Publications

BACKGROUND: A cluster of over a thousand infections with the SARS-CoV-2 delta variant was identified in a predominantly fully vaccinated population in Provincetown, Massachusetts in July 2021. Immune responses in breakthrough infections with the SARS-CoV-2 delta variant remain to be defined.

METHODS: Humoral and cellular immune responses were assessed in 35 vaccinated individuals who were tested for SARS-CoV-2 in the Massachusetts Department of Public Health outbreak investigation.

RESULTS: Vaccinated individuals who tested positive for SARS-CoV-2 demonstrated substantially higher antibody responses than vaccinated individuals who tested negative for SARS-CoV-2, including 28-fold higher binding antibody titers and 34-fold higher neutralizing antibody titers against the SARS-CoV-2 delta variant. Vaccinated individuals who tested positive also showed 4.4-fold higher Spike-specific CD8+ T cell responses against the SARS-CoV-2 delta variant than vaccinated individuals who tested negative.

CONCLUSIONS: Fully vaccinated individuals developed robust anamnestic antibody and T cell responses following infection with the SARS-CoV-2 delta variant. These data suggest important immunologic benefits of vaccination in the context of breakthrough infections.

Antibody transfer via breastmilk represents an evolutionary strategy to boost immunity in early life. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies have been observed in the breastmilk, the functional quality of these antibodies remains unclear. Here, we apply systems serology to characterize SARS-CoV-2-specific antibodies in maternal serum and breastmilk to compare the functional characteristics of antibodies in these fluids. Distinct SARS-CoV-2-specific antibody responses are observed in the serum and breastmilk of lactating individuals previously infected with SARS-CoV-2, with a more dominant transfer of immunoglobulin A (IgA) and IgM into breastmilk. Although IgGs are present in breastmilk, they are functionally attenuated. We observe preferential transfer of antibodies capable of eliciting neutrophil phagocytosis and neutralization compared to other functions, pointing to selective transfer of certain functional antibodies to breastmilk. These data highlight the preferential transfer of SARS-CoV-2-specific IgA and IgM to breastmilk, accompanied by select IgG subpopulations, positioned to create a non-pathologic but protective barrier against coronavirus disease 2019 (COVID-19).

OBJECTIVE: Compare the incidence of hypoglycemia in neonates born to patients with diabetes, based on last maternal glucose before delivery.

STUDY DESIGN: Cohort of singleton births from individuals with pregestational and gestational diabetes (GDM) from 2017 to 2019.

RESULTS: We included 853 deliveries. Maternal hyperglycemia before delivery was associated with 1.8-fold greater risk of neonatal hypoglycemia (glucose < 45 mg/dL) in patients with GDM on medication (adjusted risk ratio (aRR): 1.8; 95% CI: 1.1-2.7), compared with euglycemia. This association was not seen in diet-controlled GDM (0.5; 0.23-1.1), nor in Type 1 (1.1; 0.88-1.4), or Type 2 pregestational diabetes (1.1; 0.61-1.9). Further, pregestational diabetes, compared to GDM, regardless of intrapartum maternal glucose control, was associated with neonatal hypoglycemia and NICU admission.

CONCLUSION: Maternal hyperglycemia before delivery only carried a higher risk of neonatal hypoglycemia in those with GDM on medications. Other interventions to reduce neonatal hypoglycemia are needed.

BACKGROUND: The COVID-19 pandemic caused by the SARS-CoV-2 has increased the demand for inpatient healthcare resources; however, approximately 80% of patients with COVID-19 have a mild clinical presentation and can be managed at home.

OBJECTIVE: This study aimed to describe the feasibility and clinical and process outcomes associated with a multidisciplinary telemedicine surveillance model to triage and manage obstetrical patients with known exposures and symptoms of COVID-19.

STUDY DESIGN: We implemented a multidisciplinary telemedicine surveillance model with obstetrical physicians and nurses to standardize ambulatory care for obstetrical patients with confirmed or suspected COVID-19 based on the symptoms or exposures at an urban academic tertiary care center with multiple hospital-affiliated and community-based practices. All pregnant or postpartum patients with COVID-19 symptoms, exposures, or hospitalization were eligible for inclusion in the program. Patients were assessed by means of regular nursing phone calls and were managed according to illness severity. Patient characteristics and clinical and process outcomes were abstracted from the electronic medical record.

RESULTS: A total of 135 patients were enrolled in the multidisciplinary telemedicine model from March 17 to April 19, 2020, of whom 130 were pregnant and 5 were recently postpartum. In this study, 116 of 135 patients (86%) were managed solely in the outpatient setting and did not require an in-person evaluation; 9 patients were ultimately admitted after ambulatory or urgent evaluations, and 10 patients were observed after hospital discharge. Although only 50% of the patients were tested secondary to limitations in ambulatory testing, 1 in 3 of those patients received positive results for SARS-CoV-2 (N=22, 16% of entire cohort). Patients were enrolled in the telemedicine model for a median of 7 days (interquartile range, 4-8) and averaged 1 phone call daily, resulting in 891 nursing calls and 20 physician calls over 1 month.

