Reductions in stillbirths and preterm birth in COVID-19-vaccinated women: a multicenter cohort study of vaccination uptake and perinatal outcomes.

BACKGROUND: COVID-19 infection in pregnancy is associated with a higher risk of progression to severe disease, but vaccine uptake by pregnant women is hindered by persistent safety concerns. COVID-19 vaccination in pregnancy has been shown to reduce stillbirth, but its relationship with preterm birth is uncertain. OBJECTIVE: This study aimed to measure the rate of COVID-19 vaccine uptake among women giving birth in Melbourne, Australia, and to compare perinatal outcomes by vaccination status. STUDY DESIGN: This was a retrospective multicenter cohort study conducted after the June 2021 government recommendations for messenger RNA COVID-19 vaccination during pregnancy. Routinely collected data from all 12 public maternity hospitals in Melbourne were extracted on births at ≥20 weeks' gestation from July 1, 2021 to March 31, 2022. Maternal sociodemographic characteristics were analyzed from the total birth cohort. Perinatal outcomes were compared between vaccinated and unvaccinated women for whom weeks 20 to 43 of gestation fell entirely within the 9-month data collection period. The primary outcomes were the rates of stillbirth and preterm birth (spontaneous and iatrogenic) in singleton pregnancies of at least 24 weeks' gestation, after exclusion of congenital anomalies. Secondary perinatal outcomes included the rate of congenital anomalies among infants born at ≥20 weeks' gestation and birthweight ≤third centile and newborn intensive care unit admissions among infants born without congenital anomalies at ≥24 weeks' gestation. We calculated the adjusted odds ratio of perinatal outcomes among vaccinated vs unvaccinated women using inverse propensity score-weighting regression adjustment with multiple covariates; P<.05 was considered statistically significant. RESULTS: Births from 32,536 women were analyzed: 17,365 (53.4%) were vaccinated and 15,171 (47.6%) were unvaccinated. Vaccinated women were more likely to be older, nulliparous, nonsmoking, not requiring an interpreter, of higher socioeconomic status, and vaccinated against pertussis and influenza. Vaccination status also varied by region of birth. Vaccinated women had a significantly lower rate of stillbirth compared with unvaccinated women (0.2% vs 0.8%; adjusted odds ratio, 0.18; 95% confidence interval, 0.09-0.37; P<.001). Vaccination was associated with a significant reduction in total preterm births at <37 weeks (5.1% vs 9.2%; adjusted odds ratio, 0.60; 95% confidence interval, 0.51-0.71; P<.001), spontaneous preterm birth (2.4% vs 4.0%; adjusted odds ratio, 0.73; 95% confidence interval, 0.56-0.96; P=.02), and iatrogenic preterm birth (2.7% vs 5.2%; adjusted odds ratio, 0.52; 95% confidence interval, 0.41-0.65; P<.001). Infants born to vaccinated mothers also had lower rates of admission to the neonatal intensive care unit. There was no significant increase in the rate of congenital anomalies or birthweight ≤3rd centile in vaccinated women. Vaccinated women were significantly less likely to have an infant with a major congenital anomaly compared with the unvaccinated group (2.4% vs 3.0%; adjusted odds ratio, 0.72; 95% confidence interval, 0.56-0.94; P=.02). This finding remained significant even when the analysis was restricted to women vaccinated before 20 weeks' gestation. CONCLUSION: COVID-19 vaccination during pregnancy was associated with a reduction in stillbirth and preterm birth, and not associated with any adverse impact on fetal growth or development. Vaccine coverage was substantially influenced by known social determinants of health.

Reduction in spontaneous and iatrogenic preterm births in twin pregnancies during COVID-19 lockdown in Melbourne, Australia: a multicenter cohort study.

