Plasma sFlt-1/PlGF ratio of 11.5 multiples of median predicts preeclampsia with severe features within two weeks of testing.

BACKGROUND: Angiogenic imbalances, characterized by an excess of antiangiogenic factors (soluble fms-like tyrosine kinase 1 [sFlt-1]) and reduced angiogenic factors (VEGF and placental growth factor [PlGF]), contribute to the mechanisms of disease in preeclampsia. The ratio of sFlt-1 to PlGF has been used as a biomarker for preeclampsia, but cut-off values may vary with gestational age and assay platform. OBJECTIVES: To compare multiples of the median (MoM) of maternal plasma sFlt-1/PlGF ratio, sFlt-1, PlGF, and conventional clinical and laboratory values to predict preeclampsia with severe features. STUDY DESIGN: We conducted a cohort study across 18 U.S. centers involving hospitalized hypertensive individuals between 23-35 weeks' gestation. Receiver operating characteristic curve (ROC) analyses of maternal plasma biomarkers, highest systolic or diastolic blood pressures, and laboratory values at enrollment were performed for the prediction of preeclampsia with severe features. Their areas under the curve (AUC) were compared, and quasi-Poisson regression models were fitted to estimate relative risks. The primary outcome was preeclampsia with severe features within two weeks of enrollment. Secondary outcomes were a composite of severe adverse maternal outcomes (elevated liver enzymes, low platelets count, placental abruption, eclampsia, disseminated intravascular coagulation, and pulmonary edema) and a composite of severe adverse perinatal outcomes (birthweight <3rd percentile, very preterm birth [<32 weeks] and fetal/neonatal death). RESULTS: Out of 543 individuals included in the study, preeclampsia with severe features within two weeks was observed in 33.1% (n=180) of them. A ROC-derived cut-off of 11.5 MoM for sFlt-1/PlGF plasma ratio provided sensitivity (90.6%), specificity (76.9%), positive predictive value (66.0%), negative predictive value (94.3%), positive likelihood ratio (3.91), negative likelihood ratio (0.12), and accuracy (81.4%) for preeclampsia with severe features within two weeks. This cut-off was used to compare test positive cases (≥ cut-off) and test negative cases (< cut-off). Preeclampsia with severe features (66.0% vs. 5.7%; <0.001), and composites of severe adverse maternal (8.11% vs. 2.7%; p=0.006) or perinatal outcomes (41.3% vs. 10.14%; p=0.001) within two weeks were more frequent in test positive cases than test negative cases. sFlt-1/PlGF plasma ratio ≥11.5 MoM was independently associated with preeclampsia with severe features (adjusted incidence rate ratio [aIRR]: 9.08, 95% CI: 6.11 to 14.06; p<0.001) and a composite of severe adverse perinatal outcomes (aIRR: 9.42, 95% CI: 6.36 to 14.53; p<0.001), but not with a composite of severe adverse maternal outcomes (aIRR: 2.20, 95% CI: 0.95 to 5.54; p=0.08).The AUC of sFlt-1/PlGF plasma ratio in MoM (0.91; 95% CI: 0.89-0.94) for preeclampsia with severe features within two weeks was significantly higher (p<0.001 for all comparisons) than either plasma biomarker alone or any other parameter, with the exception of absolute sFlt-1/PlGF plasma ratio values. CONCLUSIONS: SFlt-1/PlGF plasma ratio ≥11.5 MoM among hospitalized, hypertensive patients between 23- and 35-week's gestation predicts progression to preeclampsia with severe features and severe adverse perinatal outcomes within two weeks.

Placental Malaria Induces a Unique Placental Methylation Profile Associated with Fetal Growth Restriction.

Background: Fetal growth restriction (FGR) is associated with perinatal death and other adverse birth outcomes, as well as long term complications including increased childhood morbidity, abnormal neurodevelopment, and cardio-metabolic diseases in adulthood. FGR has been associated with placental epigenetic reprogramming, which may mediate these long term outcomes. Placental malaria (PM) is the leading cause of FGR globally, but the impact on placental epigenetics is unknown. We hypothesized that methylomic profiling of placentas from non-malarial and malarial FGR would reveal common and distinct mechanistic pathways associated with FGR. Results: We used a methylation array to compare the CpG profiles between FGR from a cohort with no malaria exposure and a cohort of pregnancies complicated by both PM and FGR. Non-malarial FGR was associated with 65 differentially methylated CpGs, whereas PM-FGR was associated with 133 DMCs, compared to their corresponding controls. One DMC (cg16389901) was commonly hypomethylated in both groups, corresponding to the promoter region of BMP4 . Comparison of FGR vs. PM-FGR identified 522 DMCs between these two groups, which was not attributable to geographic location or different cellular compositions of these two groups. Conclusion: Placentas from pregnancies with PM-associated FGR showed distinct methylation profiles as compared to non-malarial FGR, suggesting novel epigenetic reprogramming in response to malaria. There may be distinct long-term health outcomes in FGR pregnancies also complicated by PM.

