Maternal SARS-CoV-2 impacts fetal placental macrophage programs and placenta-derived microglial models of neurodevelopment.

BACKGROUND: The SARS-CoV-2 virus activates maternal and placental immune responses. Such activation in the setting of other infections during pregnancy is known to impact fetal brain development. The effects of maternal immune activation on neurodevelopment are mediated at least in part by fetal brain microglia. However, microglia are inaccessible for direct analysis, and there are no validated non-invasive surrogate models to evaluate in utero microglial priming and function. We have previously demonstrated shared transcriptional programs between microglia and Hofbauer cells (HBCs, or fetal placental macrophages) in mouse models. METHODS AND RESULTS: We assessed the impact of maternal SARS-CoV-2 on HBCs isolated from 24 term placentas (N = 10 SARS-CoV-2 positive cases, 14 negative controls). Using single-cell RNA-sequencing, we demonstrated that HBC subpopulations exhibit distinct cellular programs, with specific subpopulations differentially impacted by SARS-CoV-2. Assessment of differentially expressed genes implied impaired phagocytosis, a key function of both HBCs and microglia, in some subclusters. Leveraging previously validated models of microglial synaptic pruning, we showed that HBCs isolated from placentas of SARS-CoV-2 positive pregnancies can be transdifferentiated into microglia-like cells (HBC-iMGs), with impaired synaptic pruning behavior compared to HBC models from negative controls. CONCLUSION: These findings suggest that HBCs isolated at birth can be used to create personalized cellular models of offspring microglial programming.

Stratifying Risk for Postpartum Depression at Time of Hospital Discharge.

Objective: Postpartum depression (PPD) represents a major contributor to postpartum morbidity and mortality. Beyond efforts at routine screening, risk stratification models could enable more targeted interventions in settings with limited resources. Thus, we aimed to develop and estimate the performance of a generalizable risk stratification model for PPD in patients without a history of depression using information collected as part of routine clinical care. Methods: We performed a retrospective cohort study of all individuals who delivered between 2017 and 2022 in one of two large academic medical centers and six community hospitals. An elastic net model was constructed and externally validated to predict PPD using sociodemographic factors, medical history, and prenatal depression screening information, all of which was known before discharge from the delivery hospitalization. Results: The cohort included 29,168 individuals; 2,703 (9.3%) met at least one criterion for postpartum depression in the 6 months following delivery. In the external validation data, the model had good discrimination and remained well-calibrated: area under the receiver operating characteristic curve 0.721 (95% CI: 0.707-0.734), Brier calibration score 0.088 (95% CI: 0.084 - 0.092). At a specificity of 90%, the positive predictive value was 28.0% (95% CI: 26.0-30.1%), and the negative predictive value was 92.2% (95% CI: 91.8-92.7%). Conclusions: These findings demonstrate that a simple machine-learning model can be used to stratify the risk for PPD before delivery hospitalization discharge. This tool could help identify patients within a practice at the highest risk and facilitate individualized postpartum care planning regarding the prevention of, screening for, and management of PPD at the start of the postpartum period and potentially the onset of symptoms.

Offspring cardiometabolic outcomes and postnatal growth trajectories after exposure to maternal SARS-CoV-2 infection.

OBJECTIVE: The objective of this study is to determine whether in utero exposure to SARS-CoV-2 is associated with increased risk for a cardiometabolic diagnosis by 18 months of age. METHODS: This retrospective electronic health record (EHR)-based cohort study included the live-born offspring of all individuals who delivered during the COVID-19 pandemic (April 1, 2020-December 31, 2021) at eight hospitals in Massachusetts. Offspring exposure was defined as a positive maternal SARS-CoV-2 polymerase chain reaction test during pregnancy. The primary outcome was presence of an ICD-10 code for a cardiometabolic disorder in offspring EHR by 18 months. Weight-, length-, and BMI-for-age z scores were calculated and compared at 6-month intervals from birth to 18 months. RESULTS: A total of 29,510 offspring (1599 exposed and 27,911 unexposed) were included. By 18 months, 6.7% of exposed and 4.4% of unexposed offspring had received a cardiometabolic diagnosis (crude odds ratio [OR] 1.47 [95% CI: 1.10 to 1.94], p = 0.007; adjusted OR 1.38 [1.06 to 1.77], p = 0.01). Exposed offspring had a significantly greater mean BMI-for-age z score versus unexposed offspring at 6 months (z score difference 0.19 [95% CI: 0.10 to 0.29], p < 0.001; adjusted difference 0.04 [-0.06 to 0.13], p = 0.4). CONCLUSIONS: Exposure to maternal SARS-CoV-2 infection was associated with an increased risk of receiving a cardiometabolic diagnosis by 18 months preceded by greater BMI-for-age at 6 months.