BACKGROUND: Melbourne, Australia, recorded one of the longest and most stringent pandemic lockdowns in 2020, which was associated with an increase in preterm stillbirths among singleton pregnancies. Twin pregnancies may be particularly susceptible to the impacts of pandemic disruptions to maternity care due to their higher background risk of adverse perinatal outcomes. METHODS: Multicenter retrospective cohort study of all twin pregnancies birthing in public maternity hospitals in Melbourne. Multivariable log-binomial regression models were used to compare perinatal outcomes between a pre-pandemic group to women in whom weeks 20+0 to 40+0 of gestation occurred entirely during one of two lockdown-exposure periods: exposure 1 from 22 March 2020 to 21 March 2021 and exposure 2 from 22 March 2021 to 27 March 2022. RESULTS: Total preterm births < 37 weeks were significantly lower in exposure 1 compared with the pre-pandemic period (63.1% vs 68.3%; adjusted risk ratio 0.92 95% CI 0.87-0.98, p = 0.01). This was mainly driven by fewer spontaneous preterm births (18.9% vs 20.3%; adjusted risk ratio 0.95 95% CI 0.90-0.99, p = 0.04). There were also lower rates of preterm birth < 34 weeks (19.9% vs 23.0%, adjusted risk ratio 0.93 95% CI 0.89-0.98 p = 0.01) and total iatrogenic births for fetal compromise (13.4% vs 20.4%; adjusted risk ratio 0.94 95% CI 0.89-0.98, p = 0.01). There were fewer special care nursery admissions (38.5% vs 43.4%; adjusted risk ratio 0.91 95% CI 0.87-0.95, p < 0.001) but no significant changes in stillbirth (1.5% vs 1.6%; adjusted risk ratio 1.00 95% CI 0.99-1.01, p = 0.82). Compared with the pre-pandemic period, there were more preterm births < 28 weeks and neonatal intensive care unit admissions in exposure 2. CONCLUSIONS: Melbourne's first lockdown-exposure period was associated with lower preterm births in twins without significant differences in adverse newborn outcomes. Our findings provide insights into the influences on preterm birth and the optimal timing of delivery for twins.

Increase in preterm stillbirths in association with reduction in iatrogenic preterm births during COVID-19 lockdown in Australia: a multicenter cohort study.

BACKGROUND: The COVID-19 pandemic has been associated with a worsening of perinatal outcomes in many regions around the world. Melbourne, Australia, had one of the longest and most stringent lockdowns worldwide in 2020 while recording only rare instances of COVID-19 infection in pregnant women. OBJECTIVE: This study aimed to compare the stillbirth and preterm birth rates in women who were exposed or unexposed to lockdown restrictions during pregnancy. STUDY DESIGN: This was a retrospective, multicenter cohort study of perinatal outcomes in Melbourne before and during the COVID-19 lockdown. The lockdown period was defined as the period from March 23, 2020 to March 14, 2021. Routinely-collected maternity data on singleton pregnancies ≥24 weeks gestation without congenital anomalies were obtained from all the 12 public hospitals in Melbourne. We defined the lockdown-exposed cohort as those women for whom weeks 20 to 40 of gestation occurred during the lockdown and the unexposed control group as women from the corresponding calendar periods 12 and 24 months before. The main outcome measures were stillbirth, preterm birth, fetal growth restriction (birthweight < third centile), and iatrogenic preterm birth for fetal compromise. We performed multivariable logistic regression analysis to compare the odds of stillbirth, preterm birth, fetal growth restriction, and iatrogenic preterm birth for fetal compromise, adjusting for multiple covariates. RESULTS: There were 24,817 births in the exposed group and 50,017 births in the control group. There was a significantly higher risk of preterm stillbirth in the exposed group than the control group (0.26% vs 0.18%; adjusted odds ratio, 1.49; 95% confidence interval, 1.08-2.05; P=.015). There was also a significant reduction in the preterm birth of live infants <37 weeks (5.68% vs 6.07%; adjusted odds ratio, 0.93; 95% confidence interval, 0.87-0.99; P=.02), which was largely mediated by a significant reduction in iatrogenic preterm birth (3.01% vs 3.27%; adjusted odds ratio, 0.91; 95% confidence interval, 0.83-0.99; P=.03), including iatrogenic preterm birth for fetal compromise (1.25% vs 1.51%; adjusted odds ratio, 0.82; 95% confidence interval, 0.71-0.93; P=.003). There were also significant reductions in special care nursery admissions during lockdown (11.53% vs 12.51%; adjusted odds ratio, 0.90; 95% confidence interval, 0.86-0.95; P<.0001). There was a trend to fewer spontaneous preterm births <37 weeks in the exposed group of a similar magnitude to that reported in other countries (2.69% vs 2.82%; adjusted odds ratio, 0.95; 95% confidence interval, 0.87-1.05; P=.32). CONCLUSION: Lockdown restrictions in Melbourne, Australia were associated with a significant reduction in iatrogenic preterm birth for fetal compromise and a significant increase in preterm stillbirths. This raises concerns that pandemic conditions in 2020 may have led to a failure to identify and appropriately care for pregnant women at an increased risk of antepartum stillbirth. Further research is required to understand the relationship between these 2 findings and to inform our ongoing responses to the pandemic.

