BACKGROUND:Previous single-center studies conducted in the United States in women with suspected preeclampsia indicated that serum soluble fms-like tyrosine kinase 1-to-placental growth factor ratio values of >38 measured on a widely available Elecsys immunoassay platform during the third trimester of pregnancy predicted the development of preeclampsia with severe features and adverse outcomes within 2 weeks of testing. OBJECTIVE:This study aimed to validate the Elecsys soluble fms-like tyrosine kinase 1-to-placental growth factor ratio test for the prediction of preeclampsia with severe features in a United States population using the prospective Preeclampsia Risk Assessment: Evaluation of Cut-offs to Improve Stratification cohort that recruited women with a hypertensive disorder of pregnancy (gestational hypertension, chronic hypertension, de novo and superimposed preeclampsia) across 18 tertiary and community hospitals throughout the United States. STUDY DESIGN:We measured soluble fms-like tyrosine kinase 1-to-placental growth factor ratios using the Elecsys platform in archived serum samples from the Preeclampsia Risk Assessment: Evaluation of Cut-offs to Improve Stratification study that recruited hospitalized women with a hypertensive disorder of pregnancy between 23 0/7 and 34 6/7 weeks of gestation. The primary study outcome was prediction of preeclampsia with severe features within 2 weeks after testing. The secondary outcomes included a composite of adverse maternal and fetal/neonatal outcomes and prediction of delivery within 2 weeks. RESULTS:In the validation cohort of the Preeclampsia Risk Assessment: Evaluation of Cut-offs to Improve Stratification study (556 enrollments), the serum soluble fms-like tyrosine kinase 1-to-placental growth factor ratio at a cutoff value of >38 demonstrated a 67% positive predictive value (95% confidence interval, 61-73) and a 95% negative predictive value (95% confidence interval, 92-97) for the progression to preeclampsia with severe features within 2 weeks. Among women at <30 weeks of gestation (n=188), serum soluble fms-like tyrosine kinase 1-to-placental growth factor ratio at a cutoff value of >38 demonstrated a 78% positive predictive value (95% confidence interval, 68-86) and a 100% negative predictive value (95% confidence interval, 96-100) for the progression to preeclampsia with severe features within 2 weeks. The Elecsys soluble fms-like tyrosine kinase 1-to-placental growth factor ratio test performed better than standard-of-care clinical measures, with an area under the receiver operating characteristic curve of 0.92 (95% confidence interval, 0.89-0.90) for soluble fms-like tyrosine kinase 1-to-placental growth factor ratio vs <0.70 for standard-of-care tests, such as liver enzymes, platelet count, and serum creatinine (P<.001). Compared with women with a ratio of ≤38, those with a ratio of >38 had a higher risk of developing adverse maternal (relative risk, 4.9 [95% confidence interval, 2.6-9.9]; P<.001) and fetal/neonatal (relative risk, 3.2 [95% confidence interval, 2.6-4.0]; P<.001) outcomes and were more likely to deliver within 2 weeks (adjusted hazard ratio, 3.3 [95% confidence interval, 2.7-4.0]; P<.001). CONCLUSION:The soluble fms-like tyrosine kinase 1-to-placental growth factor ratio of >38 measured on the Elecsys platform predicted the development of preeclampsia with severe features, delivery, and adverse maternal and fetal/neonatal outcomes within 2 weeks of testing among preterm pregnant women hospitalized with a hypertensive disorder of pregnancy.

BackgroundAngiogenic 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.ObjectivesTo 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 DesignWe 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).ResultsOut 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.ConclusionsSFlt-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.

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.