Monthly Sulfadoxine-Pyrimethamine During Pregnancy Prevents Febrile Respiratory Illnesses: A Secondary Analysis of a Malaria Chemoprevention Trial in Uganda.

Background: Trials evaluating antimalarials for intermittent preventive treatment in pregnancy (IPTp) have shown that dihydroartemisinin-piperaquine (DP) is a more efficacious antimalarial than sulfadoxine-pyrimethamine (SP); however, SP is associated with higher birthweight, suggesting that SP demonstrates "nonmalarial" effects. Chemoprevention of nonmalarial febrile illnesses (NMFIs) was explored as a possible mechanism. Methods: In this secondary analysis, we leveraged data from 654 pregnant Ugandan women without HIV infection who participated in a randomized controlled trial comparing monthly IPTp-SP with IPTp-DP. Women were enrolled between 12 and 20 gestational weeks and followed through delivery. NMFIs were measured by active and passive surveillance and defined by the absence of malaria parasitemia. We quantified associations among IPTp regimens, incident NMFIs, antibiotic prescriptions, and birthweight. Results: Mean "birthweight for gestational age" Z scores were 0.189 points (95% CI, .045-.333) higher in women randomized to IPTp-SP vs IPTp-DP. Women randomized to IPTp-SP had fewer incident NMFIs (incidence rate ratio, 0.74; 95% CI, .58-.95), mainly respiratory NMFIs (incidence rate ratio, 0.69; 95% CI, .48-1.00), vs IPTp-DP. Counterintuitively, respiratory NMFI incidence was positively correlated with birthweight in multigravidae. In total 75% of respiratory NMFIs were treated with antibiotics. Although overall antibiotic prescriptions were similar between arms, for each antibiotic prescribed, "birthweight for gestational age" Z scores increased by 0.038 points (95% CI, .001-.074). Conclusions: Monthly IPTp-SP was associated with reduced respiratory NMFI incidence, revealing a potential nonmalarial mechanism of SP and supporting current World Health Organization recommendations for IPTp-SP, even in areas with high-grade SP resistance. While maternal respiratory NMFIs are known risk factors of lower birthweight, most women in our study were presumptively treated with antibiotics, masking the potential benefit of SP on birthweight mediated through preventing respiratory NMFIs.

Patterns of peripartum depression and anxiety during the pre-vaccine COVID-19 pandemic.

BACKGROUND: Pregnant people are vulnerable to new or worsening mental health conditions. This study aims to describe prevalence and course of depression and anxiety symptoms in pregnancy during the pre-vaccine COVID-19 pandemic. METHODS: This is a prospective cohort study of pregnant individuals with known or suspected COVID-19. Participants completed Edinburgh Postnatal Depression Scale (EPDS) and Generalized-Anxiety Disorder-7 (GAD-7) questionnaires, screening tools for depression and anxiety, at 34weeks gestational age, 6-8weeks postpartum, and 6months postpartum. Prevalence of elevated depressive and anxiety symptoms at each visit was described. Univariable logistic regression analysis was used to determine the association between demographic and clinical factors and those with elevated depression or anxiety symptoms. RESULTS: 317 participants were included. The prevalence of elevated antepartum depression symptoms was 14.6%, 10.3%, and 20.6% at 34weeks gestational age, 6-8weeks postpartum, and 6months postpartum, respectively. The rate of elevated anxiety symptoms was 15.1%, 10.0%, and 17.3% at 34weeks gestational age, 6-8weeks postpartum, and 6months postpartum, respectively. A prior history of depression and/or anxiety (p's < 0.03), as well as higher EPDS and GAD-7 scores at enrollment (p's < 0.04) associated with elevated depression and anxiety symptoms throughout pregnancy and the postpartum period. Quarantining during pregnancy was associated with elevated anxiety symptoms at 34weeks gestational age in univariate (P = 0.027) analyses. COVID-19 diagnosis and hospitalization were not associated with elevated depression or anxiety symptoms. CONCLUSIONS: Elevated depression and anxiety symptoms were prevalent throughout pregnancy and the postpartum period, particularly in those with prior depression and/or anxiety and who quarantined. Strategies that target social isolation may mitigate potential adverse consequences for pregnant people, and continued vigilance in recognition of depression and anxiety in pregnancy should be considered.