Doppler Ultrasound of the Fetal Descending Aorta: An Objective Tool to Assess Placental Blood Flow Resistance in Pregnancies With Discordant Umbilical Arteries.

OBJECTIVES: To determine the relationship between blood flow in the fetal descending aorta and discordant umbilical arteries (UAs). METHODS: Pulsed wave Doppler of both UAs and the descending aorta was performed at 4-weekly intervals between 14 and 40 weeks of gestation in 209 pregnant women. In datasets with discordant UAs, a linear mixed effects model was used to determine the categorical relationship between the UA pulsatility index (PI) (high, low and average) and the descending aorta PI. RESULTS: Of the 209 cases, 81 had a discordance of greater than 25% in UA PI during one of their visits. There were no differences in birth outcomes between the groups with concordant and discordant UA PIs. In the cases with discordant UA PIs, the descending aorta PI was most strongly associated with both the average UA PI (P = .008), and with the UA with the lower PI (P = .008). CONCLUSIONS: The relationship between blood flow in the descending aorta and UAs is consistent with the law for combining resistances in parallel. Measurements of the descending aorta PI, particularly in a scenario with discordant UAs, may inform the stability of the feto-placental circulation where discordant UA PIs are found.

Placental vascular abnormalities in the mouse alter umbilical artery wave reflections.

Current methods to detect placental vascular pathologies that monitor Doppler ultrasound changes in umbilical artery (UA) pulsatility have only moderate diagnostic utility, particularly in late gestation. In fetal mice, we recently demonstrated that reflected pressure waves propagate counter to the direction of flow in the UA and proposed the measurement of these reflections as a means to detect abnormalities in the placental circulation. In the present study, we used this approach in combination with microcomputed tomography to investigate the relationship between altered placental vascular architecture and changes in UA wave reflection metrics. Fetuses were assessed at embryonic day (E) 15.5 and E17.5 in control C57BL6/J mice and dams treated with combination antiretroviral therapy (cART), a known model of fetal growth restriction. Whereas the reflection coefficient was not different between groups at E15.5, it was 27% higher at E17.5 in cART-treated mice compared with control mice. This increase in reflection coefficient corresponded to a 36% increase in the total number of vessel segments, a measure of overall architectural complexity. Interestingly, there was no difference in UA pulsatility index between groups, suggesting that the wave reflections convey information about vascular architecture that is not captured by conventional ultrasound metrics. The wave reflection parameters were found to be associated with the morphology of the fetoplacental arterial tree, with the area ratio between the UA and first branch points correlating with the reflection coefficient. This study highlights the potential for wave reflection to aid in the noninvasive clinical assessment of placental vascular pathology. NEW & NOTEWORTHY We used a novel ultrasound methodology based on detecting pulse pressure waves that propagate along the umbilical artery to investigate the relationship between changes in wave reflection metrics and altered placental vascular architecture visualized by microcomputed tomography. Using pregnant mice treated with combination antiretroviral therapy, a model of fetal growth restriction, we demonstrated that reflections in the umbilical artery are sensitive to placental vascular abnormalities and associated with the geometry of the fetoplacental tree.

Effect of maternal betamethasone administration on feto-placental vascular resistance in the mouse†.

Antenatal corticosteroids are often administered to women at risk of preterm birth to accelerate fetal lung development; however, there is evidence that this treatment may adversely affect placental function in some fetuses. Our group has recently demonstrated that wave reflections in the umbilical artery (UA), measured using high-frequency ultrasound, are sensitive to placental vascular abnormalities. In the present study, we used this approach to investigate the effect of maternal administration of betamethasone, a clinically relevant corticosteroid, on the feto-placental vasculature of the mouse. Fetuses were assessed at embryonic day (E)15.5 and E17.5 in C57BL6/J mice. At both gestational ages, the UA diameter, UA blood flow, and the wave reflection coefficient were significantly elevated in the betamethasone-treated mice compared to vehicle-treated controls. These observations support the interpretation that placental vascular resistance dropped with betamethasone treatment to an extent that could not be explained by vasodilation of the UA alone. Consistent with clinical studies, the effect of betamethasone on UA end-diastolic velocity was heterogeneous. Our results suggest that UA wave reflections are more sensitive to acute changes in placental vascular resistance compared with the UA pulsatility index, and this technique may have clinical application to identify a favorable placental vascular response to fetal therapies such as antenatal corticosteroids, where the fetal heart rate is likely to vary.

