Maternal hybrid immunity and risk of infant COVID-19 hospitalizations: national case-control study in Israel.

Hybrid immunity, acquired through vaccination followed or preceded by a COVID-19 infection, elicits robust antibody augmentation. We hypothesize that maternal hybrid immunity will provide greater infant protection than other forms of COVID-19 immunity in the first 6 months of life. We conducted a case-control study in Israel, enrolling 661 infants up to 6 months of age, hospitalized with COVID-19 (cases) and 59,460 age-matched non-hospitalized infants (controls) between August 24, 2021, and March 15, 2022. Infants were grouped by maternal immunity status at delivery: Naïve (never vaccinated or tested positive, reference group), Hybrid-immunity (vaccinated and tested positive), Natural-immunity (tested positive before or during the study period), Full-vaccination (two-shot regimen plus 1 booster), and Partial-vaccination (less than full three shot regimen). Applying Cox proportional hazards models to estimate the hazard ratios, which was then converted to percent vaccine effectiveness, and using the Naïve group as the reference, maternal hybrid-immunity provided the highest protection (84% [95% CI 75-90]), followed by full-vaccination (66% [95% CI 56-74]), natural-immunity (56% [95% CI 39-68]), and partial-vaccination (29% [95% CI 15-41]). Maternal hybrid-immunity was associated with a reduced risk of infant hospitalization for Covid-19, as compared to natural-immunity, regardless of exposure timing or sequence. These findings emphasize the benefits of vaccinating previously infected individuals during pregnancy to reduce COVID-19 hospitalizations in early infancy.

[NUCHAL TRANSLUCENCY CONCURRENT WITH EARLY ANOMALY SCAN: TIME TO RECONSIDER].

INTRODUCTION: During the last decades, a major achievement was reported in detecting Down's syndrome in the first trimester of pregnancy. This is attributed to the use of high-resolution accurate ultrasound machine allowing the detection of a "nuchal translucency" in the back of the fetus during 11-14 weeks' gestation. This is considered to be a physiologic finding, but when increased, may alert for chromosomal abnormality (mainly Down's syndrome), cardiac and other organ anomalies and other genetic syndromes. Later additional sonographic findings were found, including nasal bone assessment, and Doppler flow studies of the ductus venosus and tricuspid regurgitation Technology advancement accompanied by sonographers' skills enhancement allows (at the time frame of the nuchal scan) a detailed anomaly scan. Additional screening for pregnancy complication was achieved using first trimester multi marker assessment, alerting for preeclamptic toxemia or placenta accreta. Currently, many national and international professional organizations recommend performing the nuchal scan concurrent with an early anomaly scan both at the same time of gestation. This approach is different than the one performed in Israel, whereas the nuchal scan is conducted separately and 2-3 weeks later an anomaly scan is offered. We call for reconsideration of the sequential approach and performing all the tests in a comprehensive first trimester clinic.

Pregnancy trained decidual NK cells protect pregnancies from harmful Fusobacterium nucleatum infection.

Natural killer cells (NKs) found during pregnancy at the maternal-fetal interface named decidual (d)NKs, show signs of education following first pregnancy, resulting in better placentation and fetus-growth, hence termed pregnancy trained dNKs (PTdNKs). Here we show that PTdNKs provide increased protection of the fetus from Fusobacterium nucleatum (FN) infection. We demonstrate that PTdNKs secrete elevated amounts of the bacteriocidal protein granulysin (GNLY) upon incubation with FN compared to dNKs derived from first pregnancies, which leads to increased killing of FN. Furthermore, we showed mechanistically that the GNLY secretion is mediated through the interaction of the FN's Fap2 protein with Gal-GalNAc present on PTdNKs. Finally, we show in vivo, using GNLY-tg mice that enhanced protection of the fetuses from FN infection is observed, as compared to wild type and that this enhance protection is NK cell dependent. Altogether, we show a new function for PTdNKs as protectors of the fetus from bacterial infection.

Fetal Inguinal Hernia: Case Report and Review of the Literature.

