Pandemic stress induces systemic immune changes and placental inflammation independently of SARS-CoV-2 infection in pregnancies

Problem: Environmental stress during pregnancy has known impacts on both maternal and fetal health. In terms of theCOVID-19 pandemic, the majority of published work has focused on the impact of the infection itself, without considering the potential immune impact of pandemic related-stress.We, therefore, assessed the impact of pandemic stress, independently of SARS-CoV-2 infection, on the circulating and placental immune profiles of pregnant individuals. Method(s): Placentas from 239 patients were collected at the Sainte- Justine Hospital, Montreal, Canada. Of these, 199 patients delivered during the pandemic and were exposed to pandemic stress with (+: 79) or without (-: 120) SARS-CoV-2 infection, the latter exposed to pandemic stress only. Pre-pandemic historic controls (uncomplicated pregnancies, Ctrl: 40), were also included. Placental biopsies were collected to assess cytokine levels by ELISAs and histopathological lesions. A sub-study with 35 pre-pandemic pregnancies (unexposed) and 20 who delivered during the pandemic (exposed) was also conducted. The latter (exposed/unexposed) were all uncomplicated pregnancies. We collected maternal blood prior to delivery for immunophenotyping, and plasma/peripheral blood mononuclear cells (PBMCs) were isolated. Inflammatory mediators in the plasma were quantified by ELISAs. Co-culture assays with PBMCs and human umbilical vein endothelial cells (HUVECs) were performed to assess endothelial activation. Demographical/obstetrical data were obtained through chart review. Result(s): SARS-CoV-2+ patients were multiethnic (63.4%), had higher pre-pregnancyBMI (28.9 vs. 24.8 inCtrl, P<.05), and elevated preterm birth rate (16.5% vs. 5.8% in SARS-CoV-2-, P < .05 and 0.0% in Ctrl, P < .01). In the placentas, we observed an increase in the levels of IL- 1Ra (P < .05) and CRP (P < .05) in both SARS-CoV-2 groups, while IL-6 (P = .0790) and MCP-1 (P < .001) were elevated solely in SARS-CoV- 2-. These changes were predominant in placentas with inflammatory lesions on histopathological analysis. Moreover, we observed elevated CD45+ cells (P < .001) in the placentas from both SARS-CoV-2 groups versus Ctrl. Considering that the differences we observed were important in the SARS-CoV-2- group, we performed a study solely on uncomplicated pregnancies, either exposed or unexposed to pandemic stress. At the systemic level, we observed a decrease in the percentage of Th2 cells (P < .001), leading to a pro-inflammatory Th1/Th2 imbalance in exposed individuals. Decreased Treg (P < .05) and Th17 (P < .05) versus unexposed was also observed. Surprisingly, decreased levels of circulating IL-6 (P < .05), MCP-1 (P < .01), and CRP (P<.05) were seen in exposed versus unexposed individuals. Finally,we observed increased secretion of ICAM, a marker of endothelial activation, solely in endothelial cells co-cultured with PBMCs from exposed individuals. Conclusion(s): Overall, placental inflammatory profiles differed between pregnant individuals exposed to pandemic stress with or without SARS-CoV-2 infection. Moreover, we observed that the pandemic stress exposed group presented a systemic pro-inflammatory bias. This highlights the need to understand the differences between the effects of pandemic-related stress and the added burden of SARS-CoV-2 infection itself on maternal and fetal health. Our work also supports an association between an increased risk of hypertension/ preeclampsia and SARS-CoV-2 infection that might be driven in part by pandemic-related stress.

POST-MORTEM MRI to INVESTIGATE PERINATAL LOSS at COUNTIES MANUKAU HEALTH, AUCKLAND, NEW ZEALAND

Background: Magnetic Resonance Imaging (MRI) may be useful as an alternative to perinatal post-mortem autopsy. Our service has high rates of perinatal loss, and low rates of post-mortem autopsy. We have offered post-mortem MRI for the last 5 years, however how MRI is currently being used, have not been reviewed. Aim(s): To describe: (i) the number of perinatal post-mortem MRIs performed, (ii) the reasons for offering MRI, (iii) whether the MRI was contributory to diagnosing cause of perinatal loss or adding extra information. Method(s): Cases were identified crosschecking perinatal loss and radiology data from 2010 to 2021. Anonymised summaries of clinical notes and investigation results of all cases were reviewed by two multidisciplinary groups, each of whom had MRI reports for half of the cases. Congruency of final classification of cause of death was compared and groups reported for each case whether MRI provided new information. Result(s): Between 2018 and 2021 there were 426 perinatal losses, of which 17 were investigated with MRI. In all cases MRI was offered after parents declined autopsy and was performed in addition to other investigations (maternal blood tests, placental karyotype, and histology). MRI changed the final PDC code in 1 case, provided additional findings in 2 cases, confirmed antenatally diagnosed anomalies in 4 cases and was non-contributory to diagnosing cause of death in 11/17 cases. Conclusion(s): In our service, post-mortem MRI has been used infrequently as part of the investigations into perinatal loss. When used, it has been most useful in confirming presence of structural anomalies diagnosed antenatally. Conclusion(s): High COVID-19 community prevalence was associated with increased MROP numbers at our clinical site, but inferences are limited by a lack of standardisation of operative reporting.