Identifying late-onset fetal growth restriction by measuring circulating placental RNA in the maternal blood at 28 weeks' gestation.

BACKGROUND: Late-onset fetal growth restriction (FGR) is often undetected prior to birth, which puts the fetus at increased risk of adverse perinatal outcomes including stillbirth. OBJECTIVE: Measuring RNA circulating in the maternal blood may provide a noninvasive insight into placental function. We examined whether measuring RNA in the maternal blood at 26-30 weeks' gestation can identify pregnancies at risk of late-onset FGR. We focused on RNA highly expressed in placenta, which we termed "placental-specific genes." STUDY DESIGN: This was a case-control study nested within a prospective cohort of 600 women recruited at 26-30 weeks' gestation. The circulating placental transcriptome in maternal blood was compared between women with late-onset FGR (<5th centile at >36+6 weeks) and gestation-matched well-grown controls (20-95th centile) using microarray (n = 12). TaqMan low-density arrays, reverse transcription-polymerase chain reaction (PCR), and digital PCR were used to validate the microarray findings (FGR n = 40, controls n = 80). RESULTS: Forty women developed late-onset FGR (birthweight 2574 ± 338 g, 2nd centile) and were matched to 80 well-grown controls (birthweight 3415 ± 339 g, 53rd centile, P < .05). Operative delivery and neonatal admission were higher in the FGR cohort (45% vs 23%, P < .05). Messenger RNA coding 137 placental-specific genes was detected in the maternal blood and 37 were differentially expressed in late-onset FGR. Seven were significantly dysregulated with PCR validation (P < .05). Activating transcription factor-3 messenger RNA transcripts were the most promising single biomarker at 26-30 weeks: they were increased in fetuses destined to be born FGR at term (2.1-fold vs well grown at term, P < .001) and correlated with the severity of FGR. Combining biomarkers improved prediction of severe late-onset FGR (area under the curve, 0.88; 95% CI 0.80-0.97). A multimarker gene expression score had a sensitivity of 79%, a specificity of 88%, and a positive likelihood ratio of 6.2 for subsequent delivery of a baby <3rd centile at term. CONCLUSION: A unique placental transcriptome is detectable in maternal blood at 26-30 weeks' gestation in pregnancies destined to develop late-onset FGR. Circulating placental RNA may therefore be a promising noninvasive test to identify pregnancies at risk of developing FGR at term.

Measuring circulating placental RNAs to non-invasively assess the placental transcriptome and to predict pregnancy complications.

Circulating nucleic acids have revolutionized prenatal diagnosis in the last decade, allowing non-invasive screening for single gene or chromosomal defects using a single sample of maternal blood. In addition to DNAs, RNAs from the placenta are released into the maternal blood from early in pregnancy and may reflect changes in gene expression occurring within the placenta. Measuring circulating RNA may therefore provide insights into the placental transcriptome without the need for invasive testing. Combined with advances in next-generation sequencing and molecular analyses, it may be possible to measure circulating RNA to improve our understanding of placental pathology and develop novel non-invasive biomarkers for pregnancy complications and monitoring high-risk pregnancies. This review summarizes the current technologies available and the studies that have measured circulating placental RNA to predict and/or monitor pregnancies complicated by preeclampsia, fetal growth restriction, preterm birth, early pregnancy complications, invasive placentation and twin-twin transfusion syndrome. Prospective cohort studies are now required to validate these findings to determine the clinical applicability of measuring circulating placental RNA to develop novel biomarkers for a wide spectrum of pregnancy complications. © 2016 John Wiley & Sons, Ltd.

Antenatal screening for fetal structural anomalies - Routine or targeted practice?

Antenatal screening with ultrasound identifies fetal structural anomalies in 3-6% of pregnancies. Identification of anomalies during pregnancy provides an opportunity for counselling, targeted imaging, genetic testing, fetal intervention and delivery planning. Ultrasound is the primary modality for imaging the fetus in pregnancy, but magnetic resonance imaging (MRI) is evolving as an adjunctive tool providing additional structural and functional information. Screening should start from the first trimester when more than 50% of severe defects can be detected. The mid-trimester ultrasound balances the benefits of increased fetal growth and development to improve detection rates, whilst still providing timely management options. A routine third trimester ultrasound may detect acquired anomalies or those missed earlier in pregnancy but may not be available in all settings. Targeted imaging by fetal medicine experts improves detection in high-risk pregnancies or when an anomaly has been detected, allowing accurate phenotyping, access to advanced genetic testing and expert counselling.