Placental transfer dynamics and durability of maternal COVID-19 vaccine-induced antibodies in infants.

Completion of a COVID-19 vaccination series during pregnancy effectively reduces COVID-19 hospitalization among infants less than 6 months of age. The dynamics of transplacental transfer of maternal vaccine-induced antibodies, and their persistence in infants at 2, 6, 9, and 12 months, have implications for new vaccine development and optimal timing of vaccine administration in pregnancy. We evaluated anti-COVID antibody IgG subclass, Fc-receptor binding profile, and activity against wild-type Spike and RBD plus five variants of concern (VOCs) in 153 serum samples from 100 infants. Maternal IgG1 and IgG3 responses persisted in 2- and 6-month infants to a greater extent than the other IgG subclasses, with high persistence of antibodies binding placental neonatal Fc-receptor and FcγR3A. Lowest persistence was observed against the Omicron RBD-specific region. Maternal vaccine timing, placental Fc-receptor binding capabilities, antibody subclass, fetal sex, and VOC all impact the persistence of antibodies in infants through 12 months of age.

Hofbauer cells and fetal brain microglia share transcriptional profiles and responses to maternal diet-induced obesity.

Maternal immune activation is associated with adverse offspring neurodevelopmental outcomes, many mediated by in utero microglial programming. As microglia remain inaccessible throughout development, identification of noninvasive biomarkers reflecting fetal brain microglial programming could permit screening and intervention. We used lineage tracing to demonstrate the shared ontogeny between fetal brain macrophages (microglia) and fetal placental macrophages (Hofbauer cells) in a mouse model of maternal diet-induced obesity, and single-cell RNA-seq to demonstrate shared transcriptional programs. Comparison with human datasets demonstrated conservation of placental resident macrophage signatures between mice and humans. Single-cell RNA-seq identified common alterations in fetal microglial and Hofbauer cell gene expression induced by maternal obesity, as well as sex differences in these alterations. We propose that Hofbauer cells, which are easily accessible at birth, provide insights into fetal brain microglial programs and may facilitate the early identification of offspring vulnerable to neurodevelopmental disorders.

Helping Us Grow Stronger (HUGS)/Abrazos: a community-based initiative improved perinatal mental health in an urban cohort.

BACKGROUND: Targeted programs aimed at improving maternal mental health, particularly among those exposed to social determinants of health, are increasingly critical since the onset of the COVID-19 pandemic, yet the impact of such programs is poorly understood. OBJECTIVE: This study aimed to evaluate the impact of a novel, language-concordant community-based program on perinatal mental health. STUDY DESIGN: We conducted a prospective cohort study of peripartum individuals referred to a new community-based intervention known as Helping Us Grow Stronger (HUGS/Abrazos). Participants received up to 4 remote sessions with a cognitive behavioral therapy trained social worker, up to 3 resource navigation sessions with a community health worker, and direct relief with a grocery gift card and care package. Before and after the program, participants completed validated survey instruments to assess mental health and social determinants of health. RESULTS: A total of 178 participants were assessed after program completion, including 133 who were assessed before and after the program. The cohort was composed of 62.9% Hispanic or Latinx participants with a mean age of 29.8 year (standard error of mean, 0.46). There were high rates of food insecurity (111/178; 62.4%), experiences of discrimination (119/178; 66.9%), and SARS-CoV-2 infection (105/178; 59.0%). The program was associated with statistically significant improvements in the Edinburgh Postnatal Depression scores (baseline [mean±standard error of mean], 8.44±0.55 vs 6.77±0.51 after program completion; P=.0001) and Perceived Stress Scale scores (baseline, 15.2±0.74 vs 14.0±0.71; P=.035). Participants exposed to stressors including food insecurity and experiences of discrimination had higher baseline depression, stress, and anxiety scores. Those with experiences of discrimination, food insecurity, and SARS-CoV-2 infection during pregnancy were more likely to have improvements in mental health scores postintervention. CONCLUSION: In this diverse urban cohort, a novel community-based intervention was associated with improvements in depressive symptoms, perceived stress, and anxiety, particularly among those with social determinants of health.

In Utero Exposure to Maternal SARS-CoV-2 Infection Is Associated With Higher Left Ventricular Mass in Toddlers.

The intrauterine environment plays a critical role in shaping chronic disease risk over the life course. We prospectively evaluated cardiometabolic outcomes in toddlers born to mothers with versus without prenatal severe acute respiratory syndrome coronavirus 2 infection. Children with in utero severe acute respiratory syndrome coronavirus 2 exposure had higher left ventricular mass in association with altered maternal immunologic indices.

