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.

Long-Term Risk for Type 1 Diabetes and Obesity in Early Term Born Offspring: A Systematic Review and Meta-Analysis.

CONTEXT: Prematurity increases the long-term risks for endocrine and metabolic morbidity of the offspring, but there is uncertainty regarding the risks for early-term deliveries (370/7-386/7 weeks of gestation). OBJECTIVE: We aim to evaluate whether early-term deliveries increase the long-term risk for type 1 diabetes and obesity of offspring up to the age of 18 years, as compared to full-term born children. DATA SOURCES: PubMed, Medline, and EMBASE. STUDY SELECTION: Observational cohort studies addressing the association between early-term delivery and long-term risk for type 1 diabetes and obesity, were included. DATA EXTRACTION: Two independent reviewers extracted data and assessed risk of bias. Pooled relative risks (RRs) and heterogeneity were determined. Publication bias was assessed by Funnel plots with Egger's regression line and contours, and sensitivity analyses were performed. RESULTS: Eleven studies were included following a screen of 7500 abstracts. All studies were scored high quality according to the Newcastle-Ottawa Quality Assessment Scale. Early-term delivery was significantly associated with an increased risk for type 1 diabetes (RR = 1.19[1.13-1.25]), while the association was weaker for overweight and obesity (RR = 1.05 [0.97-1.12]). LIMITATIONS: It is challenging to determine whether the association between early-term births and long-term morbidity represents a cause-and-effect relationship or is attributable to confounders. Most of the included studies adjusted for at least some possible confounders. CONCLUSION: Compared to full-term born offspring, early-term delivery poses a modest risk for long-term pediatric type 1 diabetes. Our analysis support that whenever medically possible, elective delivery should be avoided before 39 completed weeks of gestation.

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.

Boosting maternal and neonatal humoral immunity following SARS-CoV-2 infection using a single messenger RNA vaccine dose.

BACKGROUND: Post-COVID-19 vaccine boosting is a potent tool in the ongoing pandemic. Relevant data regarding this approach during pregnancy are lacking, which affects vaccination policy guidance, public acceptance, and vaccine uptake during pregnancy. We aimed to investigate the dynamics of anti-SARS-CoV-2 antibody levels following SARS-CoV-2 infection during pregnancy and to characterize the effect of a single postinfection vaccine booster dose on the anti-SARS-CoV-2 antibody levels in parturients in comparison with the levels in naïve vaccinated and convalescent, nonboosted parturients. STUDY DESIGN: Serum samples prospectively collected from parturients and umbilical cords at delivery at our university-affiliated urban medical center in Jerusalem, Israel, from May to October 2021, were selected and analyzed in a case-control manner. Study groups comprised the following participants: a consecutive sample of parturients with a polymerase chain reaction-confirmed history of COVID-19 during any stage of pregnancy; and comparison groups selected according to time of exposure comprising (1) convalescent, nonboosted parturients with polymerase chain reaction-confirmed COVID-19; (2) convalescent parturients with polymerase chain reaction-confirmed COVID-19 who received a single booster dose of the BNT162b2 messenger RNA vaccine; and (3) infection-naïve, fully vaccinated parturients who received 2 doses of the BNT162b2 messenger RNA vaccine. Outcomes that were determined included maternal and umbilical cord blood anti-SARS-CoV-2 antibody levels detected at delivery, the reported side effects, and pregnancy outcomes. RESULTS: A total of 228 parturients aged 18 to 45 years were included. Of those, samples from 64 were studied to characterize the titer dynamics following COVID-19 at all stages of pregnancy. The boosting effect was determined by comparing (1) convalescent (n=54), (2) boosted convalescent (n=60), and (3) naïve, fully vaccinated (n=114) parturients. Anti-SARS-CoV-2 antibody levels detected on delivery showed a gradual and significant decline over time from infection to delivery (r=0.4371; P=.0003). Of the gravidae infected during the first trimester, 34.6% (9/26) tested negative at delivery, compared with 9.1% (3/33) of those infected during the second trimester (P=.023). Significantly higher anti-SARS-CoV-2 antibody levels were observed among boosted convalescent than among nonboosted convalescent (17.6-fold; P<.001) and naïve vaccinated parturients (3.2-fold; P<.001). Similar patterns were observed in umbilical cord blood. Side effects in convalescent gravidae resembled those in previous reports of mild symptoms following COVID-19 vaccination during pregnancy. CONCLUSION: Postinfection maternal humoral immunity wanes during pregnancy, leading to low or undetectable protective titers for a marked proportion of patients. A single boosting dose of the BNT162b2 messenger RNA vaccine induced a robust increase in protective titers for both the mother and newborn with moderate reported side effects.

Emergency department non-contrast computed tomography for suspicion of obstructive urolithiasis: Yield and consequences.