In Utero Exposure to Maternal COVID-19 Vaccination and Offspring Neurodevelopment at 12 and 18 Months.

Importance: Uptake of COVID-19 vaccines among pregnant individuals was hampered by safety concerns around potential risks to unborn children. Data clarifying early neurodevelopmental outcomes of offspring exposed to COVID-19 vaccination in utero are lacking. Objective: To determine whether in utero exposure to maternal COVID-19 vaccination was associated with differences in scores on the Ages and Stages Questionnaire, third edition (ASQ-3), at 12 and 18 months of age. Design, Setting, and Participants: This prospective cohort study, Assessing the Safety of Pregnancy During the Coronavirus Pandemic (ASPIRE), enrolled pregnant participants from May 2020 to August 2021; follow-up of children from these pregnancies is ongoing. Participants, which included pregnant individuals and their offspring from all 50 states, self-enrolled online. Study activities were performed remotely. Exposure: In utero exposure of the fetus to maternal COVID-19 vaccination during pregnancy was compared with those unexposed. Main Outcomes and Measures: Neurodevelopmental scores on validated ASQ-3, completed by birth mothers at 12 and 18 months. A score below the established cutoff in any of 5 subdomains (communication, gross motor, fine motor, problem solving, social skills) constituted an abnormal screen for developmental delay. Results: A total of 2487 pregnant individuals (mean [SD] age, 33.3 [4.2] years) enrolled at less than 10 weeks' gestation and completed research activities, yielding a total of 2261 and 1940 infants aged 12 and 18 months, respectively, with neurodevelopmental assessments. In crude analyses, 471 of 1541 exposed infants (30.6%) screened abnormally for developmental delay at 12 months vs 203 of 720 unexposed infants (28.2%; χ2 = 1.32; P = .25); the corresponding prevalences at 18 months were 262 of 1301 (20.1%) vs 148 of 639 (23.2%), respectively (χ2 = 2.35; P = .13). In multivariable mixed-effects logistic regression models adjusting for maternal age, race, ethnicity, education, income, maternal depression, and anxiety, no difference in risk for abnormal ASQ-3 screens was observed at either time point (12 months: adjusted risk ratio [aRR], 1.14; 95% CI, 0.97-1.33; 18 months: aRR, 0.88; 95% CI, 0.72-1.07). Further adjustment for preterm birth and infant sex did not affect results (12 months: aRR, 1.16; 95% CI, 0.98-1.36; 18 months: aRR, 0.87; 95% CI, 0.71-1.07). Conclusions and Relevance: Results of this cohort study suggest that COVID-19 vaccination was safe during pregnancy from the perspective of infant neurodevelopment to 18 months of age. Additional longer-term research should be conducted to corroborate these findings and buttress clinical guidance with a strong evidence base.

Distinct transcriptional profiles of maternal and fetal placental macrophages at term are associated with gravidity.

Maternal intervillous monocytes (MIMs) and fetal Hofbauer cells (HBCs) are myeloid-derived immune cells at the maternal-fetal interface. Little is known regarding the molecular phenotypes and roles of these distinct monocyte/macrophage populations. Here, we used RNA sequencing to investigate the transcriptional profiles of MIMs and HBCs in six normal term pregnancies. Our analyses revealed distinct transcriptomes of MIMs and HBCs. Genes involved in differentiation and cell organization pathways were more highly expressed in MIMs vs. HBCs. In contrast, HBCs had higher expression of genes involved in inflammatory responses and cell surface receptor signaling. Maternal gravidity influenced monocyte programming, as expression of pro-inflammatory molecules was significantly higher in MIMs from multigravidas compared to primigravidas. In HBCs, multigravidas displayed enrichment of gene pathways involved in cell-cell signaling and differentiation. In summary, our results demonstrated that MIMs and HBCs have highly divergent transcriptional signatures, reflecting their distinct origins, locations, functions, and roles in inflammatory responses. Our data further suggested that maternal gravidity influences the gene signatures of MIMs and HBCs, potentially modulating the interplay between tolerance and trained immunity. The phenomenon of reproductive immune memory may play a novel role in the differential susceptibility of primigravidas to pregnancy complications.

Perfluorooctanoic acid induces transcriptomic alterations in second trimester human cytotrophoblasts.