Statistical analyses of ordinal outcomes in randomised controlled trials: a scoping review.

BACKGROUND: Randomised controlled trials (RCTs) aim to estimate the causal effect of one or more interventions relative to a control. One type of outcome that can be of interest in an RCT is an ordinal outcome, which is useful to answer clinical questions regarding complex and evolving patient states. The target parameter of interest for an ordinal outcome depends on the research question and the assumptions the analyst is willing to make. This review aimed to provide an overview of how ordinal outcomes have been used and analysed in RCTs. METHODS: The review included RCTs with an ordinal primary or secondary outcome published between 2017 and 2022 in four highly ranked medical journals (the British Medical Journal, New England Journal of Medicine, The Lancet, and the Journal of the American Medical Association) identified through PubMed. Details regarding the study setting, design, the target parameter, and statistical methods used to analyse the ordinal outcome were extracted. RESULTS: The search identified 309 studies, of which 144 were eligible for inclusion. The most used target parameter was an odds ratio, reported in 78 (54%) studies. The ordinal outcome was dichotomised for analysis in 47 ( 33 % ) studies, and the most common statistical model used to analyse the ordinal outcome on the full ordinal scale was the proportional odds model (64 [ 44 % ] studies). Notably, 86 (60%) studies did not explicitly check or describe the robustness of the assumptions for the statistical method(s) used. CONCLUSIONS: The results of this review indicate that in RCTs that use an ordinal outcome, there is variation in the target parameter and the analytical approaches used, with many dichotomising the ordinal outcome. Few studies provided assurance regarding the appropriateness of the assumptions and methods used to analyse the ordinal outcome. More guidance is needed to improve the transparent reporting of the analysis of ordinal outcomes in future trials.

MMP-14 is expressed in preeclamptic placentas and mediates release of soluble endoglin.

Soluble endoglin is an anti-angiogenic protein that is released from the placenta and contributes to both maternal endothelial dysfunction and the clinical features of severe preeclampsia. The mechanism through which soluble endoglin is released from the placenta is currently unknown; however, recent work in colorectal cancer identified matrix metalloproteinase 14 (MMP-14) as the cleavage protease of endoglin. To determine whether this is also the mechanism responsible for soluble endoglin release in preeclampsia, we investigated the expression of MMP-14 within the placenta and the effects of its inhibition on soluble endoglin release. Placentas were obtained from severe, early onset preeclamptic pregnancies (n = 8) and gestationally matched preterm controls (n = 8). MMP-14 was predominately localized to the syncytiotrophoblast. Results from a proximity ligation assay showed protein interactions between endogenous MMP-14 and endoglin within the preeclamptic placenta. To demonstrate that this interaction produces soluble endoglin, we treated trophoblastic BeWo cells with either a broad-spectrum MMP inhibitor (GM6001) or MMP-14 siRNA. Both treatments produced a decrease in soluble endoglin (P ≤ 0.05). Treatment of mice bearing BeWo xenografts with GM6001 decreased circulating soluble endoglin levels in mouse serum (P ≤ 0.05). These findings indicate that MMP-14 is the likely cleavage protease of endoglin in the setting of preeclampsia. This approach provides a novel method for the development of potential therapeutics to reduce circulating soluble endoglin and ameliorate the clinical features of severe preeclampsia.

Quantifying mRNA coding growth genes in the maternal circulation to detect fetal growth restriction.