POLYFUNCTIONAL SARS-CoV-2-SPECIFIC T CELLS PERSIST IN TISSUE OF COVID-19 CONVALESCENTS

Background: T cells play an essential role in SARS-CoV-2 immunity, including in defense against severe COVID-19. However, most studies analyzing SARSCoV- 2-specific T cells have been limited to analysis of blood. Furthermore, the role of T cells in SARS-CoV-2 immunity in pregnant women, which are at disproportionately higher risk of severe COVID-19, is poorly understood. Method(s): Here, we quantitated and deeply phenotyped SARS-CoV-2-specific T cells from convalescent women (n=12) that had mild (non-hospitalized) COVID-19 during pregnancy. Endometrial, maternal blood, and fetal cord blood specimens were procured at term, which ranged from 3 days to 5 months post-infection. SARS-CoV-2-specific T cells were deeply analyzed by CyTOF using a tailored phenotyping panel designed to assess the effector functions, differentiation states, and homing properties of the cells. Result(s): SARS-CoV-2-specific T cells were more abundant in the endometrium than in maternal or fetal cord blood. In a particularly striking example, in one donor sampled 5 months after infection, SARS-CoV-2-specific CD8+ T cells comprised 4.8% of total endometrial CD8+ T cells, while it only reached 1.4% in blood. Endometrial SARS-CoV-2-specific T cells were more frequently of the memory phenotype relative to their counterparts in maternal and fetal cord blood, which harbored higher frequencies of naive T cells. Relative to their counterparts in blood, endometrial SARS-CoV-2-specific T cells exhibited unique phenotypic features, including preferential expression of the T resident memory marker CD69, inflammatory tissue-homing receptor CXCR4, and the activation marker 4-1BB. Endometrial T cells were highly polyfunctional, and could secrete IFNg, TNFa, MIP1b, IL2, and/or IL4 in response to spike peptide stimulation. By contrast, their counterparts in blood preferentially produced the cytolytic effectors perforin and granzyme B. Conclusion(s): Polyfunctional SARS-CoV-2-specific T cells primed by prior exposure to the virus are abundant and persist in endometrial tissue for months after infection. These cells exhibit unique phenotypic features including preferential expression of select chemokine receptors and activation molecules. Compared to their blood counterparts, the effector functions of these cells are more cytokine-driven and less cytolytic. The long-term persistence of these cells in the endometrium may help protect future pregnancies from SARS-CoV-2 re-infection.

Fetal impact of cystic fibrosis transmembrane conductance regulator modulator use during assisted and natural reproduction and partner pregnancy in men with cystic fibrosis

Background: Increasing availability of highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapy (HEMT) has improved the quality of life and long-term prognosis for many people with CF. Thus, more people with CF are considering parenthood. Almost all menwith CF (MwCF) are infertile because of congenital bilateral absence of the vas deferens (CBAVD). Based on CF animal models, CBAVD occurs early in gestation and is unlikely to be reversible using HEMT, but assisted reproductive techniques (ARTs) can enable MwCF to father children using the sperm in their testes. Animal reproductive models suggest no HEMT teratogenicity, and the amount of exposure of the fetus to HEMT via absorption of seminal fluid through the vaginal wall is predicted to be negligible, although to ensure no sperm exposure to HEMT, the life span of sperm would require MwCF to discontinue CFTR modulators for approximately 3 months before ART. Because abrupt discontinuation of CFTR modulators may result in health decline, MwCF and their providers must consider all potential risks. There are no published data in MwCF regarding use of HEMT during conception and partner pregnancy. Method(s): Beginning in August 2021, CF center staff in the United States, United Kingdom, and Australia completed a two-page anonymous questionnaire regarding MwCF who used CFTR modulators during ART (sperm retrieval and in vitro fertilization) or natural conception with subsequent partner pregnancy. Result(s): Providers have submitted 34 surveys for MwCF on CFTR modulators whose partner became pregnant after use of ART (n = 32) or natural conception (n = 2). The median age of the samplewas 32 (range 24- 43). Fifteen were homozygous for F508del, median percentage predicted forced expiratory volume in 1 second was 76% (range (22-111%), and median body mass index was 24 kg/m2 (range 18.5-32.1). Twenty-three were taking elexacaftor/tezacaftor/ivacaftor. The median time that MwCF were taking CFTR modulators before partner conception was 18 months (range 0-82). One newly diagnosed man initiated HEMT after sperm retrieval. Four MwCF stopped CFTR modulators before sperm retrieval, one of whom experienced pulmonary decline. None of the 19 MwCF whose condom use during pregnancy was known used condoms. Fetal complications in partners of MwCF included three first-trimester miscarriages, two* COVID, two breech presentation, two* vaginal bleeding, and one vasa previa. None of the complications were deemed definitively related to use of CFTR modulators. One MwCF experienced testicular infection after sperm retrieval#. Postpartum complications included three# infants with hypoxemia requiring neonatal intensive care unit stay, three maternal blood loss, one forceps delivery, and one caesarean section. No congenital anomalies were reported for any infant. (*/# overlap). Conclusion(s): Use of CFTR modulator therapy during partner conception and pregnancy in 34 MwCF has not resulted in higher-than-expected miscarriage rates or congenital anomalies. Providers should consider the risk to the health of MwCF combined with the lack of teratogenicity in animal reproductive models and limited safety data in the human fetus before discontinuing CFTR modulators before ART or natural partner conception. Survey collection is ongoing;results will be updated for presentationCopyright © 2022, European Cystic Fibrosis Society. All rights reserved