Fetal inguinal hernia (FIH) is a rare event and only few cases were published in the medical literature. In the present study, we aimed to characterize the sonographic features, clinical presentation, management, outcomes, and differential diagnoses of FIH. Accordingly, we reviewed all 17 cases of FIH published in the medical literature, including one new case evaluated by our group. All 17 cases (100%) were male, and FIH is presented as a scrotal mass with a mean diameter of 38 ± 9.5 mm. The right side was dominant (62%). Peristalsis was reported in 80% of the cases, and blood flow was reported in two-thirds. Most cases were diagnosed in the third trimester (88%) at a mean gestational age (GA) of 33.1 ± 5.2 weeks. 60% of the cases had isolated FIH, and 40% had another sonographic or genetic abnormality. Three cases (18%) were syndromic with multiple malformations: trisomy 18, skeletal anomalies due to Jarcho-Levin syndrome, and undefined multiple joint contractures. Two cases (12%) had copathologies in the gastrointestinal tract: one had an echogenic bowel due to homozygosity for cystic fibrosis, and the other had low anorectal malformation. Bowel loop dilatation was observed prenatally in both cases and in another one isolated case (18%). GA at delivery was 38 ± 1.8 weeks, and the median time between diagnosis and delivery was 3 weeks. All three cases of neonatal death occurred in syndromic fetuses. All patients with nonsyndromic inguinal hernias underwent definitive surgical repair at a median of 13 days postpartum. No signs of strangulation and only one case of edematous bowel without necrosis have been reported. In conclusion, FIH should be suspected in male fetuses when an intrascrotal mass with peristalsis is diagnosed during the third trimester. Close follow-up until term in the absence of signs of bowel obstruction is reasonable, and in isolated FIH, the prognosis is favorable.

Expert review: preeclampsia Type I and Type II.

Pregnancy involves an interplay between maternal and fetal factors affecting changes to maternal anatomy and physiology to support the developing fetus and ensure the well-being of both the mother and offspring. A century of research has provided evidence of the imperative role of the placenta in the development of preeclampsia. Recently, a growing body of evidence has supported the adaptations of the maternal cardiovascular system during normal pregnancy and its maladaptation in preeclampsia. Debate surrounds the roles of the placenta vs the maternal cardiovascular system in the pathophysiology of preeclampsia. We proposed an integrated model of the maternal cardiac-placental-fetal array and the development of preeclampsia, which reconciles the disease phenotypes and their proposed origins, whether placenta-dominant or maternal cardiovascular system-dominant. These phenotypes are sufficiently diverse to define 2 distinct types: preeclampsia Type I and Type II. Type I preeclampsia may present earlier, characterized by placental dysfunction or malperfusion, shallow trophoblast invasion, inadequate spiral artery conversion, profound syncytiotrophoblast stress, elevated soluble fms-like tyrosine kinase-1 levels, reduced placental growth factor levels, high peripheral vascular resistance, and low cardiac output. Type I is more often accompanied by fetal growth restriction, and low placental growth factor levels have a measurable impact on maternal cardiac remodeling and function. Type II preeclampsia typically occurs in the later stages of pregnancy and entails an evolving maternal cardiovascular intolerance to the demands of pregnancy, with a moderately dysfunctional placenta and inadequate blood supply. The soluble fms-like tyrosine kinase-1-placental growth factor ratio may be normal or slightly disturbed, peripheral vascular resistance is low, and cardiac output is high, but these adaptations still fail to meet demand. Emergent placental dysfunction, coupled with an increasing inability to meet demand, more often appears with fetal macrosomia, multiple pregnancies, or prolonged pregnancy. Support for the notion of 2 types of preeclampsia observable on the molecular level is provided by single-cell transcriptomic survey of gene expression patterns across different cell classes. This revealed widespread dysregulation of gene expression across all cell types, and significant imbalance in fms-like tyrosine kinase-1 (FLT1) and placental growth factor, particularly marked in the syncytium of early preeclampsia cases. Classification of preeclampsia into Type I and Type II can inform future research to develop targeted screening, prevention, and treatment approaches.

The Impact of Advanced Maternal Age on Pregnancy Outcomes: A Retrospective Multicenter Study.