Poly- and perfluroroalkylated substances (PFAS) are a major class of surfactants used in industry applications and consumer products. Despite efforts to reduce the usage of PFAS due to their environmental persistence, compounds such as perfluorooctanoic acid (PFOA) are widely detected in human blood and tissue. Although growing evidence supports that prenatal exposures to PFOA and other PFAS are linked to adverse pregnancy outcomes, the target organs and pathways remain unclear. Recent investigations in mouse and human cell lines suggest that PFAS may impact the placenta and impair trophoblast function. In this study, we investigated the effects of PFOA on cytotoxicity and the transcriptome in cultured second trimester human cytotrophoblasts (CTBs). We show that PFOA significantly reduces viability and induces cell death at 24 h, in a concentration-dependent manner. At subcytotoxic concentrations, PFOA impacted expression of hundreds of genes, including several molecules (CRH, IFIT1, and TNFSF10) linked with lipid metabolism and innate immune response pathways. Furthermore, in silico analyses suggested that regulatory factors such as peroxisome proliferator-activated receptor-mediated pathways may be especially important in response to PFOA. In summary, this study provides evidence that PFOA alters primary human CTB viability and gene pathways that could contribute to placental dysfunction and disease.

Milk antibody response after 3rd COVID-19 vaccine and SARS-CoV-2 infection and implications for infant protection.

Little is known about the persistence of human milk anti-SARS-CoV-2 antibodies after 2nd and 3rd vaccine doses and infection following 3rd dose. In this study, human milk, saliva, and blood samples were collected from 33 lactating individuals before and after vaccination and infection. Antibody levels were measured using ELISA and symptoms were assessed using questionnaires. We found that after vaccination, milk anti-SARS-CoV-2 antibodies persisted for up to 8 months. In addition, distinct patterns of human milk IgA and IgG production and higher milk RBD-blocking activity was observed after infection compared to 3-dose vaccination. Infected mothers reported more symptoms than vaccinated mothers. We examined the persistence of milk antibodies in infant saliva after breastfeeding and found that IgA was more abundant compared to IgG. Our results emphasize the importance of improving the secretion of IgA antibodies to human milk after vaccination to improve the protection of breastfeeding infants.

Minimal mRNA uptake and inflammatory response to COVID-19 mRNA vaccine exposure in human placental explants.

Despite universal recommendations for COVID-19 mRNA vaccination in pregnancy, uptake has been lower than desired. There have been limited studies of the direct impact of COVID-19 mRNA vaccine exposure in human placental tissue. Using a primary human placental explants model, we investigated the uptake of two common mRNA vaccines (BNT162b2 Pfizer-BioNTech or mRNA-1273 Moderna), and whether exposure altered villous cytokine responses. Explants derived from second or third trimester chorionic villi were incubated with vaccines at supraphysiologic concentrations and analyzed at two time points. We observed minimal uptake of mRNA vaccines in placental explants by in situ hybridization and quantitative RT-PCR. No specific or global cytokine response was elicited by either of the mRNA vaccines in multiplexed immunoassays. Our results suggest that the human placenta does not readily absorb the COVID-19 mRNA vaccines nor generate a significant inflammatory response after exposure.

Assessment of Adverse Reactions, Antibody Patterns, and 12-month Outcomes in the Mother-Infant Dyad After COVID-19 mRNA Vaccination in Pregnancy.