Covid-19 Vaccinated Maternal/Cord Blood Dont Have Neutralization for Omicron Variants

Background: Maternally derived antibodies are crucial for neonatal immunity. Understanding the binding and -cross neutralization capacity of maternal/ cord antibody responses to COVID-19 vaccination during pregnancy can inform neonatal immunity. Method(s): Here we characterized binding and neutralizing antibody profile at delivery in 24 pregnant individuals following two doses of Moderna mRNA-1273 or Pfizer BNT162b2 vaccination. We evaluated the transplacental antibody transfer by profiling maternal and umbilical cord blood. We analyzed for SARS-CoV-2 multivariant cross-neutralizing antibody levels for wildtype Wuhan, Delta, Omicron BA1, BA2, and BA4/BA5 variants by enzyme-linked immunosorbent assay Results: Our results reveal that current vaccination induced significantly higher (p=0.003) RBD-specific binding IgG titers in cord blood compared to maternal blood for both Wuhan and Omicron BA1 strain. Interestingly, binding IgG antibody levels for the Omicron BA1 strain were significantly lower (P< 0.0001) when compared to the Wuhan strain in both maternal and cord blood. In contrast to the binding, the Omicron BA1, BA2, BA4/5 specific neutralizing antibody levels were significantly lower (P< 0.0001) compared to the Wuhan and Delta variants. It is interesting to note that the BA4/5 neutralizing capacity was not at all detected in both maternal and cord blood. Conclusion(s): Our data suggest that the initial series of COVID-19 mRNA vaccines were immunogenic in pregnant women, and vaccine-elicited binding antibodies were detectable in cord blood at significantly higher levels for Wuhan and Delta variants but not for Omicron variants. Interestingly, the vaccination did not induce neutralizing antibodies for Omicron variants. These results provide novel insight into the impact of vaccination on maternal humoral immune response and transplacental antibody transfer for SARS-CoV-2 variants and support the need for boosters as new variants emerge.

Presence of SARS-CoV-2 neutralizing and vaccine spike antibodies in amniotic fluid during the second trimester of pregnancy, detected by amniocentesis (Winner of the SIMP Award, in memory of Professor Giorgio Pardi)

Objective. Thanks to the SARS-CoV-2 vaccination, pregnant women are protected from the complications of COVID-19 infection, but the benefits of this vaccination in preventing morbidity and mortality in the fetus are not yet clear: it is not well understood if and how these antibodies cross the placenta. Indeed antibodies made after a pregnant person has received an mRNA COVID-19 vaccine have been found in amniotic fluid and umbilical cord blood at term and represent a safer method of enhancing neonatal antibody levels than administration of immunoglobulin preparation to the infant. The aim of the study is to test the presence of neutralizing SARS-CoV-2 antibodies and spike antibodies in the amniotic fluid in the second trimester of pregnancy, and then to compare the antibodies level in maternal serum and amniotic fluid to evaluate their correlation. Materials and Methods. This cohort study took place at the Department of Obstetrics and Gynecology of Messina at the AOU Policlinico G. Martino from September 2021 to February 2022;the study consisted of 22 pregnant women who had amniocentesis in the gestational period between 15 weeks plus 6 days and 18 weeks: we analyzed serum and amniotic fluid samples of women who contracted the SARS-CoV-2 infection, or who were vaccinated against the same virus, within one year, or never infected by SARS-CoV-2 or vaccinated against it. During the amniocentesis, all patients underwent a single sample of maternal serum and of amniotic fluid to evaluate SARS-CoV-2 neutralizing antibody and S1 receptor binding domain IgG antibody levels. Inclusion criteria were pregnant women with the need to undergo amniocentesis. Results. 22 pregnant women were enrolled in the study:10 of them were vaccinated with a mRNA COVID-19 vaccine;12 women were not vaccinated, 4 of them had developed COVID-19 infection within one year before the collection and 2 of them developed the infection during pregnancy;the other 6 never developed the infection and have not been vaccinated, enrolled as comparators. Mann-Whitney test showed that vaccinated patients had significantly higher S1 receptor binding domain antibody levels both in amniotic fluid (p < 0.006) and maternal blood (p < 0.005) than not vaccinated women;also SARS-CoV-2 neutralizing antibody levels were higher in pregnant women who developed COVID-19 infection both in amniotic fluid (p < 0.007) and maternal blood (p < 0.004) than not vaccinated women. There was a significantly high correlation between the concentrations of spikes antibody levels in vaccinated pregnant women's serum and amniotic fluid (p = 0.000), and of neutralizing antibody levels in serum and amniotic fluid of women who developed COVID-19 infection (p = 0.000). Conclusions. To the best of our knowledge, the analysis of amniotic fluid and serum showed for the first time that all the vaccinated pregnant women samples had SARS-CoV-2 spikes immunoglobulins both in maternal blood and amniotic fluid. There is a very high correlation between maternal blood and amniotic fluid S1 receptor binding domain antibody levels in vaccinated women: this demonstrates that there is an early transplacental antibody transfer. Also neutralizing antibodies were found in the amniotic fluid of infected pregnant women, with high correlation between concentrations.