The aim of this multicenter retrospective cohort study was to examine the impact of maternal age on perinatal outcomes in multiparas, stratified according to maternal age in one- and two-year increments. The analysis involved 302,484 multiparas who delivered between the years 2003 and 2021 in four university-affiliated obstetrics departments. Maternal age was considered both as a continuous variable and in two-year intervals, as compared with a comparison group of parturients aged 25-30 years. The study focused on cesarean delivery and neonatal intensive care unit (NICU) admission as primary outcomes. The findings revealed that cesarean delivery rates increased as maternal age advanced, with rates ranging from 6.7% among 25-30 year olds, rising continuously from 13.5% to 19.9% between the age strata of 31 and 42, to exceeding 20% among those aged ≥ 43 years (p < 0.01 for each stratum when compared to 25-30 year old group). Similarly, NICU admission rates rose from 2.7% in the comparison group to 6% in parturients aged 45-46 years (p < 0.01 for each stratum when compared to 25-30 year old group). The study highlights the association between incrementally advanced maternal age and increased rates of maternal and neonatal complications, necessitating global awareness of these implications for family planning decisions and maternal care.

Two distinct molecular faces of preeclampsia revealed by single-cell transcriptomics.

INTRODUCTION: Preeclampsia is a multisystemic, pregnancy-specific disorder united by new-onset hypertension but with considerable variation in clinical manifestation, onset, and severity. For symptoms to regress, delivery of the placenta is required. For symptoms to regress, delivery of the placenta is required, making the placenta central to preeclampsia pathophysiology. To dissect which placental functions were impacted in two forms of preeclampsia, we studied molecular changes across the cell types of the placenta. METHODS: We performed a transcriptomic survey of single-cells and single-nuclei on cases of early- and late-onset preeclampsia with gestation-matched controls. FINDINGS: Our data revealed massive dysregulation of gene expression in all cell classes that was almost exclusive to early preeclampsia. For example, an important known receptor/ligand imbalance hallmarking angiogenic disfunction, sFLT1/placental growth factor (PGF), was reflected in striking, cell-autonomous dysregulation of FLT1 and PGF transcription in the syncytium in early preeclampsia only. Stromal cells and vasculature echoed an inflamed, stressed, anti-angiogenic environment. Finally, the placental immune niche set the tone for inflammation in early but not late preeclampsia. Here, fetal-origin Hofbauer and maternal-origin TREM2 macrophages were revealed as surprising main actors, while local cells of the adaptive immune system were largely unaffected. Late preeclampsia showed minimal cellular impact on the placenta. CONCLUSIONS: Our survey provides systematic molecular evidence for two distinct diseases. We resolved systematic molecular dysregulation to individual cell types with strong implications for definition, early detection, diagnosis, and treatment. FUNDING: Funded by the Preeclampsia Foundation through the Peter Joseph Pappas Research Grant.

[THE DIFFERENTIAL DIAGNOSIS OF EXTREMELY HIGH MATERNAL SERUM ALPHA FETOPROTEIN - A CASE REPORT].

INTRODUCTION: A 34 years-old woman was referred to genetic counseling due to extremely high maternal serum alpha fetoprotein (MSAFP) of 58 MoM (541 IU/mL, 654 ng/mL) in the second trimester biochemical test. The couple has five healthy children, three of them were delivered by cesarean section. Current pregnancy follow-up was uneventful except for the demonstration of placenta percreta during anomaly scan. The test also ruled out neural tube or abdominal wall defect. AFP levels in amniotic fluid were normal thus fetal disease was ruled out as the etiology. Total body MRI ruled out space occupying lesion as a source of ectopic secretion of AFP. After exclusion of other ominous etiologies for this extremely high MSAFP, it was related to the placental pathology and probably to abnormal feto-maternal shunts. Fetal fraction in cell free DNA was 18%, considered relatively high, a hint for those speculated shunts. We reviewed the literature regarding the differential diagnosis of high MSAFP including fetal, maternal and placental sources.

Pluripotency-independent induction of human trophoblast stem cells from fibroblasts.