OBJECTIVE: To examine whether mRNA circulating in maternal blood coding genes regulating fetal growth are differentially expressed in (1) severe preterm fetal growth restriction (FGR) and (2) at 28 weeks' gestation in pregnancies destined to develop FGR at term. STUDY DESIGN: mRNA coding growth genes were measured in 2 independent cohorts. The first was women diagnosed with severe preterm FGR (<34 weeks' gestation; n = 20) and gestation matched controls (n = 15), where the mRNA was measured in both maternal blood and placenta. The second cohort was a prospective longitudinal study (n = 52) of women whom had serial ultrasound assessments of fetal growth. mRNA coding growth genes in maternal blood were measured at 28 and 36 weeks in pregnancies with declining growth trajectories (ending up with term FGR; n = 10 among the 52 recruited) and controls who maintained normal growth trajectory (n = 15). RESULTS: In women with severe preterm FGR, there was increased expression of placental growth hormone (6.3-fold), insulin-like growth factors (IGF1, 3.4-fold; IGF2, 5.0-fold), IGF receptors (2.1-fold) and IGF binding proteins (3.0-fold), and reduced expression of ADAM12 (0.5-fold) in maternal blood (and similar trends in placenta) compared with controls (P < .05). Notably, at 28 weeks' gestation there was increased IGF2 (3.9-fold), placental growth hormone (2.7-fold), and IGF BP2 (2.1-fold) expression in maternal blood in women destined to develop FGR at term (P < .05). CONCLUSION: Measuring mRNA coding growth genes in maternal blood may detect unsuspected severe preterm FGR already present in utero, and predict term FGR when measured at 28 weeks' gestation.

Statistical analyses of ordinal outcomes in randomised controlled trials: protocol for a scoping review.

INTRODUCTION: Randomised controlled trials (RCTs) aim to assess the effect of one (or more) unproven health interventions relative to other reference interventions. RCTs sometimes use an ordinal outcome, which is an endpoint that comprises of multiple, monotonically ordered categories that are not necessarily separated by a quantifiable distance. Ordinal outcomes are appealing in clinical settings as specific disease states can represent meaningful categories that may be of clinical importance to researchers. Ordinal outcomes can also retain information and increase statistical power compared to dichotomised outcomes and can allow multiple clinical outcomes to be comprised in a single endpoint. Target parameters for ordinal outcomes in RCTs may vary depending on the nature of the research question, the modelling assumptions and the expertise of the data analyst. The aim of this scoping review is to systematically describe the use of ordinal outcomes in contemporary RCTs. Specifically, we aim to: [Formula: see text] Identify which target parameters are of interest in trials that use an ordinal outcome, and whether these parameters are explicitly defined. [Formula: see text] Describe how ordinal outcomes are analysed in RCTs to estimate a treatment effect. [Formula: see text] Describe whether RCTs that use an ordinal outcome adequately report key methodological aspects specific to the analysis of the ordinal outcome. Results from this review will outline the current state of practice of the use of ordinal outcomes in RCTs. Ways to improve the analysis and reporting of ordinal outcomes in RCTs will be discussed. METHODS AND ANALYSIS: We will review RCTs that are published in the top four medical journals (British Medical Journal, New England Journal of Medicine, The Lancet and the Journal of the American Medical Association) between 1 January 2012 and 31 July 2022 that use an ordinal outcome as either a primary or a secondary outcome. The review will identify articles through a PubMed-specific search strategy. Our review will adhere to guidelines for scoping reviews as described in the PRISMA-ScR checklist. The study characteristics and details of the study design and analysis, including the target parameter(s) and statistical methods used to analyse the ordinal outcome, will be extracted from eligible studies. The screening, review and data extraction will be conducted using Covidence, a web-based tool for managing systematic reviews. The data will be summarised using descriptive statistics.

Immune profiling of SARS-CoV-2 infection during pregnancy reveals NK cell and γδ T cell perturbations.

Pregnancy poses a greater risk for severe COVID-19; however, underlying immunological changes associated with SARS-CoV-2 during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in unvaccinated pregnant and nonpregnant women with acute and convalescent COVID-19, quantifying 217 immunological parameters. Humoral responses to SARS-CoV-2 were similar in pregnant and nonpregnant women, although our systems serology approach revealed distinct antibody and FcγR profiles between pregnant and nonpregnant women. Cellular analyses demonstrated marked differences in NK cell and unconventional T cell activation dynamics in pregnant women. Healthy pregnant women displayed preactivated NK cells and γδ T cells when compared with healthy nonpregnant women, which remained unchanged during acute and convalescent COVID-19. Conversely, nonpregnant women had prototypical activation of NK and γδ T cells. Activation of CD4+ and CD8+ T cells and T follicular helper cells was similar in SARS-CoV-2-infected pregnant and nonpregnant women, while antibody-secreting B cells were increased in pregnant women during acute COVID-19. Elevated levels of IL-8, IL-10, and IL-18 were found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, we demonstrate perturbations in NK cell and γδ T cell activation in unvaccinated pregnant women with COVID-19, which may impact disease progression and severity during pregnancy.