A Study of Prevalence of Igg Antibodies against Covid 19 in Maternal and Cord Blood

Introduction: The pandemic of COVID-19 has spread a wave of insecurity, fear and anxiety because of unknown facts about the pathogen. To have a better understanding about this infection, a systematic study is required by the principles of epidemiology with detailed investigations and researches from different angles. Hence, we are undertaking the study of seroprevalence of IgG antibody to get the idea about herd immunity in pregnant patients coming for delivery and their newborns. Objective(s): To find out the correlation between subclinical attack / mild attack of COVID 19 in the antenatal period. Method(s): This Cross-sectional study was conducted after getting cleared from Board of Studies and Ethical committee. The study population was calculated to be of 500 serum samples of both mother and newborns each. Result(s): The maternal age was 20-25 years among 230 (36.0%), 26-30 years among 164 (32.8%), 31-35 years among 88 (17.6%) and > 35 years among 18 (3.6%) patients. The maternal gestational age was <37 weeks 0 days at the time of delivery in 82 (16.4%) and that of >= 37 weeks was 418 (83.6%) patients. The exposure of COVID 19 virus and/or even the asymptomatic carriers, led to a data showing 18% (90 patients) of the study population being affected in 2nd trimester, 48.6% (243 patients) in 3rd trimester and 33.4% (167 patients) not affected at all in the pregnancy. IgG in mother at delivery was present among 21.4 % mothers. IgG in cord blood was present among 12.0% newborns. Conclusion(s): Although even at the time of diagnosis, asymptomatic pregnant women are able to reliably build a powerful IgG for receptor binding domain with neutralising response to COVID 19, as our results reveal. In addition, our findings indicate that this reaction was long-lasting, which lends credence to the notion that immunisation in this population will be successful. And after extensive research studies, pregnant females were allowed to be vaccinated against COVID 19. Copyright © 2022 Authors. All rights reserved.

A Study of Prevalence of Igg Antibodies against Covid 19 in Maternal and Cord Blood

Introduction: The pandemic of COVID-19 has spread a wave of insecurity, fear and anxiety because of unknown facts about the pathogen. To have a better understanding about this infection, a systematic study is required by the principles of epidemiology with detailed investigations and researches from different angles. Hence, we are undertaking the study of sero prevalence of IgG antibody to get the idea about herd immunity in pregnant patients coming for delivery and their newborns. Objective(s): To find out the correlation between subclinical attack/ mild attack of COVID 19 in the antenatal period. Method(s): This Cross-sectional study was conducted after getting cleared from Board of Studies and Ethical committee. The study population was calculated to be of 500 serum samples of both mother and newborns each. Result(s): The maternal age was 20-25 years among 179 (35.8%), 26-30 years among 129 (25.8%), 31-35 years among 118 (23.6%) and > 35 years among 74 (14.8%)patients. The maternal gestational age was 32-34 weeks among 59 (11.8%), 34.1-38 weeks among 98 (19.6%), 38.1-40 weeks among 275 (55.0%) and > 40 weeks among 68 (13.6%) patients. The Trimester with COVID-19 was 2nd among 152 (30.4%) and 3rd among 348 (69.6%) patients. IgG in mother at delivery was present among 59.0% mothers and IgG in cord blood was present among 54.0% newborns. Conclusion(s): Even at the time of diagnosis, aymptomatic pregnant women are able to reliably build a powerful IgG for receptor binding domain with neutralising response to COVID 19, as our results reveal. Although with opposition, majority of studies suggest that earlier the COVID 19 infection in pregnancy, better the transfer of IgG to fetus. As it is an evolving disease, extensive researches need to be established for a better result. Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

Cord blood and maternal cytokine levels following SARS-CoV-2 infection during pregnancy

Background. Pregnant people and fetuses are uniquely vulnerable to SARS-CoV-2, a driver of inflammation and immune dysregulation. Prior investigations have shown that pregnant people with SARS-CoV-2 are at higher risk of severe illness, mortality, and obstetric complications. We investigated the impact of SARS-CoV-2 infection severity and latency on maternal and infant cytokine levels. Methods. We collected maternal blood and cord blood at delivery from motherinfant dyads (Chicago, IL;3/2020-1/2022). A multiplex cytokine panel (IsoPlexis) was run on plasma from 93 SARS-CoV-2 infected dyads and 32 matched controls. Clinical data was ed by chart review, including latency (acute being <=14 days and distant >14 days from SARS-CoV-2 infection to delivery) and severity (NIH criteria: asymptomatic, mild, moderate, severe/critical). Kruskal-Wallis tests with post-hoc pairwise Dunn Tests were used (alpha=0.05). Results. SARS-CoV-2 exposed infants had lower levels of MIP-1b (p=0.037) and PDGF (p=0.008) than controls [Fig 1]. There were no differences in maternal blood cytokines at time of delivery following SARS-CoV-2 infection during pregnancy (pooled analysis of all SARS-CoV-2). Stratifying by latency, acutely exposed infants showed higher levels of MCP-1 than controls or those with distant maternal SARS-CoV-2 (p=0.016). There were no significant differences in maternal cytokines between control, acute, and distant SARS-CoV-2. In mothers with acute SARS-CoV-2, differences in levels of IL-1B (p=0.011) and IL-10 (p=0.046) were observed across severity groups, with a significant linear trend for each among severity groups (p for trend < 0.001, respectively). Severe/critical acute infection resulted in higher maternal granzyme and IL-8 than mild infection (p=0.037 and 0.047) [Fig 2]. There were no differences across severity groups in 1) mothers with distant infection, 2) infants with acute maternal infection, or 3) infants with distant maternal infection. Conclusion. Cytokine levels in SARS-CoV-2 positive dyads were altered only in the setting of acute or more severe infection and demonstrated anti-inflammatory, anti-viral, and anti-angiogenic responses. In acute infection, greater severity drives higher levels of both a pro- and anti-inflammatory cytokine in pregnant people.