Human trophoblast stem cells (hTSCs) can be derived from embryonic stem cells (hESCs) or be induced from somatic cells by OCT4, SOX2, KLF4 and MYC (OSKM). Here we explore whether the hTSC state can be induced independently of pluripotency, and what are the mechanisms underlying its acquisition. We identify GATA3, OCT4, KLF4 and MYC (GOKM) as a combination of factors that can generate functional hiTSCs from fibroblasts. Transcriptomic analysis of stable GOKM- and OSKM-hiTSCs reveals 94 hTSC-specific genes that are aberrant specifically in OSKM-derived hiTSCs. Through time-course-RNA-seq analysis, H3K4me2 deposition and chromatin accessibility, we demonstrate that GOKM exert greater chromatin opening activity than OSKM. While GOKM primarily target hTSC-specific loci, OSKM mainly induce the hTSC state via targeting hESC and hTSC shared loci. Finally, we show that GOKM efficiently generate hiTSCs from fibroblasts that harbor knockout for pluripotency genes, further emphasizing that pluripotency is dispensable for hTSC state acquisition.

Maternal third dose of BNT162b2 mRNA vaccine and risk of infant COVID-19 hospitalization.

Infants are at a higher risk of Coronavirus Disease 2019 (COVID-19)-related hospitalizations compared to older children. In this study, we investigated the effect of the recommended third maternal dose of BNT162b2 COVID-19 vaccine during pregnancy on rates of infant COVID-19-related hospitalizations. We conducted a nationwide cohort study of all live-born infants delivered in Israel between 24 August 2021 and 15 March 2022 to estimate the effectiveness of the third booster dose versus the second dose against infant COVID-19-related hospitalizations. Data were analyzed for the overall study period, and the Delta and Omicron periods were analyzed separately. Cox proportional hazard regression models estimated hazard ratios and 95% confidence intervals (CIs) for infant hospitalizations according to maternal vaccination status at delivery. Among 48,868 live-born infants included in the analysis, rates of COVID-19 hospitalization were 0.4%, 0.6% and 0.7% in the third-dose, second-dose and unvaccinated groups, respectively. Compared to the second dose, the third dose was associated with reduced infant hospitalization with estimated effectiveness of 53% (95% CI: 36-65%). Greater protection was associated with a shorter interval between vaccination and delivery. A third maternal dose during pregnancy reduced the risk of infant hospitalization for COVID-19 during the first 4 months of life, supporting clinical and public health guidance for maternal booster vaccination to prevent infant COVID-19 hospitalization.

A Scoring System Developed by a Machine Learning Algorithm to Better Predict Adnexal Torsion.

STUDY OBJECTIVE: To establish a clinically relevant prediction score for the diagnosis of adnexal torsion (AT) in women who were operated on for suspected AT. DESIGN: A retrospective cohort study conducted between 2014 and 2021. SETTING: A large tertiary teaching medical center. PATIENTS: Women who underwent urgent laparoscopy for suspected AT. INTERVENTIONS: Analyses included univariate and multivariate models combined with the machine learning (ML) Random Forest model, which included all information available about the women and reported the accuracy of the model and the importance of each variable. Based on this model, we created a predictive score and evaluated its accuracy by receiver operating characteristic (ROC) curve. MEASUREMENTS AND MAIN RESULTS: A total of 503 women were included in our study, 244 (49%) of whom were diagnosed with AT during the surgery, and 44 (8.8%) cases of necrotic ovary were found. Based on the Random Forrest and multivariate models, the most important preoperative clinical predictive variables for AT were vomiting, left-side complaints, and concurrent pregnancy; cervical tenderness and urinary symptoms decreased the likelihood of surgically confirmed AT. The most important sonographic findings that predicted increased risk of surgically confirmed AT were ovarian edema and decreased vascular flow; in contrast, hemorrhagic corpus luteum decreased the likelihood of surgically confirmed AT. The accuracy of the Random Forest model was 71% for the training set and 68% for the testing set, and the area under the curve for the multivariate model was 0.75 (95% confidence interval [CI] 0.69-0.80). Based on these models, we created a predictive score with a total score that ranges from 4 to 12. The area under the curve for this score was 0.72 (95% CI 0.67-0.76), and the best cutoff for the final score was >5, with a sensitivity, specificity, positive predictive value, and negative predictive value of 64%, 73%, 70%, and 67%, respectively. CONCLUSION: Clinical characteristics and ultrasound findings may be incorporated into the emergency room workup of women with suspected AT. ML in this setting has no diagnostic/predictive advantage over the performance of logistic regression methods. Additional prospective studies are needed to confirm the accuracy of this model.

