SARS-CoV-2 to evolve poses challenges to conventional prevention and treatment options such as vaccination and monoclonal antibodies, as they rely on viral receptor binding domain (RBD) sequences from previous strains. Additionally, animal CoVs, especially those of the SARS family, are now appreciated as a constant pandemic threat. We present here a new antiviral approach featuring inhalation delivery of a recombinant viral trap composed of ten copies of angiotensin-converting enzyme 2 (ACE2) fused to the IgM Fc. This ACE2 decamer viral trap is designed to inhibit SARS-CoV-2 entry function, regardless of viral RBD sequence variations as shown by its high neutralization potency against all known SARS-CoV-2 variants, including Omicron BQ.1, BQ.1.1, XBB.1 and XBB.1.5. In addition, it demonstrates potency against SARS-CoV-1, human NL63, as well as bat and pangolin CoVs. The multivalent trap is effective in both prophylactic and therapeutic settings since a single intranasal dosing confers protection in human ACE2 transgenic mice against viral challenges. Lastly, this molecule is stable at ambient temperature for more than twelve weeks and can sustain physical stress from aerosolization. These results demonstrate the potential of a decameric ACE2 viral trap as an inhalation solution for ACE2-dependent coronaviruses of current and future pandemic concerns.

Placental pathology, birthweight discordance, and growth restriction in twin pregnancy: results of the ESPRiT Study.

OBJECTIVE: We sought to evaluate the association between placental histological abnormalities and birthweight discordance and growth restriction in twin pregnancies. STUDY DESIGN: We performed a multicenter, prospective study of twin pregnancies. Placentas were examined for evidence of infarction, retroplacental hemorrhage, chorangioma, subchorial fibrin, or abnormal villus maturation. Association of placental lesions with chorionicity, birthweight discordance, and growth restriction were assessed. RESULTS: In all, 668 twin pairs were studied, 21.1% monochorionic and 78.9% dichorionic. Histological abnormalities were more frequent in placentas of smaller twins of birthweight discordant pairs (P = .02) and in placentas of small for gestational age infants (P = .0001) when compared to controls. The association of placental abnormalities with both birthweight discordance and small for gestational age was significant for dichorionic twins (P = .01 and .0001, respectively). No such association was seen in monochorionic twins. CONCLUSION: In a large, prospective, multicenter study, we observed a strong relationship between abnormalities of placental histology and birthweight discordance and growth restriction in dichorionic, but not monochorionic, twin pregnancies.

Passive Immunotherapy Against SARS-CoV-2: From Plasma-Based Therapy to Single Potent Antibodies in the Race to Stay Ahead of the Variants.

The COVID-19 pandemic is now approaching 2 years old, with more than 440 million people infected and nearly six million dead worldwide, making it the most significant pandemic since the 1918 influenza pandemic. The severity and significance of SARS-CoV-2 was recognized immediately upon discovery, leading to innumerable companies and institutes designing and generating vaccines and therapeutic antibodies literally as soon as recombinant SARS-CoV-2 spike protein sequence was available. Within months of the pandemic start, several antibodies had been generated, tested, and moved into clinical trials, including Eli Lilly's bamlanivimab and etesevimab, Regeneron's mixture of imdevimab and casirivimab, Vir's sotrovimab, Celltrion's regdanvimab, and Lilly's bebtelovimab. These antibodies all have now received at least Emergency Use Authorizations (EUAs) and some have received full approval in select countries. To date, more than three dozen antibodies or antibody combinations have been forwarded into clinical trials. These antibodies to SARS-CoV-2 all target the receptor-binding domain (RBD), with some blocking the ability of the RBD to bind human ACE2, while others bind core regions of the RBD to modulate spike stability or ability to fuse to host cell membranes. While these antibodies were being discovered and developed, new variants of SARS-CoV-2 have cropped up in real time, altering the antibody landscape on a moving basis. Over the past year, the search has widened to find antibodies capable of neutralizing the wide array of variants that have arisen, including Alpha, Beta, Gamma, Delta, and Omicron. The recent rise and dominance of the Omicron family of variants, including the rather disparate BA.1 and BA.2 variants, demonstrate the need to continue to find new approaches to neutralize the rapidly evolving SARS-CoV-2 virus. This review highlights both convalescent plasma- and polyclonal antibody-based approaches as well as the top approximately 50 antibodies to SARS-CoV-2, their epitopes, their ability to bind to SARS-CoV-2 variants, and how they are delivered. New approaches to antibody constructs, including single domain antibodies, bispecific antibodies, IgA- and IgM-based antibodies, and modified ACE2-Fc fusion proteins, are also described. Finally, antibodies being developed for palliative care of COVID-19 disease, including the ramifications of cytokine release syndrome (CRS) and acute respiratory distress syndrome (ARDS), are described.