Antibody Detection of Vaccine-induced Secretory Effects(ADVISE): A Prospective Study of Lactating Mothers Who Receive Sars-Cov-2 Vaccination

Background: The CDC recommends SARS-CoV-2 (COVID-19) vaccination for all adults, but vaccine safety for breastfeeding dyads and potential effects on lactation remain incompletely understood. Breastmilk immunological responses also have not been fully elucidated after COVID vaccination, specifically the formation of secretory IgA antibodies against viral Spike protein. Methods: ADVISE (NCT04895475) is a prospective trial evaluating breastmilk antibodies among lactating women who receive COVID vaccination. Maternal and infant demographics, breastfeeding characteristics including exclusivity, and vaccination type and side-effects were recorded. Milk samples before vaccination, and weekly after Dose 1 and Dose 2, were delivered using a convenient drop-off system. Maternal blood samples at monthly intervals, along with optional infant samples using a finger-stick Mitra® microsampler device (Neoteryx), were also collected. Breastmilk was frozen at -80C until processing, and fat-free supernatant was tested for quantitative ELISA titers against SARS-CoV-2 Spike protein and neutralizing activity using a pseudo-virus blocking assay. Results: A total of 66 women were consented, 3 of whom withdrew before data or sample collection. Of the remaining 63 (55 White, 5 Black, 3 Other), the median maternal age was 34.7 years (range 23.2-42.7 years);36 received the Moderna vaccine series and 27 received the Pfizer series. The median infant age at enrollment was 6 months;most were born full-term except 3 at <32 weeks and 5 at 33-36 weeks. Three mothers (5%) reported vaccine-related lactation sideeffects including 2 with a temporary decrease in milk supply and 1 who reported transient blue discoloration of the milk. Secretory IgA Spike antibodies (1:4 dilution, OD >0.5) were detected in the initial breastmilk samples from 14% of mothers, almost all of whom had either documented COVID infection or vaccination during pregnancy. For women who received vaccination while breastfeeding, 78% of the lactating mothers had secretory IgA antibodies in breastmilk within 2 weeks, which then dropped in titer and prevalence until the booster vaccine dose (Figure). Maximum breastmilk IgA titers were not associated with specific maternal or infant characteristics, including vaccine manufacturer. IgG breastmilk antibodies were also detected after the first vaccine, but titers were consistently high and sustained after the second dose (Figure). In preliminary analyses, most breastmilk samples had measurable neutralizing activity. Blood from mothers (1:400 dilution) had variable IgA responses but consistent IgG antibodies against Spike protein. In contrast, blood from infants only contained detectable Spike IgG and IgA antibodies if their mothers had COVID infection or vaccination during pregnancy, with no evidence that breastmilk antibodies transfer into the infant circulation. Conclusion: COVID vaccination during lactation is well tolerated with few side-effects and generates a strong immune response. Secretory IgA antibodies are routinely detected in breastmilk and have viral neutralizing activity, supporting wider immunization among breastfeeding mothers.

Spinal anaesthesia for EXIT procedure

Introduction: The EXIT (ex-utero intrapartum treatment) procedure allows management of an abnormal fetal airway during operative delivery while they remain on utero-placental circulation. The vast majority of published cases were conducted under deep volatile anaesthesia [1] in order to provide uterine relaxation and a degree of fetal anaesthesia.10 cases have been reported under combined spinalepidural anaesthesia or intrathecal catheter, with supplemental GTN (glyceryl trinitrate) and remifentanil infusions. Recent research has improved the ability to predict the likelihood and complexity of surgical intervention. Regional anaesthesia cases all had a hysterotomy time of under 21 minutes. Here we present the first case report of an EXIT procedure conducted with simple spinal anaesthesia. Case Report: A 35-year-old woman with a BMI of 37 kg/m2, asthma and a recent COVID-19 pneumonia, had a history of post-dural puncture headache after a difficult epidural for labour, spinal anaesthetics requiring ultrasound and a lumbar puncture requiring x-ray guidance. Her fetal MRI had shown a 5.6 cm cystic neck mass, with a deviated but patent airway. The ENT team predicted surgical interventionwas unlikely or would be very short, but intubation likely. We advised a general anaesthetic as our centre did not yet have experience with EXIT under regional anaesthesia, but the patient adamantly wanted spinal anaesthesia until the baby was born, to be aware of their outcome on delivery. She preferred to avoid an epidural. An arterial line aided the challenging blood pressure management with intrathecal hyperbaric bupivacaine 13.5 mg and diamorphine 300 μg, remifentanil and GTN infusions. The uterus remained relaxed on 2.3 μg/kg/minute of GTN. Uterine tonewas later re-established with intravenous Syntocinon 10 U and intramuscular ergometrine 500 μg, with only 500 mL maternal blood loss. Despite remifentanil target controlled infusion (Minto model) at 3.5 ng/mL for 15 minutes before hysterotomy, the baby cried spontaneously. Hysterotomy timewas two minutes. Discussion: Our team were satisfied with this technique, allowing us to offer more choice to mothers with an expected short EXIT procedure. The utero-placental transfer of remifentanil has previously been found to be variable, but cases have described no fetal response to intubation from maternal remifentanil titrated to light sedation [2]. It is common for additional drugs to be given directly to the fetus even with volatile anaesthetic.