Importance: Longitudinal data on COVID-19 messenger RNA (mRNA) vaccine reactogenicity and immunogenicity in pregnancy and for the mother-infant dyad are needed. Objective: To examine COVID-19 mRNA vaccine reactogenicity and immunogenicity in pregnancy and observe longitudinal maternal and infant outcomes. Design, Setting, and Participants: This prospective cohort study of pregnant individuals enrolled in the COVID-19 Vaccination in Pregnancy and Lactation study from December 1, 2020, through December 31, 2021, with follow-up through March 31, 2022, was conducted at a large academic medical center in an urban metropolitan area in California. Pregnant individuals receiving COVID-19 mRNA vaccines (mRNA-1273 [Moderna] and BNT162b2 [Pfizer-BioNTech]) were eligible. Of 81 participants enrolled, 5 were excluded after enrollment: 1 terminated pregnancy, 1 received the third vaccine dose prior to delivery, and 3 delivered prior to completing the initial vaccine series. Exposure: COVID-19 mRNA vaccination at any time during pregnancy. Main Outcomes and Measures: The primary outcomes were vaccine response as measured by blood Immunoglobulin G (IgG) titers after each vaccine dose and self-reported postvaccination symptoms. Patients' IgG titers were measured in cord blood and in infant blood at intervals up to 1 year of life; IgG and IgA titers were measured in maternal milk. Clinical outcomes were collected from medical records. Results: Of 76 pregnant individuals included in final analyses (median [IQR] maternal age, 35 [29-41] years; 51 [67.1%] White; 28 [36.8%] primigravid; 37 [48.7%] nulliparous), 42 (55.3%) received BNT162b2 and 34 (44.7%) received mRNA-1237. There were no significant differences in maternal characteristics between the 2 vaccine groups. Systemic symptoms were more common after receipt of the second vaccine dose than after the first dose (42 of 59 [71.2%] vs 26 of 59 [44.1%]; P = .007) and after mRNA-1237 than after BNT162b2 (25 of 27 [92.6%] vs 17 of 32 53.1%; P = .001). Systemic symptoms were associated with 65.6% higher median IgG titers than no symptoms after the second vaccine dose (median [IQR], 2596 [1840-4455] vs 1568 [1114-4518] RFU; P = .007); mean cord titers in individuals with local or systemic symptoms were 6.3-fold higher than in individuals without symptoms. Vaccination in all trimesters elicited a robust maternal IgG response. The IgG transfer ratio was highest among individuals vaccinated in the second trimester. Anti-SARS-CoV-2 IgG was detectable in cord blood regardless of vaccination trimester. In milk, IgG and IgA titers remained above the positive cutoff for at least 5-6 months after birth, and infants of mothers vaccinated in the second and third trimesters had positive IgG titers for at least 5 to 6 months of life. There were no vaccine-attributable adverse perinatal outcomes. Conclusions and Relevance: The findings of this cohort study suggest that mRNA COVID-19 vaccination in pregnancy provokes a robust IgG response for the mother-infant dyad for approximately 6 months after birth. Postvaccination symptoms may indicate a more robust immune response, without adverse maternal, fetal, or neonatal outcomes.

Retrospective analysis of wildfire smoke exposure and birth weight outcomes in the San Francisco Bay Area of California.

Despite the occurrence of wildfires quadrupling over the past four decades, the health effects associated with wildfire smoke exposures during pregnancy remains unknown. Particulate matter less than 2.5 µms (PM2.5) is among the major pollutants emitted in wildfire smoke. Previous studies found PM2.5 associated with lower birthweight, however, the relationship between wildfire-specific PM2.5 and birthweight is uncertain. Our study of 7923 singleton births in San Francisco between January 1, 2017 and March 12, 2020 examines associations between wildfire smoke exposure during pregnancy and birthweight. We linked daily estimates of wildfire-specific PM2.5 to maternal residence at the ZIP code level. We used linear and log-binomial regression to examine the relationship between wildfire smoke exposure by trimester and birthweight and adjusted for gestational age, maternal age, race/ethnicity, and educational attainment. We stratified by infant sex to examine potential effect modification. Exposure to wildfire-specific PM2.5 during the second trimester of pregnancy was positively associated with increased risk of large for gestational age (OR = 1.13; 95% CI: 1.03, 1.24), as was the number of days of wildfire-specific PM2.5 above 5 µg m-3 in the second trimester (OR = 1.03; 95% CI: 1.01, 1.06). We found consistent results with wildfire smoke exposure in the second trimester and increased continuous birthweight-for-gestational age z-score. Differences by infant sex were not consistent. Counter to our hypothesis, results suggest that wildfire smoke exposures are associated with increased risk for higher birthweight. We observed strongest associations during the second trimester. These investigations should be expanded to other populations exposed to wildfire smoke and aim to identify vulnerable communities. Additional research is needed to clarify the biological mechanisms in this relationship between wildfire smoke exposure and adverse birth outcomes.

Validated Calculators Predicting Cesarean Delivery After Induction: Accuracy in an External Population.

OBJECTIVE: To evaluate the performance of two previously published calculators in predicting cesarean delivery after induction of labor in an external population. METHODS: This was a cohort study including all nulliparous pregnant patients with singleton, term, vertex fetuses; intact membranes; and unfavorable cervices who underwent induction of labor between 2015 and 2017 at an academic tertiary care institution. Individual predicted cesarean risk scores were calculated with two previously published calculators. For each calculator, patients were stratified into three risk groups (lower, middle, and upper thirds) of approximately equivalent size. Predicted and observed incidences of cesarean delivery were compared with two-tailed binomial tests of probability in the overall population and in each risk group. RESULTS: A total of 846 patients met inclusion criteria, and 262 (31.0%) had cesarean deliveries, which was significantly lower than overall predicted rates of 40.0% and 36.2% with the two calculators (both P <.01). Both calculators significantly overestimated risk of cesarean delivery in higher risk tertiles (all P <.05). The areas under the receiver operating characteristic for both calculators were 0.57 or less in the overall population and in each risk group, suggesting poor predictive value. Higher predicted risk tertile in both calculators was not associated with any maternal or neonatal outcomes except wound infection. CONCLUSION: Both previously published calculators had poor performance in this population, with neither calculator accurately predicting the incidence of cesarean delivery. Patients and health care professionals might be discouraged regarding trial of labor induction by falsely high predicted risk-of-cesarean scores. We caution against widespread implementation of these calculators without further population-specific refinement and adjustment.