Background: National Institutes of Health funding to address basic reproductive health for common female conditions remains disproportionately low, in part because of low success rates of grant applications by obstetrician-gynecologists.Objective: This study aimed to evaluate the scholarly productivity of individuals supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Women's Reproductive Health Research K12 career development award, created to advance careers of obstetrician-gynecologist physician-scientists.Study Design: We performed a cohort study of individuals who completed at least 2 years of Women's Reproductive Health Research training by June 30, 2015, and had at least 5-year follow-up. Earliest training start date was December 1, 1998. Primary outcomes from public data sources (National Institutes of Health RePORTER, PubMed, iCite) were (1) number of total and R01 National Institutes of Health grants as principal investigator; (2) numbers of total and first and last author publications; and (3) median and highest publication impact factor measured by the relative citation ratio. Secondary outcomes from an email survey subcohort were total number of research grants, federally funded grants, and number of National Institutes of Health grants as coinvestigator; institutional promotions and academic appointments, national and National Institutes of Health leadership roles; and career and mentorship satisfaction. Outcomes were recorded at 5, 10, and 15 years postgraduation, and aggregate anonymized data were divided into 3 groups using Women's Reproductive Health Research completion dates: June 30 of 2005, 2010, and 2015. Temporal trends were assessed. Results were stratified by gender, number of awarded grant cycles (1-2 vs 3-4), and specialty type. Analyses used Fisher exact or Pearson chi-square tests, and Mantel-Haenszel tests of trend.Results: The distribution of the cohort (N=178) by graduation completion date was: on or before June 30, 2005 (57 [32%]); July 1, 2005 to June 30, 2010 (60 [34%]); and July 1, 2010 to June 30, 2015 (61 [34%]). Most participants were female (112 [64%]) and maternal-fetal medicine trained (53 [30%]), followed by no fellowship (50 [28%]). Of the 178 participants, 72 (40%) received additional National Institutes of Health funding as a principal investigator, 45 (25%) received at least 1 R01, and 23 (13%) received 2 to 5 R01s. There were 52 (31%) scholars with >10 first author publications, 66 (39%) with >10 last author publications, and 108 (63%) with >= 25 publications. The highest relative citation ratio was a median of 8.07 (interquartile range, 4.20-15.16). There were 121 (71%) scholars with relative citation ratio >= 5, indicating >5-fold greater publication impact than that of other National Institutes of Health-funded scientists in similar areas of research. No differences by gender, institution, or temporal trends were observed. Of the full cohort, 69 (45.7%) responded to the survey; most self-identified as women (50 [73%]) and White (51 [74%]).Conclusion: Our findings suggest that the infrastructure provided by an institutional K award is an advantageous career development award mechanism for obstetrician-gynecologists, a group of predominantly women surgeons. It may serve as a corrective for the known inequities in National Institutes of Health funding by gender.

The mechanisms that underlie the timing of labor in humans are largely unknown. In most pregnancies, labor is initiated at term (≥ 37 weeks gestation), but in a signifiicant number of women spontaneous labor occurs preterm and is associated with increased perinatal mortality and morbidity. The objective of this study was to characterize the cells at the maternal–fetal interface (MFI) in term and preterm pregnancies in both the laboring and non-laboring state in Black women, who have among the highest preterm birth rates in the U.S. Using mass cytometry to obtain high-dimensional single-cell resolution, we identified 31 cell populations at the MFI, including 25 immune cell types and six non-immune cell types. Among the immune cells, maternal PD1 + CD8 T cell subsets were less abundant in term laboring compared to term non-laboring women. Among the non-immune cells, PD-L1 + maternal (stromal) and fetal (extravillous trophoblast) cells were less abundant in preterm laboring compared to term laboring women. Consistent with these observations, the expression of CD274 , the gene encoding PD-L1, was significantly depressed and less responsive to fetal signaling molecules in cultured mesenchymal stromal cells from the decidua of preterm compared to term women. Overall, these results suggest that the PD1/PD-L1 pathway at the MFI may perturb the delicate balance between immune tolerance and rejection and contribute to the onset of spontaneous preterm labor.

The advancement of women leaders in obstetrics and gynecology does not reflect the changes in the physician workforce seen over the last 50 years. A core value of our culture in obstetrics and gynecology must be gender equity. Departmental, institutional, and professional society efforts should explicitly prioritize and demonstrate a commitment to gender equity with tangible actions. This commentary from the American Gynecological and Obstetrical Society synthesizes available information about women holding academic leadership roles within obstetrics and gynecology. We propose specific principles and leadership practices to promote gender equity.