Antigenic target, antibody subclass, function and glycans and SARS-CoV-2 coinfection impact the placental transfer of herpes simplex virus antibodies

Primary versus recurrent herpes simplex virus 1 or 2 (HSV-1 or HSV- 2) infection during pregnancy carries a higher risk of neonatal herpes suggesting that placental transfer of antibodies protects against transmission and infection. Murine and clinical studies demonstrate that antibody-dependent cellular cytotoxicity (ADCC) provides greater protection than neutralizing antibodies (nAbs) against disseminated neonatal disease. To quantify the relative transfer of HSV-specific Abs with different functions and targets and whether SARS-CoV-2 coinfection modified transfer, we conducted a prospective cohort study of mother-infant dyads prior to and during COVID-19. Total and HSV lysate, glycoprotein D (gD) and glycoprotein B (gB)- specific IgG, IgG1 and IgG3, nAbs, and ADCC were quantified in paired 3rd trimester maternal and cord blood. Transfer ratios (TR) were defined as cord: maternal Ab levels. IgG1 and IgG3 subclass and gD or gB-specific Abs were isolated by column purification and glycan profiles were assessed using mass spectrometry. The pre-COVID study population included 21 term and 15 preterm dyads who were HSV-1 (± HSV-2) seropositive (+) enrolled between 2018-2019 and the peri- COVID cohort included 25 HSV-1 (±HSV-2)+term dyadswhosemothers were also SARS-CoV-2 PCR and COVID Ab+ at delivery;14 were asymptomatic and 11 had mild-moderate COVID disease. None of the mothers had active genital HSV lesions during delivery. HSV-specific IgG, IgG1, and IgG3 TR were higher in term compared to preterm pre-COVID dyads (all p< 0.05). Similarly, the neutralizing Ab TR was 2.4[1.5, 4.0] in term vs 0.8[0.6, 1] in preterm (median [95%CI], p< 0.0001) but the ADCC TR was < 1.0 for both groups. To determine if the low ADCC TR reflected antigenic target, subclass, and/or glycans, we enriched for anti-gD and anti-gB specific and IgG1 and IgG3 Abs. These envelope glycoproteins are primary targets of neutralizing and ADCC responses, respectively. The anti-gD Abs were exclusively IgG1 and had only neutralizing activity. In contrast, anti-gB Abs were both IgG1 and IgG3;the IgG1 gB Abs had both neutralizing and ADCC activity whereas the IgG3 were only neutralizing. The anti-gD Abs were enriched for glycans associated with an affinity for FcRn, whereas anti-gB Abs expressed glycans associated with both FcRn and FcγRIIIa (receptor-associated with ADCC activity) binding. There was no significant difference in HSV-specific IgG TR in pre-COVID vs COVID dyads (0.42) but the nAb TR was lower (p = 0.018) and ADCC TR higher (p<0.001) in COVID compared to pre-COVID patients. Studies are in progress to assess whether this reflects increased placental colocalization of FcRn and FcgRIIIA, which would favor the transfer of ADCCAbs or modified Fc glycans. ADCC Abs transfer relatively inefficiently compared to nAbs, particularly in preterm infants and this may contribute to an increased risk of HSV disease. ADCC Ab transfer increased with SARS-CoV-2 coinfection, which may reflect differences in glycans and/or alterations in the placental architecture. Defining the determinants of ADCC transfer has implications for future vaccine and monoclonal Ab strategies to prevent/treat neonatal herpes. We speculate that increasing the transfer of ADCC may be a key element in providing immune protection.