Prenatal findings and associated survival rates in fetal ventriculomegaly: A prospective observational study.

OBJECTIVES: Fetal ventriculomegaly is associated with varying degrees of genetic and structural abnormalities. The objective was to present the experience of fetal ventriculomegaly in a large European center in relation to: 1. grade of ventriculomegaly; 2. additional chromosomal/structural abnormalities; and 3. perinatal survival rates. METHODS: This was a prospective observational study of patients referred with fetal ventriculomegaly from January 2011 to July 2020. Data were obtained from the hospital database and analyzed to determine the rate of isolated ventriculomegaly, associated structural abnormalities, chromosomal/genetic abnormalities, and survival rates. Data were stratified into three groups; mild (Vp = 10-12 mm), moderate (Vp = 13-15 mm) and severe (Vp > 15 mm) ventriculomegaly. RESULTS: There were 213 fetuses included for analysis. Of these 42.7% had mild ventriculomegaly, 44.6% severe and 12.7% had moderate ventriculomegaly. Initial ultrasound assessment reported isolated ventriculomegaly in 45.5% fetuses, with additional structural abnormalities in 54.5%. The rate of chromosomal/genetic abnormalities was high,16.4%. After all investigations, the true rate of isolated VM was 36.1%. The overall survival was 85.6%. Survival was higher for those with isolated VM across all groups (P < 0.05). CONCLUSION: Ventriculomegaly is a complex condition and patients should be counselled that even with apparently isolated VM, there remains the possibility of additional genetic and/or structural problems being diagnosed in up to 10% of fetuses.

A multidisciplinary fetal neurosurgical service-5 years of fetal outcomes from a national referral centre.

BACKGROUND: A specialist fetal neurosurgical clinic was set up in order to improve patient care in a tertiary referral fetal medicine centre. The clinic provides a targeted clinical service for women diagnosed with fetal neurological abnormalities. The service consists of fetal MRI, fetal ultrasound and joint assessment and counselling from neurosurgery and fetal medicine teams. AIMS: We aimed to review this service that provides MDT expertise directly to parents and record the cases and pregnancy outcomes involved. METHODS: This is a prospective study of clinic data from Jan 2013 to Dec 2017. Information includes ultrasound scan findings, MRI results, karyotype results and pregnancy outcome data including post mortem results and data from the paediatric neurosurgery service at the affiliated children's hospital. RESULTS: From 2013 to 2017, there were 1852 major fetal anomalies diagnosed antenatally at the tertiary referral fetal medicine service and n = 306/1852 [16%] were primarily neurological in origin. The neurosurgical clinic reviewed 125 patients since 2013. The most common reasons for referral were spina bifida, n = 60 [48%] and isolated ventriculomegaly n = 43 [34%]. Other reasons for referral include agenesis of the corpus callosum n = 4 [3%], encephalocoele n = 5 [4%] and intracranial mass lesions n = 3 [2.4%]. Cases with borderline ventriculomegaly and cases with known chromosomal or genetic abnormalities were not typically referred to the clinic. Full outcome data were available on 110 of 125 women seen. Thirty-two women [29%] underwent invasive testing and 14 women [12.7%] had a termination of pregnancy. CONCLUSION: Multidisciplinary antenatal counselling supported with in utero MRI provides families with optimum information to inform them of likely neonatal outcome.