BACKGROUND: Among women with hypertensive disorders of pregnancy, biomarkers may stratify risk for developing preeclampsia with severe features (sPE). METHODS: Across 18 U.S. centers, we prospectively measured the ratio of serum soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) in pregnant women hospitalized between 23 and 35 weeks of gestation. The primary outcome was predicting sPE, and secondary outcomes included predicting adverse outcomes within 2 weeks. The prognostic performance of the sFlt-1:PlGF ratio was assessed by using a derivation/validation design. RESULTS: A total of 1014 pregnant women were evaluated; 299 were included in the derivation cohort and 715 in the validation cohort. In the derivation cohort, the median sFlt-1:PlGF ratio was 200 (interquartile range, 53 to 458) among women who developed sPE compared with 6 (interquartile range, 3 to 26) in those who did not (P<0.001). The discriminatory ratio of ≥40 was then tested in the validation cohort and yielded a 65% positive (95% confidence interval [CI], 59 to 71) and a 96% negative (95% CI, 93 to 98) predictive value for the primary outcome. The ratio performed better than standard clinical measures (area under the receiver-operating characteristic curve, 0.92 versus <0.75 for standard-of-care tests). Compared with women with a ratio <40, women with a ratio ≥40 were at higher risk for adverse maternal outcomes (16.1% versus 2.8%; relative risk, 5.8; 95% CI, 2.8 to 12.2). CONCLUSIONS: In women with a hypertensive disorder of pregnancy presenting between 23 and 35 weeks of gestation, measurement of serum sFlt-1:PlGF provided stratification of the risk of progressing to sPE within the coming fortnight. (Funded by Cedars-Sinai Medical Center and Thermo Fisher Scientific; ClinicalTrials.gov NCT03815110.)

Pregnancy confers unique immune responses to infection and vaccination across gestation. To date, there are limited data comparing vaccine-and infection-induced neutralizing Abs (nAbs) against COVID-19 variants in mothers during pregnancy. We analyzed paired maternal and cord plasma samples from 60 pregnant individuals. Thirty women vaccinated with mRNA vaccines (from December 2020 through August 2021) were matched with 30 naturally infected women (from March 2020 through January 2021) by gestational age of exposure. Neutralization activity against the 5 SARS-CoV-2 spike sequences was measured by a SARS-CoV-2???pseudotyped spike virion assay. Effective nAbs against SARS-CoV-2 were present in maternal and cord plasma after both infection and vaccination. Compared with WT spike protein, these nAbs were less effective against the Delta and Mu spike variants. Vaccination during the third trimester induced higher cord-nAb levels at delivery than did infection during the third trimester. In contrast, vaccine-induced nAb levels were lower at the time of delivery compared with infection during the first trimester. The transfer ratio (cord nAb level divided by maternal nAb level) was greatest in mothers vaccinated in the second trimester. SARS-CoV-2 vaccination or infection in pregnancy elicits effective nAbs with differing neutralization kinetics that are influenced by gestational time of exposure.

INTRODUCTION: Conducting research is critical to the development of physician scientists; the authors’ obstetrics and gynecology department requires each resident to conduct an original research project that is then presented during an annual trainee Research Day (RD). A department research fund (DRF) was implemented in 2008 and a formal research curriculum subsequently implemented in effort to foster trainee academic success. This analysis explores associations between trainee DRF funding, peer-reviewed publication, and future National Institutes of Health (NIH) funding at a single academic institution over a 32-year period. METHODS: RD project titles and funding status were compiled from a single academic obstetrics and gynecology department from 1989-2020. Significant milestones were the DRF (2008) and implementation of a formal research curriculum (2017). Outcomes were peer-reviewed publication of the RD project within 5 years of RD presentation and subsequent NIH funding of the trainee. Chi-squared tests were used to investigate these relationships. RESULTS: Among 361 obstetrics and gynecology trainee (238 resident and 123 fellow) research projects presented at RD between 1989-2020, 169/361(46.8%) were peer-review published. Any funding of an RD project was associated with increased publication rate across the study period (85.9% versus 32%; P<.01). DRF-funded projects were also more likely to be published within 5 years (78.6% versus 57.7%; P=.03). DRF recipients were more likely to garner future NIH funding than non-recipients (37.9% versus 6.5%; P<.001). CONCLUSION: Trainee receipt of DRF funding is associated with both future NIH funding and trainee research publication. Program leaders may consider a formal research curriculum and a DRF to enhance the trainee research experience.