Collaborative maternity and newborn dashboard (CoMaND) for the COVID-19 pandemic: a protocol for timely, adaptive monitoring of perinatal outcomes in Melbourne, Australia.

BACKGROUND: The COVID-19 pandemic has resulted in a range of unprecedented disruptions to maternity care with documented impacts on perinatal outcomes such as stillbirth and preterm birth. Metropolitan Melbourne has endured one of the longest and most stringent lockdowns in globally. This paper presents the protocol for a multicentre study to monitor perinatal outcomes in Melbourne, Australia, during the COVID-19 pandemic. METHODS: Multicentre observational study analysing monthly deidentified maternal and newborn outcomes from births >20 weeks at all 12 public maternity services in Melbourne. Data will be merged centrally to analyse outcomes and create run charts according to established methods for detecting non-random 'signals' in healthcare. Perinatal outcomes will include weekly rates of total births, stillbirths, preterm births, neonatal intensive care admissions, low Apgar scores and fetal growth restriction. Maternal outcomes will include weekly rates of: induced labour, caesarean section, births before arrival to hospital, postpartum haemorrhage, length of stay, general anaesthesia for caesarean birth, influenza and COVID-19 vaccination status, and gestation at first antenatal visit. A prepandemic median for all outcomes will be calculated for the period of January 2018 to March 2020. A significant shift is defined as ≥6 consecutive weeks, all above or below the prepandemic median. Additional statistical analyses such as regression, time series and survival analyses will be performed for an in-depth examination of maternal and perinatal outcomes of interests. ETHICS AND DISSEMINATION: Ethics approval for the collaborative maternity and newborn dashboard project has been obtained from the Austin Health (HREC/64722/Austin-2020) and Mercy Health (ref. 2020-031). TRIAL REGISTRATION NUMBER: ACTRN12620000878976; Pre-results.

Sex differences in modulation of fetoplacental vascular resistance in growth-restricted mouse fetuses following betamethasone administration: comparisons with human fetuses.

BACKGROUND: Maternally administered corticosteroids are routinely used to accelerate fetal lung maturation in pregnancies at risk of early preterm delivery. Although, among the subgroup with growth restriction, a majority show a temporary improvement in umbilical artery Doppler waveforms that may be sustained up to 7 days, a minority will acutely decompensate in response to corticosteroids in association with deteriorating umbilical and fetal Doppler waveforms. The basis for such acute Doppler changes is presently unknown. Our group has developed a noninvasive ultrasound methodology to measure wave reflections in the umbilical artery and have established that wave reflection metrics are sensitive to structural changes in the placental vasculature and to acute changes in vascular tone. Using this approach, we demonstrated in healthy pregnant mice that fetoplacental vascular resistance decreased in betamethasone-treated mice compared with saline-treated controls. OBJECTIVE: This study aimed to investigate the effects of betamethasone administration on the wave reflection metrics in a mouse model of fetal growth restriction and to compare these findings with equivalent measurements in human fetuses. STUDY DESIGN: Pregnant CD-1 mice were housed from embryonic day 14.5 to embryonic day 17.5 in either a normoxic (21% O2, n=24) or hypoxic environment (11% O2, n=22), the latter being an established mouse model of fetal growth restriction. To investigate the effect of maternally administered betamethasone on the fetoplacental vasculature, ultrasound imaging was performed at baseline and 4 hours after treatment (either betamethasone or sterile saline). Umbilical artery wave reflection metrics were compared between the groups and for the effect of fetal sex. In addition, a cohort of 10 pregnant women with elevated umbilical artery pulsatility index and evidence of fetal growth restriction and 6 controls were imaged before and after corticosteroid administration. RESULTS: In the mouse model, after betamethasone administration, the female fetuses from the hypoxia group showed a 15% increase in umbilical artery diameter, a 98% increase in umbilical artery blood flow, and a 27% decrease in umbilical artery reflection coefficient, whereas the males from the hypoxia group showed no substantial changes. In agreement with our mouse findings, umbilical artery reflections were found to be larger in human growth-restricted fetuses than controls in women at risk of preterm birth. CONCLUSION: Our studies provide insight into the mechanism whereby the human growth-restricted fetus may exhibit a temporary favorable fetoplacental vascular response to maternally administered corticosteroids. Further investigations are needed to understand why the male growth-restricted fetus seems unable to mount this favorable vascular response.