CONCLUSION: A multidisciplinary telemedicine surveillance model for outpatient management of obstetrical patients with COVID-19 symptoms and exposures is feasible and resulted in rates of ambulatory management similar to those seen in nonpregnant patients. A centralized model for telemedicine surveillance of obstetrical patients with COVID-19 symptoms may preserve inpatient resources and prevent avoidable staff and patient exposures, particularly in centers with multiple ambulatory practice settings.

PROBLEM: Evaluation of Zika virus (ZIKV)-specific humoral and cellular immune response in pregnant women exposed to ZIKV.

METHOD OF STUDY: In this observational, prospective cohort study, we recruited pregnant women presenting for prenatal ultrasound for ZIKV exposure at a single academic teaching hospital in Boston, MA from November 2016 to December 2018. We collected blood, urine, and cervicovaginal swabs antepartum, intrapartum, and postpartum; and cord blood and placenta at delivery. We used experimental assays to calculate quantitative viral loads, ZIKV-specific immunoglobulin titers, and ZIKV-specific T-cell responses.

RESULTS: We enrolled 22 participants, three of which had serologic-confirmed ZIKV infection. No participants demonstrated sustained ZIKV shedding. ZIKV-specific IgG/IgM antibody was sustained throughout pregnancy and postpartum. ZIKV envelope and capsid-specific T-cell responses were also observed, albeit inconsistent. No newborns in this cohort had congenital Zika syndrome. Infant cord blood of infected mothers exhibited ZIKV-specific IgG, but not IgM antibodies.

CONCLUSION: We detected a robust, prolonged maternal humoral immune response to ZIKV during pregnancy and postpartum. We also demonstrated evidence for efficient transplacental antibody transfer from mother to infant at birth, supporting the importance of neonatal passive immunity to ZIKV. Maternal T-cell responses were less consistent among pregnant women infected with ZIKV.

IMPORTANCE: Biological data are lacking with respect to risk of vertical transmission and mechanisms of fetoplacental protection in maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

OBJECTIVE: To quantify SARS-CoV-2 viral load in maternal and neonatal biofluids, transplacental passage of anti-SARS-CoV-2 antibody, and incidence of fetoplacental infection.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study was conducted among pregnant women presenting for care at 3 tertiary care centers in Boston, Massachusetts. Women with reverse transcription-polymerase chain reaction (RT-PCR) results positive for SARS-CoV-2 were recruited from April 2 to June 13, 2020, and follow-up occurred through July 10, 2020. Contemporaneous participants without SARS-CoV-2 infection were enrolled as a convenience sample from pregnant women with RT-PCR results negative for SARS-CoV-2.

EXPOSURES: SARS-CoV-2 infection in pregnancy, defined by nasopharyngeal swab RT-PCR.

MAIN OUTCOMES AND MEASURES: The main outcomes were SARS-CoV-2 viral load in maternal plasma or respiratory fluids and umbilical cord plasma, quantification of anti-SARS-CoV-2 antibodies in maternal and cord plasma, and presence of SARS-CoV-2 RNA in the placenta.

RESULTS: Among 127 pregnant women enrolled, 64 with RT-PCR results positive for SARS-CoV-2 (mean [SD] age, 31.6 [5.6] years) and 63 with RT-PCR results negative for SARS-CoV-2 (mean [SD] age, 33.9 [5.4] years) provided samples for analysis. Of women with SARS-CoV-2 infection, 23 (36%) were asymptomatic, 22 (34%) had mild disease, 7 (11%) had moderate disease, 10 (16%) had severe disease, and 2 (3%) had critical disease. In viral load analyses among 107 women, there was no detectable viremia in maternal or cord blood and no evidence of vertical transmission. Among 77 neonates tested in whom SARS-CoV-2 antibodies were quantified in cord blood, 1 had detectable immunoglobuilin M to nucleocapsid. Among 88 placentas tested, SARS-CoV-2 RNA was not detected in any. In antibody analyses among 37 women with SARS-CoV-2 infection, anti-receptor binding domain immunoglobin G was detected in 24 women (65%) and anti-nucleocapsid was detected in 26 women (70%). Mother-to-neonate transfer of anti-SARS-CoV-2 antibodies was significantly lower than transfer of anti-influenza hemagglutinin A antibodies (mean [SD] cord-to-maternal ratio: anti-receptor binding domain immunoglobin G, 0.72 [0.57]; anti-nucleocapsid, 0.74 [0.44]; anti-influenza, 1.44 [0.80]; P < .001). Nonoverlapping placental expression of SARS-CoV-2 receptors angiotensin-converting enzyme 2 and transmembrane serine protease 2 was noted.