Predictors of antepartum maternal sepsis and effects on neonatal outcomes: a population-based cohort study.

OBJECTIVE: To examine the relationship between maternal sepsis, type of infection, and short-term neonatal outcomes. STUDY DESIGN: We conducted a retrospective cohort study investigating pregnancies between 2005 and 2008 in California with antepartum maternal sepsis diagnosis. Comparisons were made between sepsis cases and controls, using chi-squared or Fisher's exact test. Multivariable logistic regression was performed, adjusting for maternal characteristics. RESULTS: Several maternal characteristics were associated with increased odds of maternal sepsis. Both obstetric and non-obstetric infections were associated with maternal sepsis (p < 0.001). The positive predictive value of maternal sepsis for preterm delivery was 55.03%. Neonates born to maternal sepsis patients had a higher risk of developing neonatal complications including neonatal shock. CONCLUSION: Maternal sepsis was associated with neonatal complications. Efforts to reduce maternal sepsis may improve neonatal outcomes. Further studies are required for a better understanding of these associations and whether prevention or more rapid diagnosis and treatment can lower these risks.

Analysis of placental pathology after COVID-19 by timing and severity of infection.

BACKGROUND: COVID-19 during pregnancy can have serious effects on pregnancy outcomes. The placenta acts as an infection barrier to the fetus and may mediate adverse outcomes. Increased frequency of maternal vascular malperfusion has been detected in the placentas of patients with COVID-19 compared with controls, but little is known about how the timing and severity of infection affect placental pathology. OBJECTIVE: This study aimed to examine the effects of SARS-CoV-2 infection on placental pathology, specifically whether the timing and severity of COVID-19 affect pathologic findings and associations with perinatal outcomes. STUDY DESIGN: This was a descriptive retrospective cohort study of pregnant people diagnosed with COVID-19 who delivered between April 2020 and September 2021 at 3 university hospitals. Demographic, placental, delivery, and neonatal outcomes were collected through medical record review. The timing of SARS-CoV-2 infection was noted, and the severity of COVID-19 was categorized on the basis of the National Institutes of Health guidelines. The placentas of all patients with positive nasopharyngeal reverse transcription-polymerase chain reaction COVID-19 testing were sent for gross and microscopic histopathologic examinations at the time of delivery. Nonblinded pathologists categorized histopathologic lesions according to the Amsterdam criteria. Univariate linear regression and chi-square analyses were used to assess how the timing and severity of SARS-CoV-2 infection affected placental pathologic findings. RESULTS: This study included 131 pregnant patients and 138 placentas, with most patients delivered at the University of California, Los Angeles (n=65), followed by the University of California, San Francisco (n=38) and Zuckerberg San Francisco General Hospital (n=28). Most patients were diagnosed with COVID-19 in the third trimester of pregnancy (69%), and most infections were mild (60%). There was no specific placental pathologic feature based on the timing or severity of COVID-19. There was a higher frequency of placental features associated with response to infection in the placentas from infections before 20 weeks of gestation than that from infections after 20 weeks of gestation (P=.001). There was no difference in maternal vascular malperfusion by the timing of infection; however, features of severe maternal vascular malperfusion were only found in the placentas of patients with SARS-CoV-2 infection in the second and third trimesters of pregnancy, not in the placentas of patients with COVID-19 in the first trimester of pregnancy. CONCLUSION: Placentas from patients with COVID-19 showed no specific pathologic feature, regardless of the timing or severity of the disease. There was a higher proportion of placentas from patients with COVID-19-positive tests in earlier gestations with evidence of placental infection-associated features. Future studies should focus on understanding how these placental features in SARS-CoV-2 infections go on to affect pregnancy outcomes.

Nirmatrelvir-Ritonavir (Paxlovid) for Mild Coronavirus Disease 2019 (COVID-19) in Pregnancy and Lactation.