Boosting maternal and neonatal anti-SARS-CoV-2 humoral immunity using a third mRNA vaccine dose.

BACKGROUND: To minimize COVID-19 pandemic burden and spread, 3-dose vaccination campaigns commenced worldwide. Since patients who are pregnant are at increased risk for severe disease, they were recently included in that policy, despite the lack of available evidence regarding the impact of a third boosting dose during pregnancy, underscoring the urgent need for relevant data. We aimed to characterize the effect of the third boosting dose of mRNA Pfizer BNT162b2 vaccine in pregnancy. METHODS: We performed a prospective cohort study of anti-SARS-CoV-2 antibody titers (n = 213) upon delivery in maternal and cord blood of naive fully vaccinated parturients who received a third dose (n = 86) as compared with 2-dose recipients (n = 127). RESULTS: We found a robust surge in maternal and cord blood levels of anti-SARS-CoV-2 titers at the time of delivery, when comparing pregnancies in which the mother received a third boosting dose with 2-dose recipients. The effect of the third boosting dose remained significant when controlling for the trimester of last exposure, suggesting additive immunity extends beyond that obtained after the second dose. Milder side effects were reported following the third dose, as compared with the second vaccine dose, among the fully vaccinated group. CONCLUSION: The third boosting dose of mRNA Pfizer BNT162b2 vaccine augmented maternal and neonatal immunity with mild side effects. These data provide evidence to bolster clinical and public health guidance, reassure patients, and increase vaccine uptake among patients who are pregnant. FUNDING: Israel Science Foundation KillCorona grant 3777/19; Research grant from the "Ofek" Program of the Hadassah Medical Center.

The role of vaginal progesterone for preterm birth prevention in women with threatened labor and shortened cervix diagnosed after 24 weeks of pregnancy.

OBJECTIVE: To determine whether vaginal progesterone treatment for women with a short cervix, diagnosed after 24 weeks of pregnancy, reduces preterm birth rates. METHODS: A retrospective cohort study that included women with a singleton pregnancy, threatened preterm labor, and a short cervix measured between 24+0 and 33+6 weeks. Women who received vaginal progesterone were compared with women who did not receive progesterone. The primary outcome was spontaneous preterm birth before 37 weeks of pregnancy. RESULTS: Patients who received vaginal progesterone had a lower rate of preterm delivery at less than 37 weeks of pregnancy (18.2% [22/121] versus 28.9% [73/253]; adjusted hazard ratio 0.50; 95% confidence interval 0.28-0.73, P = 0.001). The diagnosis-to-delivery interval was significantly greater in patients who received progesterone than in those who did not-median time to delivery in weeks: 8.2 (interquartile range [IQR] 6.2-9.8) versus 6.6 (4.8-8.8), (P < 0.001). The frequency of neonatal intensive care unit admission was significantly lower in patients who received progesterone than in those who did not (8.3% [10/121] versus 16.2% [41/253], P = 0.04). CONCLUSIONS: The administration of vaginal progesterone to patients with an episode of threatened premature labor and a short cervix presenting after 24 weeks of pregnancy was associated with lower rates of premature births.

Improved differentiation between hypo/hypertelorism and normal fetuses based on MRI using automatic ocular biometric measurements, ocular ratios, and machine learning multi-parametric classification.