Studies are needed to evaluate the safety and effectiveness of mRNA SARS-CoV-2 vaccination during pregnancy, and the levels of protection provided to their newborns through placental transfer of antibodies. We evaluated the transplacental transfer of mRNA vaccine products and functional anti-SARS-CoV-2 antibodies during pregnancy and early infancy in a cohort of 20 individuals vaccinated during pregnancy. We found no evidence of mRNA vaccine products in maternal blood, placenta tissue, or cord blood at delivery. However, we found time-dependent efficient transfer of IgG and neutralizing antibodies to the neonate that persisted during early infancy. Additionally, using phage immunoprecipitation sequencing, we found a vaccine-specific signature of SARS-CoV-2 Spike protein epitope binding that is transplacentally transferred during pregnancy. In conclusion, products of mRNA vaccines are not transferred to the fetus during pregnancy, however timing of vaccination during pregnancy is critical to ensure transplacental transfer of protective antibodies during early infancy.

Many studies have evaluated birth outcomes in patients with COVID-19, but less attention has been paid to the risk of early pregnancy loss (EPL) despite the known association of miscarriage with viral infection.1Rasti S. Ghasemi F.S. Abdoli A. Piroozmand A. Mousavi S.G. Fakhrie-Kashan Z. ToRCH "coinfections" are associated with increased risk of abortion in pregnant women.Congenit Anom (Kyoto). 2016; 56: 73-78Crossref PubMed Scopus (38) Google Scholar The current literature is limited by a small number of cases, a focus on inpatient visits, and lack of longitudinal follow-up.2Cosma S. Carosso A.R. Cusato J. et al.Coronavirus disease 2019 and first-trimester spontaneous abortion: a case-control study of 225 pregnant patients.Am J Obstet Gynecol. 2021; 224: 391.e1-391.e7Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 3Juan J. Gil M.M. Rong Z. Zhang Y. Yang H. Poon L.C. Effects of coronavirus disease 2019 (COVID-19) on maternal, perinatal and neonatal outcome: systematic review.Ultrasound Obstet Gynecol. 2020; 56: 15-27Crossref PubMed Scopus (397) Google Scholar, 4la Cour Freiesleben N. Egerup P. Hviid K.V.R. et al.SARS-CoV-2 in first trimester pregnancy: a cohort study.Hum Reprod. 2021; 36: 40-47PubMed Google Scholar, 5Yan J. Guo J. Fan C. et al.Coronavirus disease 2019 in pregnant women: a report based on 116 cases.Am J Obstet Gynecol. 2020; 223: 111.e1-111.e14Abstract Full Text Full Text PDF Scopus (452) Google Scholar These studies have primarily been conducted in Europe and Asia, which limits generalizability to a diverse US population with unique patient characteristics. To address this evidence gap, we present data on a cohort of US women with SARS-CoV-2 infection in early pregnancy to help inform clinical practice. The Pregnancy Coronavirus Outcomes Registry (PRIORITY) study is an ongoing, nationwide, prospective cohort study of pregnant people COVID-19 during pregnancy in the United States. Participants were ≥13 years, under investigation for or had confirmed COVID-19 (defined as a positive polymerase chain reaction test for SARS-CoV-2), and were enrolled from March 2020 to October 2020. For this analysis, we selected participants who were enrolled at <14 weeks gestation and who underwent SARS-CoV-2 testing; 7 were excluded owing to a lack of longitudinal follow-up. The study was approved by the University of California, San Francisco Institutional Review Board (IRB #20-30410). Participants completed questionnaires at enrollment, weekly thereafter for 4 weeks, and then