Prenatal Visit Vitals: Comparison Between Virtual And Traditional Visits

INTRODUCTION: Prenatal visits via a virtual platform are increasingly offered to patients. Previous studies have shown favorable acceptance by patients. The COVID-19 pandemic dramatically accelerated adoption of this new technology. This study was designed to compare documentation of maternal blood pressure and weight between virtual visits and traditional face-to-face visits. METHODS: The study is a retrospective comparison of documentation of blood pressure and maternal weight between virtual and traditional face-to-face prenatal visits between January 2019 and June 2021. IRB exemption was obtained. The electronic medical record of a large midwest U.S. health system was utilized to identify prenatal visit encounters for all patients at all gestations. The visits were grouped into virtual visits and face-to-face visits. Data analytics were used to compare documentation of maternal weight, systolic blood pressure, and diastolic blood pressure for both subgroups. Data were further broken down by month to show comparison over time. Comparison was also made by gestational age. RESULTS: A total of 108,428 prenatal visits were identified. Of these, 7,004 (6.5%) were virtual visits. Appropriate documentation of blood pressure was absent in 3% of face-to-face visits and 46% of virtual visits. For the maternal weight, data were missing for 3% of face-to-face visits and 66% of virtual visits. CONCLUSION: Studies validating the safety of virtual prenatal visits are lacking. This analysis identifies obstacles that need to be overcome to improve the safety of virtual care.

Pattern of blood component utilization in a tertiary care oncology only institution

Background: Blood transfusion services are of paramount importance in cancer care. Streamlined and judicious usage of this scarce resource against the higher demand is one of the greatest challenges. Continuous monitoring of the utilization pattern of the blood components paves the way for better picturization of the transfusion practices and formulating strategies for implementation of better patient blood management. National blood policy of India encourages appropriate clinical use of blood components. An oncology care facility poses an additional challenge of random variation in demands against a low supply. This warrants a more stringent monitoring of the blood component utilization pattern according to the patient profiles, indications for transfusions and onward therapeutic benefits. Aims: Evaluation of pattern of blood component utilization in a blood storage center catering to oncology only. Methods: This retrospective study was conducted in a blood storage center of an oncology-only center. Time frame of the study was June 2019 through August 2021. The procurement of components from the mother blood center, onward issue details to different wards for transfusion of all blood components [Packed red blood cells units (PRBC), Fresh frozen plasma units (FFP), Platelet units (PLT)], and discard of components with reference to their respective causes were recorded. Effects of COVID-19 pandemic on the utilization pattern was also recorded to assess the variations in the utilization pattern. The statistical analysis was done by using Microsoft Excel (Office 365 version, Microsoft, USA). Results: A total of 4599 component units were procured which is comprised of 2196 (47.75%) PRBC, 2012 (43.75%) PLTs and 391 (8.5%) FFPs. A total of 3624 of 4599 units (78.8%) were requested during the study period which is comprised of 2076 of 2196 PRBCs (94.5% utilization), 1189 of 2012 PLTs (59.1% utilization) and 359 of 391 FFPs (91.8% utilization). A total of 652 of 4599 units were received back which is comprised of 76 of 2196 PRBCs (3.5%), 565 of 2012 PLTs (28.1%) and 11 of 391 FFPs (2.8%). Majority of the blood components 1553 of 3624 (42.85%) were issued to patients admitted under medical oncology comprised of 924 of 2076 (44.5%) PRBCs, 533 of 1189 (44.8%) PLTs and 96 of 359 (26.75%) FFPs followed by to onco-emergency and patients admitted under surgical oncology. COVID surge led to curtailment of oncology care as the facility catered to the COVID patients with 310 PRBCs (14.9%), 408 RDPs (34.31%) and 102 FFPs (28.4%). A total of 271 units (5.9%) were discarded during this time which is comprised of only 4 of 2196 PRBCs (0.18%) due to failure in cold chain maintenance, 254 of 2012 PLTs (12.6%) and 13 of 391 FFPs (3.32%) due to breakage of units or receive back from wards beyond 30 min. Summary/Conclusions: Blood utilization patterns change with the patient profiles, level of organization in an oncology center. This storage center data presented here is a preliminary step for planning and maintaining a balance between demand, supply, and wastage. Although the utilization rate of PRBCs and FFPs were >90%, the same for the PLTs was <60%. This is attributed to planning errors and unpredictable demand to supply. The proportions of wastage were <5% for PRBCs and FFPs but was >12% for RDPs due to logistic issues, expirations, and non-compliance to good clinical practices. A comprehensive approach by a multi-disciplinary team will help streamline the judicious usage of the blood components at our center.