Sex differences in uterine artery Doppler during gestation in pregnancies complicated by placental dysfunction.

BACKGROUND: There is growing evidence of sex differences in placental vascular development. The objective of this study was to investigate the effect of fetal sex on uterine artery pulsatility index (PI) throughout gestation in a cohort of normal and complicated pregnancies. METHODS: A prospective longitudinal study was conducted in 240 pregnant women. Pulsed wave Doppler ultrasound of the proximal uterine arteries was performed at a 4-weekly interval between 14 and 40 weeks of gestation. The patients were classified retrospectively as normal or complicated (one or more of maternal preeclampsia, preterm birth, or small for gestational age). To assess if the change in uterine artery PI during gestation differed between normal and complicated pregnancies and between fetal sexes, the uterine artery PI was modeled using a linear function of gestational age and the rate of change was estimated from the slope. RESULTS: While the uterine artery PI did not differ over gestation between females and males for normal pregnancies, the trajectory of this index differed by fetal sex for pregnancies complicated by either preeclampsia, preterm birth, or fetal growth restriction (p < 0.0001). The male fetuses in the complicated pregnancy group had an elevated slope compared to the other groups (p < 0.0001), suggesting a more progressive deterioration in uteroplacental perfusion over gestation. CONCLUSIONS: The uterine artery PI is widely used to assess uteroplacental function in clinical settings. The observation that this metric changes more rapidly in complicated pregnancies where the fetus was male highlights the importance of sex when interpreting hemodynamic markers of placental maturation.

Sex differences in fetal Doppler parameters during gestation.

BACKGROUND: Fetal sex is known to affect pregnancy outcomes. In current clinical practice, monitoring of fetal well-being is based on Doppler ultrasound measurements of major placental and fetal vessels. The objective of this study was to investigate the effect of fetal sex on Doppler parameters throughout gestation in healthy pregnancy. METHODS: A prospective study was conducted in 240 pregnant women with ultrasound examinations at a 4-weekly interval between 12 and 38 weeks of gestation. Pulsed Doppler spectra were collected for the umbilical arteries (UAs), middle cerebral artery (MCA), descending abdominal aorta (DAo), and ductus venosus (DV). Linear mixed effects models were used to determine if the pulsatility indices (PIs) of these vessels depended on gestational age and fetal sex. RESULTS: While there were no differences in the MCA PI and DV PIV over gestation between female and male fetuses, the trajectory of the UA and DAo PIs differed by fetal sex (p = 0.02 and p = 0.01, respectively). CONCLUSIONS: Doppler ultrasound parameters were found to be dependent on fetal sex for some vessels and not for others in healthy pregnancies. Further investigations are needed to understand the physiological mechanisms for these sex differences and the relevance for disease processes in pregnancy.

Wave reflections in the umbilical artery measured by Doppler ultrasound as a novel predictor of placental pathology.

BACKGROUND: The umbilical artery (UA) Doppler pulsatility index is used clinically to detect elevated feto-placental vascular resistance. However, this metric is confounded by variation in fetal cardiac function and is only moderately predictive of placental pathology. Our group developed a novel ultrasound methodology that measures wave reflections in the UA, thereby isolating a component of the Doppler signal that is specific to the placenta. The present study examined whether wave reflections in the UA are predictive of placental vascular pathology. METHODS: Standard clinical Doppler ultrasound of the UAs was performed in 241 pregnant women. Of these, 40 women met narrowly defined preset criteria for the control group, 36 had maternal vascular malperfusion (MVM) and 16 had fetal vascular malperfusion (FVM). Using a computational procedure, the Doppler waveforms were decomposed into a pair of forward and backward propagating waves. FINDINGS: Compared to controls, wave reflections were significantly elevated in women with either MVM (p<0.0001) or FVM pathology (p = 0.02). In contrast, the umbilical and uterine artery pulsatility indices were only elevated in the MVM group (p<0.0001) and there were no differences between women with FVM and the controls. INTERPRETATION: The measurement of wave reflections in the UA, combined with standard clinical ultrasound parameters, has the potential to improve the diagnostic performance of UA Doppler to detect placental vascular pathology. Identifying women with FVM pathology is particularly challenging prenatally and future investigations will determine if women at risk of this specific placental disease could benefit from this novel diagnostic technique.