multiple times throughout pregnancy. Medical record review was used to adjudicate adverse outcomes in a subsample of the population. We calculated the incidence and 95% confidence intervals (CIs) for EPL, defined as pregnancy loss at <20 weeks' gestation. Among the 1338 PRIORITY participants, 109 were enrolled at <14 weeks gestation and comprised the analysis set; 94 had a positive test result for COVID-19 and 15 had a negative test result for COVID-19. All of the 109 patients were outpatients, and all were symptomatic. The average age of the population was 31 years; 33% of the participants were Hispanic (Table). The mean gestational age at enrollment was approximately 9 weeks; 83% of participants had at least 1 month of longitudinal follow-up before the end of pregnancy.TableDemographic and clinical characteristics of the study population according to COVID-19 statusCharacteristicsCOVID-19 positive, n=94COVID-19 negative, n=15Age (y), mean±SD31.2±4.7730.5±5.37Race and ethnicity, n (%) Asian4 (4.0)1 (5.9) American Indian or Alaska Native1 (1.0)0 (0.0) Black or African American2 (2.1)2 (13.3) Hispanic or Latina33 (35.1)3 (20.0) Native Hawaiian or Pacific Islander1 (1.1)0 (0.0) White62 (66.0)10 (66.7)Region, n (%) Midwest14 (14.9)4 (26.7) Northeast31 (33.0)1 (6.7) South17 (18.1)4 (26.7) West29 (30.9)6 (40.0)Gravida, mean±SD2.68±1.791.87±0.99Parity, mean±SD1.02±1.360.467±0.64Body mass index (kg/m2), mean±SD26.8±6.4524±4.22Gestational age at enrollment (wk), mean±SD9.76±2.849.83±3.24Health history, n (%) Asthma10 (10.6)1 (6.7) Hypertension2 (2.1)0 (0.0) Thyroid disease4 (4.3)3 (20.0) Depression15 (16.0)3 (20.0) Anxiety17 (18.1)6 (40.0) Current smoker1 (1.1)0 (0.0)SD, standard deviation.Jacoby. Risk of pregnancy loss at <20 weeks' gestation with COVID-19. Am J Obstet Gynecol 2021. Open table in a new tab SD, standard deviation. Jacoby. Risk of pregnancy loss at <20 weeks' gestation with COVID-19. Am J Obstet Gynecol 2021. In the COVID-19–positive group, 6 of 94 patients (6.4%; 95% CI, 2.4%–13.4%) had EPL compared with 1 of 15 in the COVID-19–negative group (6.7%; 95% CI, 0.1%–31.9%). In the COVID-19–positive group, 5 EPLs occurred at 7 to 12 weeks' gestation and 1 occurred at 15 weeks' gestation. In a subgroup analysis of 34 COVID-19–positive participants enrolled at <8 weeks' gestation, 2 of 34 patients had EPL (5.9%). In the COVID-19–positive group, 82 of 90 patients (91.1%; 95% CI, 83.2%–96.1%) had live births, of which 82.9% (95% CI, 73%–90.3%) were at term and 17.1% (95% CI 9.7%–27%) were at <37 weeks' gestation; 4 of 94 pregnancies are ongoing but all are at >24 weeks' gestation. In this nationwide study of pregnant people in the United States, the risk for pregnancy loss at <20 weeks' gestation was about 6% for both the participants with COVID-19 (n=94) and the controls without COVID-19 (n=15). These data compare favorably with the 10% rate of miscarriage among clinically recognized first-trimester pregnancies before the pandemic.6Magnus M.C. Wilcox A.J. Morken N.H. Weinberg C.R. Håberg S.E. Role of maternal age and pregnancy history in risk of miscarriage: prospective register based study.BMJ. 2019; 364: l869Crossref PubMed Scopus (338) Google Scholar This study conducted analyses of COVID-19 in 109 pregnant people in the first trimester in a longitudinal US cohort. With this sample size, the upper bound of the CI for pregnancy loss of 13.4% is reassuring because it is not significantly higher than the expected miscarriage rate without viral infection. These results can guide counseling for people infected with SARS-CoV-2 early in pregnancy.