Nirmatrelvir-ritonavir (Paxlovid) is recommended to reduce the risk of hospitalization from coronavirus disease 2019 (COVID-19) in pregnancy. Data on use in pregnancy, including prescribing patterns and patient experience (adverse effects, incidence of rebound), are limited. We performed a cross-sectional study in which we surveyed a cohort of vaccinated pregnant or lactating individuals with breakthrough COVID-19. Of 35 pregnant respondents, 51.4% were prescribed and 34.3% took nirmatrelvir-ritonavir; of these, 91.7% experienced dysgeusia and 50.0% had rebound (50.0% positive test result, 33.3% return of symptoms). Three of five lactating respondents were prescribed and two took nirmatrelvir-ritonavir. There were no significant adverse outcomes. Unknown risk was the most common reason for declining nirmatrelvir-ritonavir. More research is needed to establish the safety of nirmatrelvir-ritonavir in pregnancy and lactation, to improve public health messaging, and to increase uptake of this treatment.

Minimal mRNA uptake and inflammatory response to COVID-19 mRNA vaccine exposure in human placental explants.

Despite universal recommendations for COVID-19 mRNA vaccination in pregnancy, uptake has been lower than desired. There have been limited studies of the direct impact of COVID-19 mRNA vaccine exposure in human placental tissue. Using a primary human villous explant model, we investigated the uptake of two common mRNA vaccines (BNT162b2 Pfizer-BioNTech or mRNA-1273 Moderna), and whether exposure altered villous cytokine responses. Explants derived from second or third trimester chorionic villi were incubated with vaccines at supraphysiologic concentrations and analyzed at two time points. We observed minimal uptake of mRNA vaccines in placental explants by in situ hybridization and quantitative RT-PCR. No specific or global cytokine response was elicited by either of the mRNA vaccines in multiplexed immunoassays. Our results suggest that the human placenta does not readily absorb the COVID-19 mRNA vaccines nor generate a significant inflammatory response after exposure.

Gestational age-dependent decrease in fetal Hofbauer cells in placentas from pregnancies exposed to wildfire smoke in California.

OBJECTIVE: Wildfires are more common over the last decade and the frequency of wildfire events has been accelerated by climate change. The existing body of literature suggests that exposure to wildfire smoke during pregnancy contributes to adverse perinatal outcomes such as preterm birth and fetal growth restriction. We hypothesize that exposures to wildfire smoke and its constituents triggers a fetal inflammatory response which contributes to pathological changes that underlie these adverse pregnancy outcomes. In this study, we quantified the presence of fetal macrophages (i.e., Hofbauer cells) in human placentas obtained between 2018 and 2020 to assess the relationship between fetal immune status and wildfire exposure. STUDY DESIGN: We collected placentas from pregnancies from two hospitals in San Francisco over a two-year period that included two severe major wildfires. The average particulate matter < 2.5 µm (PM2.5) or wildfire specific PM2.5 levels were estimated over the gestational duration of each sample. Immunostaining against CK7 and CD68 was performed to identify intravillous fetal Hofbauer cells. We assessed the gestational-age dependent relationship between placental CD68+ cell density and mean daily PM2.5 or wildfire-specific PM2.5 via linear regression and Welch's t-test. Additionally, we compared placental CD68+ cell density with estimated peak wildfire exposures during the gestation to determine if timing of exposure during pregnancy may influence the occurrence of Hofbauer cells in the placenta. RESULTS: The gestational ages ranged from 7-41 weeks (n = 67). The majority of samples were collected during one of two major wildfire events in Northern California (70%; n = 47). In general, we observed a significant inverse relationship between placental CD68 density and PM2.5 or wildfire specific PM2.5, however, these associations were only observed in first or second trimester samples, and not in term samples. For example, among first trimester samples (n=22), we observed lower mean CD68 density among samples likely to be exposed to wildfire events (mean = 1.42, SD = 0.8) as compared to those not exposed (mean = 3.73, SD = 1.983) (p = 0.0015). Based on our linear regression model results, we predicted that a one µg/m3 increase in daily mean wildfire PM2.5 was associated with a 0.457 decrease in CD68 density (ß =-0.457; 95% CI: -0.722, -0.193). This association was also significant for daily mean overall PM2.5, though smaller in magnitude (ß = -0.139; 95% CI: -0.218, -0.059). CONCLUSIONS: Our results suggest that wildfire smoke exposures are associated with decreased presence of fetal Hofbauer cells in first and second trimester placentas, suggesting exposure may lead to impaired placental function via altered presence of fetal Hofbauer cells and changes in immune status.

Patterns of Peripartum Depression and Anxiety During the Pre-Vaccine COVID-19 Pandemic.

