Publications by Year: 2023

BACKGROUND: Preterm birth remains a major public health issue affecting 10% of all pregnancies and increases risks of neonatal morbidity and mortality. Approximately 50% to 60% of preterm births are spontaneous, resulting from preterm premature rupture of membranes or preterm labor. The pathogenesis of spontaneous preterm birth is incompletely understood, and prediction of preterm birth remains elusive. Accurate prediction of preterm birth would reduce infant morbidity and mortality through targeted patient referral to hospitals equipped to care for preterm infants. Two previous studies have analyzed cervical microRNAs in association with spontaneous preterm birth and the length of gestation, but the extent to which microRNAs serve as predictive biomarkers remains unknown.

OBJECTIVE: This study aimed to examine associations between cervical microRNA expression and spontaneous preterm birth, with the specific goal of identifying a subset of microRNAs that predict spontaneous preterm birth.

STUDY DESIGN: We performed a prospective, nested, case-control study of 25 cases with spontaneous preterm birth and 49 term controls. Controls were matched to cases in a 2:1 ratio on the basis of age, parity, and self-identified race. Cervical swabs were collected at a mean gestational age of 17.1 (4.8) weeks of gestation, and microRNAs were analyzed using a quantitative polymerase chain reaction array. Normalized microRNA expression was compared between cases and controls, and a false discovery rate of 0.2 was applied to account for multiple comparisons. Histopathologic analysis of slides of cervical swab samples was performed to quantify leukocyte burden for adjustment in conditional regression models. We explored the use of Relief-based unsupervised identification of top microRNAs and support vector machines to predict spontaneous preterm birth. We performed microRNA enrichment analysis to explore potential biologic targets and pathways in which up-regulated microRNAs might be involved.

RESULTS: Of the 754 microRNAs on the polymerase chain reaction array, 346 were detected in ≥75% of participants' cervical swabs. Average cervical microRNA expression was significantly higher in cases of spontaneous preterm birth than in controls (P=.01). There were 95 significantly up-regulated individual microRNAs (>2-fold change) in cases of subsequent spontaneous preterm birth compared with term controls (P<.05; q<0.2). Notably, miR-143, miR-30e-3p, and miR-199b were all significantly up-regulated, which is consistent with the 1 previous study of cervical microRNA and spontaneous preterm birth. A Relief-based, novel variable (feature) selection machine learning approach had low-to-moderate prediction accuracy, with an area under the receiver operating curve of 0.71. Enrichment analysis revealed that identified microRNAs may modulate inflammatory cell signaling.

CONCLUSION: In this prospective nested case-control study of cervical microRNA expression and spontaneous preterm birth, we identified a global increase in microRNA expression and up-regulation of 95 distinct microRNAs in association with subsequent spontaneous preterm birth. Larger and more diverse studies are required to determine the ability of microRNAs to accurately predict spontaneous preterm birth, and mechanistic work to facilitate development of novel therapeutic interventions to prevent spontaneous preterm birth is warranted.

The COVID-19 pandemic has generated an unprecedented amount of novel and repurposed vaccines and therapeutics that have been rapidly developed and implemented into clinical use. Unfortunately, pregnant persons have been excluded from most phase III clinical studies; therefore, our understanding regarding their safety for use in this population stems from understanding of theoretic risks and observational data. In this review, the authors discuss pregnancy-specific considerations for COVID-19 therapeutics.

Conventional and regulatory T cells (Treg) are dynamic mediators of maternal immune tolerance to the developing feto-placental unit. Functional evaluation of T cells at the maternal-fetal interface is crucial to elucidate the immunologic basis of obstetric complications. Our objective was to define the T cell phenotype and function of uterine intervillous blood (IVB) in pregnancy with and without preeclampsia. We hypothesize that preeclampsia is associated with impaired immune tolerance and a pro-inflammatory uterine T cell microenvironment. In this cross-sectional study, maternal peripheral blood (PB) and uterine IVB (obtained from the surgical sponge used to clean the placental bed during cesarean delivery) were collected from participants with and without preeclampsia. Proportion, activation, and cytokine production of T cell subsets were quantified by flow cytometry. T cell parameters were compared by tissue source and by preeclampsia status. Sixty participants, 26 with preeclampsia, were included. Induced Treg made up a greater proportion of IVB T cells compared to PB and had greater cytokine-producing capacity. Preeclampsia was associated with increased ratio of pro-inflammatory IL-17α to suppressive IL-10 cytokine production by CD4 T cell subsets in IVB, but not in PB. Human uterine IVB is composed of activated, cytokine-producing T cell subsets distinct from maternal PB. Preeclampsia is associated with a pro-inflammatory IVB profile, with increased IL-17α /IL-10 ratio in all CD4 T cell subsets. IVB sampling is a useful tool for investigating human T cell biology at the maternal-fetal interface that may inform immunotherapeutic strategies for preeclampsia.