BackgroundData regarding symptoms in the lactating mother-infant dyad and their immune response to COVID-19 mRNA vaccination during lactation are needed to inform vaccination guidelines.MethodsFrom a prospective cohort of 50 lactating individuals who received mRNA-based vaccines for COVID-19 (mRNA-1273 and BNT162b2), blood and milk samples were collected prior to first vaccination dose, immediately prior to 2nd dose, and 4-10 weeks after 2nd dose. Symptoms in mother and infant were assessed by detailed questionnaires. Anti-SARS-CoV-2 antibody levels in blood and milk were measured by Pylon 3D automated immunoassay and ELISA. In addition, vaccine-related PEGylated proteins in milk were measured by ELISA. Blood samples were collected from a subset of infants whose mothers received the vaccine during lactation (4-15 weeks after mothers’ 2nd dose).ResultsNo severe maternal or infant adverse events were reported in this cohort. Two mothers and two infants were diagnosed with COVID-19 during the study period before achieving full immune response. PEGylated proteins were not found at significant levels in milk after vaccination. After vaccination, levels of anti-SARS-CoV-2 IgG and IgM significantly increased in maternal plasma and there was significant transfer of anti-SARS-CoV-2-Receptor Binding Domain (anti-RBD) IgA and IgG antibodies to milk. Milk IgA levels after the 2nd dose were negatively associated with infant age. Anti-SARS-CoV-2 IgG antibodies were not detected in the plasma of infants whose mothers were vaccinated during lactation.ConclusionsCOVID-19 mRNA vaccines generate robust immune responses in plasma and milk of lactating individuals without severe adverse events reported.

While a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWASs), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of functional genomic annotations in human cell types relevant to pregnancy and PTB. We generated transcriptome (RNA-seq), epigenome (ChIP-seq of H3K27ac, H3K4me1, and H3K4me3 histone modifications), open chromatin (ATAC-seq), and chromatin interaction (promoter capture Hi-C) annotations of cultured primary decidua-derived mesenchymal stromal/stem cells and in vitro differentiated decidual stromal cells and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. Using these resources, we uncovered additional loci associated with gestational duration and target genes of associated loci. Our strategy illustrates how functional annotations in pregnancy-relevant cell types aid in the experimental follow-up of GWAS for PTB and, likely, other pregnancy-related conditions.

To evaluate antenatal corticosteroids (ANS) use in pregnant women with hypertension. Retrospective analysis of ANS use in the Perinatal Quality Collaborative of North Carolina between 2015 and 2017. Twenty-five centers participated, with 9% (1580/17,692) of mothers delivering at <34 weeks; of these, 81% (1286/1580) received a full course of ANS, which was not different between phases (p = 0.32), or between Level III/IV neonatal intensive care units (NICUs; 82%), and I/II NICUs (76%) (p = 0.05). In Level III/IV NICUs, White mothers were more likely to receive ANS (87%) than African Americans (77%) or other race/ethnicity (80%) (including Hispanics) (p = 0.001). ANS use did not differ among mothers with different payers (p = 0.94). The rates of full ANS courses did not significantly increase from 2015–2017 and disparities persisted. Targeted efforts to improve ANS exposures among hypertensive African American and Hispanic mothers, as well as in community hospital settings are needed.