CONCLUSIONS AND RELEVANCE: In this cohort study, there was no evidence of placental infection or definitive vertical transmission of SARS-CoV-2. Transplacental transfer of anti-SARS-CoV-2 antibodies was inefficient. Lack of viremia and reduced coexpression and colocalization of placental angiotensin-converting enzyme 2 and transmembrane serine protease 2 may serve as protective mechanisms against vertical transmission.

The rising trend in pregnancy-related deaths during the past 2 decades in the United States stands out among other high-income countries where pregnancy-related deaths are declining. Cardiomyopathy and other cardiovascular conditions, hemorrhage, and other chronic medical conditions are all important causes of death. Unintentional death from violence, overdose, and self-harm are emerging causes that require medical and public health attention. Significant racial/ethnic inequities exist in pregnancy care with non-Hispanic black women incurring 3 to 4 times higher rates of pregnancy-related death than non-Hispanic white women. Varied terminology and lack of standardized methods for identifying maternal deaths in the United States have resulted in nuanced data collection and interpretation challenges. State maternal mortality review committees are important mechanisms for capturing and interpreting data on cause, timing, and preventability of maternal deaths. Importantly, a thorough standardized review of each maternal death leads to recommendations to prevent future pregnancy-associated deaths. Key interventions to improve maternal health outcomes include 1) integrating multidisciplinary care for women with high-risk comorbidities during preconception care, pregnancy, postpartum, and beyond; 2) addressing structural racism and the social determinants of health; 3) implementing hospital-wide safety bundles with team training and simulation; 4) providing patient education on early warning signs for medical complications of pregnancy; and 5) regionalizing maternal levels of care so that women with risk factors are supported when delivering at facilities with specialized care teams.

OBJECTIVE: To investigate characteristics of receiving a medical evaluation for infertility among infertile women.

DESIGN: Prospective cohort.

SETTING: Academic institution.

PATIENT(S): A total of 7,422 women who reported incident infertility between 1989 and 2009 in the Nurses' Health Study II.

INTERVENTION(S): None.

MAIN OUTCOME MEASURE(S): Report of receiving a medical evaluation for infertility.

RESULT(S): Approximately 65% of women who reported infertility had a medical evaluation for infertility. Infertile women who were parous (relative risk [RR] = 0.81, 95% confidence interval [CI] 0.78-0.84), older, current smokers (RR = 0.89, 95% CI 0.83-0.96), or who had a higher body mass index (BMI) were less likely to report receiving a medical infertility evaluation. Infertile women who exercised frequently, took multivitamins (RR = 1.03, 95% CI 1.00-1.07), lived in states with comprehensive insurance coverage (RR = 1.09, 95% CI 1.00-1.19), had a high household income, or who had a recent physical examination (RR = 1.15, 95% CI 1.06-1.24) were more likely to report receiving a medical infertility evaluation.

CONCLUSION(S): These findings highlight demographic, lifestyle, and access barriers to receiving medical infertility care. Historically, the discussion of barriers to infertility care has centered on financial access, geographic access, and socioeconomic status. Our findings build off literature by supporting previously reported associations and showcasing the importance of demographic and lifestyle factors in accessing care.

Fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs) are nonhematopoietic stromal cells of lymphoid organs. They influence the migration and homeostasis of naive T cells; however, their influence on activated T cells remains undescribed. Here we report that FRCs and LECs inhibited T cell proliferation through a tightly regulated mechanism dependent on nitric oxide synthase 2 (NOS2). Expression of NOS2 and production of nitric oxide paralleled the activation of T cells and required a tripartite synergism of interferon-γ, tumor necrosis factor and direct contact with activated T cells. Notably, in vivo expression of NOS2 by FRCs and LECs regulated the size of the activated T cell pool. Our study elucidates an as-yet-unrecognized role for the lymph node stromal niche in controlling T cell responses.

Lymph node stromal cells (LNSCs) can induce potent, antigen-specific T cell tolerance under steady-state conditions. Although expression of various peripheral tissue-restricted antigens (PTAs) and presentation to naive CD8+ T cells has been demonstrated, the stromal subsets responsible have not been identified. We report that fibroblastic reticular cells (FRCs), which reside in the T cell zone of the LN, ectopically express and directly present a model PTA to naive T cells, inducing their proliferation. However, we found that no single LNSC subset was responsible for PTA expression; rather, each subset had its own characteristic antigen display. Studies to date have concentrated on PTA presentation under steady-state conditions; however, because LNs are frequently inflammatory sites, we assessed whether inflammation altered stromal cell-T cell interactions. Strikingly, FRCs showed reduced stimulation of T cells after Toll-like receptor 3 ligation. We also characterize an LNSC subset expressing the highest levels of autoimmune regulator, which responds potently to bystander inflammation by up-regulating PTA expression. Collectively, these data show that diverse stromal cell types have evolved to constitutively express PTAs, and that exposure to viral products alters the interaction between T cells and LNSCs.