Background: Pregnant people are vulnerable to new or worsening mental health conditions. This study aims to describe prevalence and course of symptomatic depression and anxiety in pregnancy during the pre-vaccine COVID-19 pandemic. Methods: This is a prospective cohort study of pregnant individuals with known or suspected COVID-19. Participants completed Edinburgh Postnatal Depression Scale (EPDS) and Generalized-Anxiety Disorder-7 (GAD-7) questionnaires at 34weeks gestational age, 6-8weeks postpartum, and 6months postpartum. Prevalence of symptomatic depression and anxiety at each visit was described. Univariable logistic regression analysis was used to determine the association between demographic and clinical factors and symptomatic depression or anxiety. Results: 317 participantswere included. The prevalence of antepartum depression was 14.6%, 10.3%, and 20.6% at 34weeks gestational age, 6-8weeks postpartum, and 6months postpartum, respectively. The rate of anxiety was 15.1%, 10.0%, and 17.3% at 34weeks gestational age, 6-8weeks postpartum, and 6months postpartum, respectively. A prior history of depression and/or anxiety (p's<0.03), as well as higher EPDS and GAD-7 scores at enrollment (p's<0.04) associated with depression and anxiety throughout pregnancy and the postpartum period. Quarantining during pregnancy was associated with symptomatic anxiety at 34weeks gestational age in univariate (P=0.027) analyses. COVID-19 diagnosis and hospitalization were not associated with depression or anxiety. Conclusions: Depression and anxiety were prevalent throughout pregnancy and the postpartum period, particularly in those with prior depression and/or anxiety and who quarantined. Strategies that target social isolation may mitigate potential adverse consequences for pregnant people, and continued vigilance in recognition of depression and anxiety in pregnancy should be considered.

Milk antibody response after 3rd dose of COVID-19 mRNA vaccine and SARS-CoV-2 breakthrough infection and implications for infant protection.

Anti-SARS-CoV-2 antibodies have been found in human-milk after COVID-19 infection and vaccination. However, little is known about their persistence in milk after booster vaccination and breakthrough infection. In this study, human-milk, saliva and blood samples were collected from 33 lactating individuals before and after mRNA-based vaccination and COVID-19 breakthrough infections. Antibody levels were measured using ELISA and symptoms were assessed using questionnaires. Evaluation of maternal and infant symptomatology revealed that infected mothers reported more symptoms than vaccinated mothers. We found that after vaccination, human-milk anti-SARS-CoV-2 antibodies persisted for up to 8 months. In addition, distinct patterns of human milk IgA and IgG production we observed after breakthrough infection compared to 3-dose vaccination series alone, indicating a differential central and mucosal immune profiles in hybrid compared with vaccine-induced immunity. To investigate passively-derived milk antibody protection in infants, we examined the persistence of these antibodies in infant saliva after breastfeeding. We found that IgA was more abundant in infant saliva compared to IgG and persist in infant saliva longer after feeding. Our results delineate the differences in milk antibody response to vaccination as compared to breakthrough infection and emphasize the importance of improving the secretion of IgA antibodies to human milk after vaccination to improve the protection of breastfeeding infants.

Wildfire Smoke Exposure during Pregnancy: A Review of Potential Mechanisms of Placental Toxicity, Impact on Obstetric Outcomes, and Strategies to Reduce Exposure.

Climate change is accelerating the intensity and frequency of wildfires globally. Understanding how wildfire smoke (WS) may lead to adverse pregnancy outcomes and alterations in placental function via biological mechanisms is critical to mitigate the harms of exposure. We aim to review the literature surrounding WS, placental biology, biological mechanisms underlying adverse pregnancy outcomes as well as interventions and strategies to avoid WS exposure in pregnancy. This review includes epidemiologic and experimental laboratory-based studies of WS, air pollution, particulate matter (PM), and other chemicals related to combustion in relation to obstetric outcomes and placental biology. We summarized the available clinical, animal, and placental studies with WS and other combustion products such as tobacco, diesel, and wood smoke. Additionally, we reviewed current recommendations for prevention of WS exposure. We found that there is limited data specific to WS; however, studies on air pollution and other combustion sources suggest a link to inflammation, oxidative stress, endocrine disruption, DNA damage, telomere shortening, epigenetic changes, as well as metabolic, vascular, and endothelial dysregulation in the maternal-fetal unit. These alterations in placental biology contribute to adverse obstetric outcomes that disproportionally affect the most vulnerable. Limiting time outdoors, wearing N95 respirator face masks and using high quality indoor air filters during wildfire events reduces exposure to related environmental exposures and may mitigate morbidities attributable to WS.