SARS-CoV-2 infection elucidates unique features of pregnancy-specific immunity.

Pregnancy is a risk factor for increased severity of SARS-CoV-2 and other respiratory infections. The mechanisms underlying this risk have not been well-established, partly due to a limited understanding of how pregnancy shapes immune responses. To gain insight into the role of pregnancy in modulating immune responses at steady state and upon perturbation, we collected peripheral blood mononuclear cells (PBMC), plasma, and stool from 226 women, including 152 pregnant individuals (n = 96 with SARS-CoV-2 infection and n = 56 healthy controls) and 74 non-pregnant women (n = 55 with SARS-CoV-2 and n = 19 healthy controls). We found that SARS-CoV-2 infection was associated with altered T cell responses in pregnant compared to non-pregnant women. Differences included a lower percentage of memory T cells, a distinct clonal expansion of CD4-expressing CD8 + T cells, and the enhanced expression of T cell exhaustion markers, such as programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain-3 (Tim-3), in pregnant women. We identified additional evidence of immune dysfunction in severely and critically ill pregnant women, including a lack of expected elevation in regulatory T cell (Treg) levels, diminished interferon responses, and profound suppression of monocyte function. Consistent with earlier data, we found maternal obesity was also associated with altered immune responses to SARS-CoV-2 infection, including enhanced production of inflammatory cytokines by T cells. Certain gut bacterial species were altered in pregnancy and upon SARS-CoV-2 infection in pregnant individuals compared to non-pregnant women. Shifts in cytokine and chemokine levels were also identified in the sera of pregnant individuals, most notably a robust increase of interleukin-27 (IL-27), a cytokine known to drive T cell exhaustion, in the pregnant uninfected control group compared to all non-pregnant groups. IL-27 levels were also significantly higher in uninfected pregnant controls compared to pregnant SARS-CoV-2-infected individuals. Using two different preclinical mouse models of inflammation-induced fetal demise and respiratory influenza viral infection, we found that enhanced IL-27 protects developing fetuses from maternal inflammation but renders adult female mice vulnerable to viral infection. These combined findings from human and murine studies reveal nuanced pregnancy-associated immune responses, suggesting mechanisms underlying the increased susceptibility of pregnant individuals to viral respiratory infections.

Hofbauer cells and fetal brain microglia share transcriptional profiles and responses to maternal diet-induced obesity.

Maternal immune activation is associated with adverse offspring neurodevelopmental outcomes, many mediated by in utero microglial programming. As microglia remain inaccessible throughout development, identification of noninvasive biomarkers reflecting fetal brain microglial programming could permit screening and intervention. We used lineage tracing to demonstrate the shared ontogeny between fetal brain macrophages (microglia) and fetal placental macrophages (Hofbauer cells) in a mouse model of maternal diet-induced obesity, and single-cell RNA-seq to demonstrate shared transcriptional programs. Comparison with human datasets demonstrated conservation of placental resident macrophage signatures between mice and humans. Single-cell RNA-seq identified common alterations in fetal microglial and Hofbauer cell gene expression induced by maternal obesity, as well as sex differences in these alterations. We propose that Hofbauer cells, which are easily accessible at birth, provide novel insights into fetal brain microglial programs, and may facilitate the early identification of offspring vulnerable to neurodevelopmental disorders in the setting of maternal exposures.

Maternal SARS-CoV-2 impacts fetal placental macrophage programs and placenta-derived microglial models of neurodevelopment.

The SARS-CoV-2 virus activates maternal and placental immune responses, which in the setting of other infections occurring during pregnancy are known to impact fetal brain development. The effects of maternal immune activation on neurodevelopment are mediated at least in part by fetal brain microglia. However, microglia are inaccessible for direct analysis, and there are no validated non-invasive surrogate models to evaluate in utero microglial priming and function. We have previously demonstrated shared transcriptional programs between microglia and Hofbauer cells (HBCs, or fetal placental macrophages) in mouse models. Here, we assessed the impact of maternal SARS-CoV-2 on HBCs isolated from term placentas using single-cell RNA-sequencing. We demonstrated that HBC subpopulations exhibit distinct cellular programs, with specific subpopulations differentially impacted by SARS-CoV-2. Assessment of differentially expressed genes implied impaired phagocytosis, a key function of both HBCs and microglia, in some subclusters. Leveraging previously validated models of microglial synaptic pruning, we showed that HBCs isolated from placentas of SARS-CoV-2 positive pregnancies can be transdifferentiated into microglia-like cells, with altered morphology and impaired synaptic pruning behavior compared to HBC models from negative controls. These findings suggest that HBCs isolated at birth can be used to create personalized cellular models of offspring microglial programming.