LONGITUDINAL SARS-CoV-2 ANTIBODY RESPONSE in PREGNANCY and TRANSPLACENTAL TRANSFER

Background: Longitudinal assessment of SARS-CoV-2 antibody (Ab) response during pregnancy after infection and transplacental transfer may inform durability of maternally derived Ab for mothers and infants. Methods: Between October 2020-September 2021, pregnant people testing SARS-CoV-2 IgG positive by Abbott Architect chemiluminescent immunoassay (CMIA) for anti-nucleocapsid (N) antibody (semi-quantitative index ≥1.4 considered IgG+) during pregnancy or delivery in a seroprevalence study, or identified with RT-PCR+ results via medical records, were invited to enroll in a longitudinal evaluation of maternal Ab responses and transplacental transfer. Maternal blood collected at 1, 2, 3, and 6 months after enrollment and maternal and cord blood collected at delivery were tested with the same assay. Results: Among 40 participants testing IgG+ for anti-N, 31 (78%) had a prior RT-PCR+ result. Median age was 32 years (IQR 29-35);27 (68%) enrolled during pregnancy at median 18 weeks gestation (IQR 13-33), while 13 (33%) enrolled at delivery or early postpartum. Median Abbott index was 3.06 (IQR 1.96-5.74) at first IgG+ result obtained at a median of 9 weeks (IQR 4-16) after RT-PCR+ result, for those with a known RT-PCR. Among 23 participants with ≥2 samples, 50% had IgG results below positivity threshold at median 17 weeks (IQR 12-28) after first IgG+ result (Figure). Seventeen mother-infant pairs had delivery samples collected at median 66 days (IQR 60-71 days) from maternal RT-PCR+ result. Six (35%) maternal samples remained IgG+ (median Abbott index 2.97 [IQR 2.35-7.01]) at delivery (gestational age 30-40 weeks) with all 6 paired cord sera testing IgG+ (median Abbott index 4.30 [IQR 2.93-7.22]). Median placental transfer ratio of maternally derived IgG Abs based on a positive Abbott index was 1.13 (95%CI 0.98-1.30) among mothers with samples remaining IgG+ at delivery. Conclusion: Within 4 months after first IgG+ result primarily in second trimester, about half of pregnant persons had SARS-CoV-2 IgG anti-N Ab levels below the Abbott CMIA positive threshold. Among evaluable mother-infant pairs, two-thirds of mothers no longer tested anti-N IgG+ at delivery. Transplacental transfer of maternal antibodies was confirmed in all infants born to mothers with samples remaining IgG+ at delivery. Durability of maternal SARS-CoV-2 Ab response and transplacental transfer following infection has implications for maternal and neonatal susceptibility to SARS-CoV-2 infection.

Vertical transmission and humoral immune response following maternal infection with SARS-CoV-2

Objective: To explore maternal humoral immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and the rate of vertical transmission. Study Design: A prospective cohort study was conducted at two university-affiliated medical centers. Women positive for SARS-CoV-2, as determined by reverse-transcription-polymerase-chain-reaction (RT-PCR), during pregnancy were enrolled just prior to delivery. Levels of anti-SARS-CoV-2 nucleocapsid IgG, spike IgG and spike-IgM were tested in maternal and cord blood at delivery, and neonatal nasopharyngeal swabs were subjected to PCR testing. The primary endpoint was the rate of vertical transmission, defined as either positive neonatal IgM, positive neonatal IgG with sero-negative mother or positive neonatal PCR. The rate of vertical transmission was estimated to be 7% when defined by RT-PCR. Assuming that using serology tests increases the rate to 10% versus 0% in non-infected population, 71 women were required (80% power, 5% one-sided alpha) Results: Among 72 women, 36 (50%), 39 (54%) and 30 (42%) were positive for anti-spike-IgM, anti-spike-IgG and anti-nucleocapsid-IgG, respectively (p < 0.0001 for IgG antibodies;table). At least 8/72 (11%) neonates were infected in utero;one had a positive PCR and seven had positive IgG while their mothers were seronegative for the same IgG. IgM was not detected in cord blood. Anti-nucleocapsid-IgG and anti-spike-IgG were detected in 83% and 85% of neonates of seropositive mothers, respectively (Pearson coefficient correlation 0.8, p< 0.001). The highest rate of positive maternal serology tests was 8-12 weeks post-infection (89% anti-spike IgG, 78% anti-spike IgM and 67% anti-nucleocapsid IgG). Thereafter, the rate of positive serology tests declined gradually;at 20 weeks post-infection, only anti-spike IgG was detected in 33-50% (figure). Conclusion: The rate of vertical transmission was at least 11%. Vaccination should be considered 3 months post-infection in pregnant women due to a decline in antibody levels. [Formula presented] [Formula presented]

Abnormal placental pathology and anti-SARS-CoV-2 transplacental antibody transfer following natural infection

Objective: Studies have shown that the antibodies developed in pregnant mothers who have been infected with severe acute respiratory syndrome coronavirus (SARS-COV-2) are able to cross the placenta;though, there is a decreased efficiency ratio of cord to maternal anti-receptor-binding domain IgG titers. Viral mediated placental injury may explain this finding. The objective of this study is to examine the relationship between transplacental antibody transfer and abnormal placental pathology in pregnant patients following infection with SARS-COV-2. Study Design: Pregnant patients with COVID-19 delivering at Grady Memorial Hospital were identified and enrolled into a prospective cohort study. Maternal and cord blood samples were collected at the time of delivery, and concentrations of anti- SARS-COV-2 IgG spike protein quantified using an enzyme-linked immunosorbent assay (ELISA). Placentas were sent for pathologic examination at the discretion of the obstetric provider and examined by trained pathologists for size, presence of infarcts, and other histologic findings. Results: A total of 12 women were included in the study. Demographic characteristics and clinical outcomes are reported in Table 1. There was no statistically significant difference in the mean transplacental antibody ratio for patients with and without placental infarcts, with the mean (SD) maternal:cord antibody IgG ratio for patients with infarcts at 0.67 (0.47) and without was 0.73 (0.35) (p=0.81). Maternal hypertensive disorder and the presence of symptoms at time of infection were not associated with infarct in this small sample. Conclusion: Results demonstrate that in this limited sample, placental infarcts were not associated with difference in transplacental antibody transfer. Further studies are needed to understand mechanisms underlying transplacental antibody transfer. [Formula presented] [Formula presented]