OBJECTIVES: To differentiate hypo-/hypertelorism (abnormal) from normal fetuses using automatic biometric measurements and machine learning (ML) classification based on MRI. METHODS: MRI data of normal (n = 244) and abnormal (n = 52) fetuses of 22-40 weeks' gestational age (GA), scanned between March 2008 and June 2020 on 1.5/3T systems with various T2-weighted sequences and image resolutions, were included. A fully automatic method including deep learning and geometric algorithms was developed to measure the binocular (BOD), inter-ocular (IOD), ocular (OD) diameters, and ocular volume (OV). Two new parameters, BOD-ratio and IOD-ratio, were defined as the ratio between BOD/IOD relative to the sum of both globes' OD, respectively. Eight ML classifiers were evaluated to detect abnormalities using measured and computed parameters. RESULTS: The automatic method yielded a mean difference of BOD = 0.70 mm, IOD = 0.81 mm, OD = 1.00 mm, and a 3D-Dice score of OV = 93.7%. In normal fetuses, all four measurements increased with GA. Constant values were detected for BOD-ratio = 1.56 ± 0.05 and IOD-ratio = 0.60 ± 0.05 across all GA and when calculated from previously published reference data of both MRI and ultrasound. A random forest classifier yielded the best results on an independent test set (n = 58): AUC-ROC = 0.941 and F1-Score = 0.711 in comparison to AUC-ROC = 0.650 and F1-Score = 0.385 achieved based on the accepted criteria that define hypo/hypertelorism based on IOD (< 5th or > 95th percentiles). Using the explainable ML method, the two computed ratios were found as the most contributing parameters. CONCLUSIONS: The developed fully automatic method demonstrates high performance on varied clinical imaging data. The new BOD and IOD ratios and ML multi-parametric classifier are suggested to improve the differentiation of hypo-/hypertelorism from normal fetuses. KEY POINTS: • A fully automatic method for computing fetal ocular biometry from MRI is proposed, achieving high performance, comparable to that of an expert fetal neuro-radiologist. • Two new parameters, IOD-ratio and BOD-ratio, are proposed for routine clinical use in ultrasound and MRI. These two ratios are constant across gestational age in normal fetuses, consistent across studies, and differentiate between fetuses with and without hypo/hypertelorism. • Multi-parametric machine learning classification based on automatic measurements and the two new ratios improves the identification of fetal ocular anomalies beyond the accepted criteria (<5th or >95th IOD percentiles).

Exome sequencing for structurally normal fetuses-yields and ethical issues.

The yield of chromosomal microarray analysis (CMA) is well established in structurally normal fetuses (0.4-1.4%). We aimed to determine the incremental yield of exome sequencing (ES) in this population. From February 2017 to April 2022, 1,526 fetuses were subjected to ES; 482 of them were structurally normal (31.6%). Only pathogenic and likely pathogenic (P/LP) variants, per the American College of Medical Genetics and Genomics (ACMG) classification, were reported. Additionally, ACMG secondary findings relevant to childhood were reported. Four fetuses (4/482; 0.8%) had P/LP variants indicating a moderate to severe disease in ATP7B, NR2E3, SPRED1 and FGFR3, causing Wilson disease, Enhanced S-cone syndrome, Legius and Muenke syndromes, respectively. Two fetuses had secondary findings, in RET and DSP. Our data suggest that offering only CMA for structurally normal fetuses may provide false reassurance. Prenatal ES mandates restrictive analysis and careful management combined with pre and post-test genetic counseling.

Prediction of the degree of abnormal invasive placentation by obstetric history.