The rate of decline in fetal hemoglobin following intrauterine blood transfusion in the management of red cell alloimmunization.

OBJECTIVE: Hemolytic disease of the fetus and newborn is characterized by fetal anemia, secondary to maternal alloantibody-mediated fetal erythrocyte destruction. Despite our reliance on intrauterine blood transfusion (IUT) to maintain severely affected pregnancies, it remains difficult to predict the fetal response to an infusion of donor blood. Our objective was to determine the daily rate of decline in fetal hemoglobin following one, two, and three transfusions. We also evaluated the relationship between the fetal hemoglobin level and the corresponding doppler measurement of the fetal middle cerebral artery peak systolic velocity (MCA-PSV). STUDY DESIGN: A prospective observational study of all singleton pregnancies treated with intrauterine transfusion for fetal anemia secondary to maternal alloimmunization at the National Maternity Hospital, a tertiary referral centre, was conducted over a 10-year period (2011-2020). Demographic and clinical data was obtained from the electronic patient records. Ethical approval was granted by the Ethics and Research Committee of the National Maternity Hospital. RESULTS: A total of 90 intrauterine blood transfusions were performed in 41 fetuses affected by maternal alloimmunization, of which 70% (n = 29), 34% (n = 14) and 15% (n = 6) required a 2nd, 3rd, and 4th transfusion, respectively. The mean rate of decline in fetal hemoglobin following the first transfusion was 0.4 g/dl/day (range, 0.12-0.64 g/dl/day). The mean rate of decline was lower after repeat transfusions at 0.27 g/dl/day (range, 0.16-0.45 g/dl/day). The sensitivity of MCA-PSV threshold of 1.5 Multiples of the Median (MoM) to detect moderate-severe anaemia declined with rank of IUT, from 82% after one previous transfusion, to 75% after two or more previous transfusions. No fetal mortality was seen in our series. CONCLUSION: Knowledge of the expected rate of decline in fetal hemoglobin following an IUT aids in the determination of appropriate timing of subsequent transfusions in a fetus affected by red cell alloimmunization. We observed a reducing rate of daily decline in hemoglobin in fetuses requiring successive transfusions. Our findings suggest a reduced accuracy of the MCA-PSV threshold of 1.5 MoM in determining the optimal timing of 2nd, 3rd, and 4th transfusions.

Comparing three-dimensional models of placenta accreta spectrum with surgical findings.

OBJECTIVE: Placenta accreta spectrum (PAS) is associated with significant maternal morbidity mainly related to blood loss. Pre-operative planning is aided by antenatal ultrasound and magnetic resonance imaging. We sought to assess whether three-dimensional (3D) models from MR images were accurate when compared with surgical and pathological findings. METHODS: Digital Imaging and Communications in Medicine files containing MR images with varying severity of PAS (n = 4) were modeled using 3D Slicer. Placenta, bladder, and myometrial defects were modeled. Myometrial defects at three different uterine locations were included-anterior, lateral and inferior. 3D models were used to identify the relationship between the myometrial defect and the internal cervical os. Findings were validated in a larger series of PAS cases (n = 14) where patterns of invasion were compared with estimated blood loss and distance from defect to the internal os. RESULTS: The defect illustrated in the four 3D models correlates to both surgical and pathological findings in terms of depth and pattern of invasion, location of defect, bladder involvement. Blood loss and topography of the defect from 3D modeling were examined in 14 further cases. Inferior defects were associated with increased blood loss compared with anterior defects. Increased distance from cervix was associated with reduced blood loss (R2  = 0.352, P = 0.01). CONCLUSION: Three-dimensional models of PAS provide an accurate preoperative description of placental invasion and should be investigated as a tool for selecting patients for uterine-conserving surgery. Accurate 3D models of placenta accreta spectrum are achievable and may provide additional information, such as distance of the defect from the internal os.