Previous studies have demonstrated the presence of microbial DNA in the fetal environment. However, it remains unclear whether this DNA represents viable bacteria and how it relates to the maternal microbiota across body sites. We studied the microbiota of human and mouse dyads to understand these relationships, localize bacteria in the fetus, and demonstrate bacterial viability. In human preterm and full-term mother-infant dyads at the time of cesarean delivery, the oral cavity and meconium of newborn infants born as early as 24 weeks of gestation contained a microbiota that was predicted to originate from in utero sources, including the placenta. Using operative deliveries of pregnant mice under highly controlled, sterile conditions in the laboratory, composition, visualization, and viability of bacteria in the in utero compartment and fetal intestine were demonstrated by 16S rRNA gene sequencing, fluorescence in situ hybridization, and bacterial culture. The composition and predicted source of the fetal gut microbiota shifted between mid- and late gestation. Cultivatable bacteria in the fetal intestine were found during mid-gestation but not late gestation. Our results demonstrate a dynamic, viable mammalian fetal microbiota during in utero development.

Oxidative stress—mediated fetal membrane cell aging is activated prematurely in preterm premature rupture of membranes (PPROMs). The mechanism of this phenomenon is largely understudied. Progesterone receptor membrane component 1 (PGRMC1) has been recognized as a potential protective component for maintaining fetal membrane integrity and healthy pregnancies. We aimed to investigate the effects of oxidative stress (represented by hydrogen peroxide [H2O2]) on fetal membrane and chorion cell senescence, p38 mitogen-activated protein kinase (MAPK) phosphorylation, and sirtuin 3 (SIRT3) and to examine the roles of PGRMC1 in these effects. Following serum starvation for 24 hours, full-thickness fetal membrane explants and primary chorion cells were treated with H2O2 at 100, 300, and 500 µM for 24 hours. Cells were fixed for cell senescence-associated β-galactosidase assay. Cell lysates were harvested for quantitive reverse transcription polymerase chain reaction to quantify SIRT3 messenger RNA. Cell lysates were harvested for Western blot to semi-quantify SIRT3 protein and p38 MAPK phosphorylation levels, respectively. To examine the role of PGRMC1, primary chorion cells underwent the same treatment mentioned above following PGRMC1 knockdown using validated PGRMC1-specific small-interfering RNA. Hydrogen peroxide significantly induced cell senescence and p38 MAPK phosphorylation, and it significantly decreased SIRT3 expression in full-thickness fetal membrane explants and chorion cells. These effects were enhanced by PGRMC1 knockdown. This study further demonstrated that oxidative stress—induced cell aging is one of the mechanisms of PPROM and PGRMC1 acts as a protective element for maintaining fetal membrane integrity by inhibiting oxidative stress—induced chorion cell aging.

OBJECTIVE:To determine the prevalence of Mycoplasmataceae species in pregnant women and evaluate their association with immune system mediators. METHODS:Women were prospectively enrolled between 16-22 weeks' gestation. Vaginal swabs were self-collected and analyzed with PCR for Mycoplasma hominis (MH) and Mycoplasma genitalium (MG) as well as Ureaplasma urealyticum (UU) and Ureaplasma parvum (UP) (collectively, Myc). Immune mediators were measured via Luminex multiplex assay. Women with vaginal Mycoplasmataceae were compared to women without Myc, and women with Mycoplasma species (MH or MG) were compared to women without MH or MG. Linear regression models were used to investigate the relationship of the presence of Mycoplasmataceae on log-transformed immune mediators while controlling for confounders using propensity scores. RESULTS:One-hundred-twenty women were enrolled and had complete lab data available. Colonization was 20.8, 2.5, 10.0, and 48.3% for MH, MG, UU, and UP, respectively. Women with any Mycoplasmataceae were more likely to be younger, of the Black race, and have public insurance. There were no significant differences in immune mediators between women with vaginal Mycoplasmataceae versus those without. After controlling for confounders, women with MH and/or MG had significantly elevated levels of IL-1β compared to women without MH or MG (estimate =  1.12; 95% CI =  0.33, 1.93). There were no other significant differences in immune mediators in women with MH and/or MG compared to those without. CONCLUSIONS:Colonization rates were highest for UP and lowest for MG. Higher IL-1β levels were seen in the presence of MH and/or MG, indicating that these less frequently encountered organisms may incite a stronger host response. There were no other significant differences in immune mediator levels.