BACKGROUND: Diagnosis of placenta accrete spectrum (PAS) disorders is of utmost importance and mostly relies on high index of suspicion and sonographic criteria. The degree of abnormal invasive placentation is strongly associated with patients' outcomes. We aimed to determine the association between prior obstetric characteristics and the degree of PAS. METHODS: A retrospective cohort study. The study cohort comprised all women who delivered by cesarean delivery with a histopathological diagnosis of PAS during 2005-2019. We divided the cohort into 2 groups: severe PAS (increta/percreta) and mild PAS (accrete). Obstetrical characteristics and last delivery and cesarean characteristics were compared. RESULTS: Overall, 130 cases of histopathologically proven PAS were included. Of those 104 (80.0%) were mild PAS and 26 (20.0%) severe PAS. Both groups did not differ in terms of age and obstetric history. Mean parity of both study groups was 4. Intrapartum fever as noticed in 2.9-3.8% of primary cesarean (P=1.0). Cervical dilation at time of primary cesarean delivery was similar between the groups (mean 5 vs. 6 centimeters, P=0.73). Urgent cesarean delivery rate did not differ between groups (69.2% vs. 50.%, P=0.07). Method of hysterotomy closure was comparable as well. The only different variable found between groups was the rate of cephalic presentation at previous cesarean was higher in mild PAS group 69 (66.3%) vs. 11 (42.3%), P=0.024. odds ratio 2.68, 95% confidence interval 1.11-6.45. CONCLUSIONS: Discrimination of PAS severity by obstetric and previous surgical history is questionable. Our findings might be limited by sample size. Future prospective studies are warranted.

Effectiveness of a third BNT162b2 mRNA COVID-19 vaccination during pregnancy: a national observational study in Israel.

The Centers for Disease Control (CDC) recommend a third dose of COVID-19 vaccine for pregnant women, although data regarding effectiveness during pregnancy are lacking. This national, population-based, historical cohort study of pregnant women in Israel, delivering between August 1, 2021 and March 22, 2022, aims to analyze and compare the third and second doses' vaccine effectiveness in preventing COVID-19-related hospitalizations during pregnancy during two COVID-19 waves (Delta variant in the summer of 2021 and Omicron, BA.1, variant in the winter of 2022). Time-dependent Cox proportional-hazards regression models estimate the hazard ratios (HR) and 95% confidence intervals (CI) for COVID-related outcomes according to vaccine dose, and vaccine effectiveness as 1-HR. Study includes 82,659 and 33,303 pregnant women from the Delta and Omicron waves, respectively. Compared with the second dose, the third dose effectively prevents overall hospitalizations with SARS-CoV-2 infections, with estimated effectiveness of 92% (95% CI 83-96%) during Delta, and enhances protection against significant disease during Omicron, with effectiveness of 92% (95% CI 26-99%), and 48% (95% CI 37-57%) effectiveness against hospitalization overall. A third dose of the BNT162b2 mRNA COVID-19 vaccine during pregnancy, given at least 5 months after the second vaccine dose, enhances protection against adverse COVID-19-related outcomes.

SARS-CoV-2 IgG Antibody Levels in Women with IBD Vaccinated during Pregnancy.

INTRODUCTION: Regulatory agencies supported vaccination of pregnant women with SARS-CoV-2 mRNA vaccines, including patients with IBD. No data exist regarding these vaccines in IBD during pregnancy. AIM: To assess the serologic response to two doses of the mRNA SARS-CoV-2 BNT162b2 vaccine in pregnant women with IBD vaccinated during pregnancy, compared to that of pregnant women without IBD, and non-pregnant women with IBD. METHODS: Anti-spike antibody levels were assessed in all women and in cord blood of consenting women. RESULTS: From December 2020 to December 2021, 139 women were assessed: pregnant with IBD-36, pregnant without IBD-61, and not pregnant with IBD-42. Antibodies were assessed in cords of two and nine newborns of women with and without IBD, respectively. Mean gestational ages at administration of the second vaccine doses were 22.0 weeks in IBD and 23.2 weeks in non-IBD, respectively. Mean (SD) duration from the second vaccine dose to serology analysis in pregnant women with IBD, without IBD, and in non-pregnant women with IBD was 10.6 (4.9), 16.4 (6.3), and 4.3 (1.0) weeks, respectively. All women mounted a serologic response. In multivariable analysis, no correlation was found between the specific group and antibody levels. In both pregnancy groups, an inverse correlation between antibody levels and the interval from the second vaccine dose was demonstrated. Cord blood antibody levels exceeded maternal levels in women with and without IBD. CONCLUSION: All patients with IBD mounted a serologic response. The interval between vaccine administration to serology assessment was the most important factor determining antibody levels. A third vaccine dose should be considered in pregnant women with IBD vaccinated at early stages of pregnancy.