The SARS-CoV-2 Omicron variant has continued to evolve. XBB is a recombinant between two BA.2 sublineages, XBB.1 includes the G252V mutation, and XBB.1.5 includes the G252V and F486P mutations. XBB.1.5 has rapidly increased in frequency and has become the dominant virus in New England. The bivalent mRNA vaccine boosters have been shown to increase neutralizing antibody (NAb) titers to multiple variants, but the durability of these responses remains to be determined. We assessed humoral and cellular immune responses in 30 participants who received the bivalent mRNA boosters and performed assays at baseline prior to boosting, at week 3 after boosting, and at month 3 after boosting. Our data demonstrate that XBB.1.5 substantially escapes NAb responses but not T cell responses after bivalent mRNA boosting. NAb titers to XBB.1 and XBB.1.5 were similar, suggesting that the F486P mutation confers greater transmissibility but not increased immune escape. By month 3, NAb titers to XBB.1 and XBB.1.5 declined essentially to baseline levels prior to boosting, while NAb titers to other variants declined less strikingly.

PURPOSE: In the US, preterm birth (PTB) is 55% more common among Black compared to White individuals and psychosocial stressors may contribute. Resilience is associated with improved health outcomes; whether it modifies PTB inequity is unknown. We hypothesized high resilience would reduce inequities in PTB risk.

METHODS: This study analyzes data from 535 pregnancies among Black (n = 101, 19%) and White (n = 434, 81%) participants from a prospective cohort. Participants completed the Connor-Davidson Resilience Scale. We calculated risk ratios (RR) stratified by resilience tertiles to test for effect measure modification.

RESULTS: Among those in the lowest resilience tertile, there were six (20.7%) PTBs among Black and seven (4.9%) among White participants (RR: 4.26; 95% confidence interval (CI): 1.53, 11.81). Among those in the highest resilience tertile, there were 8 (18.2%) PTBs among Black and 14 (9.5%) among White participants (RR: 1.92; 95% CI: 0.87, 4.24. The adjusted Black:White RR was 2.00 (95% CI 0.47, 8.64) in the lowest and 3.49 (95% CI 1.52, 8.01) in the highest tertile.

CONCLUSIONS: Black-White PTB inequity did not differ among resilience strata and remained significant in the highest tertile. Our findings suggest that high resilience is inadequate to overcome Black:White racial inequity in PTB.

The number of mutations in the omicron (B.1.1.529) BA.1 variant of concern led to an unprecedented evasion of vaccine induced immunity. However, despite rise in global infections, severe disease did not increase proportionally and is likely linked to persistent recognition of BA.1 by T cells and non-neutralizing opsonophagocytic antibodies. Yet, the emergence of new sublineage BA.2, which is more transmissible than BA.1 despite relatively preserved neutralizing antibody responses, has raised the possibility that BA.2 may evade other vaccine-induced responses. Here, we comprehensively profiled the BNT162b2 vaccine-induced response to several VOCs, including omicron BA.1 and BA.2. While vaccine-induced immune responses were compromised against both omicron sublineages, vaccine-induced antibody isotype titers, and non-neutralizing Fc effector functions were attenuated to the omicron BA.2 spike compared to BA.1. Conversely, FcγR2a and FcγR2b binding was elevated to BA.2, albeit lower than BA.1 responses, potentially contributing to persistent protection against severity of disease.

Thrombosis with thrombocytopenia syndrome (TTS) is a rare but potentially severe adverse event following immunization with adenovirus vector-based COVID-19 vaccines such as Ad26.COV2.S (Janssen) and ChAdOx1 (AstraZeneca). However, no case of TTS has been reported in over 1.5 million individuals who received a second immunization with Ad26.COV2.S in the United States. Here we utilize transcriptomic and proteomic profiling to compare individuals who receive two doses of Ad26.COV2.S with those vaccinated with BNT162b2 or mRNA-1273. Initial Ad26.COV2.S vaccination induces transient activation of platelet and coagulation and innate immune pathways that resolve by day 7; by contrast, patients with TTS show robust upregulation of these pathways on days 15-19 following initial Ad26.COV2.S vaccination. Meanwhile, a second immunization or a reduced initial dose of Ad26.COV2.S induces lower activation of these pathways than does the full initial dose. Our data suggest a role of coagulation and proinflammatory pathways in TTS pathogenesis, which may help optimize vaccination regimens to reduce TTS risk.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variant BA.2.86 has over 30 mutations in spike compared with BA.2 and XBB.1.5, which raised the possibility that BA.2.86 might evade neutralizing antibodies (NAbs) induced by vaccination or infection. In this study, we show that NAb titers are substantially lower to BA.2.86 compared with BA.2 but are similar or slightly higher than to other current circulating variants, including XBB.1.5, EG.5.1, and FL.1.5.1. Moreover, NAb titers against all these variants were higher in vaccinated individuals with a history of XBB.1.5 infection compared with vaccinated individuals with no history of XBB.1.5 infection, suggesting the potential utility of the monovalent XBB.1.5 mRNA boosters.