INTRODUCTION: We aimed to analyze patterns of referral, yield, and clinical implications of non-contrast computed tomography (NCCT) in the acute evaluation of flank pain suspected as obstructive urolithiasis (OU) in a high-volume emergency department (ED). METHODS: The study comprised 506 consecutive NCCTs performed in the ED over four months. Detection rates of OU, incidental, and alternative findings were calculated. Imaging signs suspicious for recent passage of stones were considered positive for OU, while renal stones without signs of obstruction were considered unrelated to the acute presentation. OU, other findings requiring hospitalization, and incidental findings warranting further workup were considered situations in which NCCTs were warranted. RESULTS: NCCTs confirmed an OU diagnosis in 162 (32%) patients and non-clinically significant nephrolithiasis in 125 (25%). They revealed other findings in 108 (21%) patients, including 42 (8%) with clinically significant incidental findings and 26 (5%) with alternative diagnoses requiring hospitalization. NCCTs were entirely negative in 111 (22%) patients. Corroboration of these outcomes, together with overlapping of OU, incidental, and alternative significant findings in some patients resulted in an overall justified NCCT request rate of 44%. CONCLUSIONS: The yield of NCCT performed in acute presentations of flank pain suspected as OU is relatively low, and over one-half of the scans are unwarranted. The pattern of requesting NCCT in the ED needs refinement to avoid abuse that may lead to radiation overexposure, psychological burden, physical harm, and financial overload.

Safety of SARS-CoV-2 vaccination during pregnancy- obstetric outcomes from a large cohort study.

BACKGROUND: COVID-19 during pregnancy is associated with adverse outcomes for mother and fetus. SARS-CoV-2 vaccination has significantly reduced the risk of symptomatic disease. Several small studies have reported the safety of SARS-CoV-2 vaccination during pregnancy, with no adverse effect on obstetric outcomes. OBJECTIVE: To examine the association between SARS-CoV-2 vaccination during pregnancy and maternal and neonatal outcomes in a large cohort study. Furthermore, to evaluate if timing of vaccination during pregnancy is related to adverse outcomes. METHODS: A retrospective cohort study of women who delivered between December 2020 and July 2021 at a large tertiary medical center. Excluded were women with multiple pregnancy, vaccination prior to pregnancy, COVID-19 infection during or before pregnancy, or unknown timing of vaccination. Primary outcomes were the incidence of preterm labor and of small for gestational age. Secondary outcomes were other maternal and neonatal complications. A secondary analysis investigating the association between time of vaccination and outcomes was also performed. Multivariable logistic regression models were used to adjust for potential confounders. RESULTS: There were 5618 women who met the inclusion criteria: 2,305 (41%) women were vaccinated and 3,313 (59%) were unvaccinated. There were no differences between vaccinated and non-vaccinated patients with respect to primary outcomes. The rate of preterm birth was 5.5% in the vaccinated group compared to 6.2% in the unvaccinated group (p = 0.31). Likewise, the rates of small for gestational age were comparable between the two groups (6.2% vs. 7.0% respectively, p = 0.2). In a secondary analysis focusing on time of vaccination and its relationship with outcomes, patients vaccinated in the second trimester (n = 964) and in the third trimester (n = 1329) were independently compared to their unvaccinated counterparts. Women who were vaccinated in the second trimester were more likely to have a preterm birth (8.1% vs. 6.2%, p < 0.001). This association persisted after adjusting for potential confounders (adjusted odds ratio 1.49, 95%CI 1.11, 2.01). CONCLUSIONS: SARS-CoV-2 vaccine appears to be safe during pregnancy with no increase in incidence of preterm labor and small for gestational age compared to unvaccinated women. However, in women vaccinated during the second trimester there may be an increase in the rate of preterm birth.

Long-term respiratory outcomes in early-term born offspring: a systematic review and meta-analysis.

OBJECTIVE: Newborns exhibit the lowest immediate respiratory morbidity rates when born at full term (39-40 completed weeks of gestation). We evaluated whether early-term deliveries (37 0/7 to 38 6/7 weeks of gestation) bear a substantial impact on overall and specific long-term respiratory outcomes of offspring up to the age of 18 years compared with full-term or later deliveries. DATA SOURCES: We searched PubMed, Medline, Embase, and relevant reference lists from January 2012 to May 2020. STUDY ELIGIBILITY CRITERIA: This systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews guidelines and was registered on International Prospective Register of Systematic Reviews. Any observational or randomized human trials addressing the association between early-term delivery and long-term respiratory outcomes in the offspring, restricted to studies published in English, were included. The search included terms relating to gestational age, pediatric morbidity, and respiratory outcomes. We included studies assessing long-term respiratory disease (1-18 years) of offspring born early term compared with offspring born full term and later. METHODS: Here, 2 independent reviewers extracted data and assessed the risk of bias. Using a random-effect meta-analysis, pooled relative risk with their 95% confidence intervals and heterogeneity were determined. Publication bias was assessed using funnel plots with Egger regression line and contours, and sensitivity analyses were performed using Baujat plots. RESULTS: Overall, 14 studies were included after screening nearly 2500 abstracts. These studies included nearly 8 million patients and were subjected to qualitative and quantitative analyses. Early-term delivery significantly increased the risk of total respiratory morbidity in the offspring (relative risk, 1.20; 95% confidence interval, 1.16-1.26) compared with full-term delivery. The increased respiratory morbidity was attributed to obstructive airway diseases (relative risk, 1.19; 95% confidence interval, 1.12-1.27) and infectious respiratory diseases (relative risk, 1.22; 95% confidence interval, 1.17-1.29). Most studies were of acceptable quality. CONCLUSION: This comprehensive meta-analysis suggested that early-term delivery poses a risk of long-term pediatric respiratory morbidity compared with full-term delivery. Other factors throughout the years cannot be accounted for. Our study has added an important perspective to be considered when balancing the fetal, maternal, and neonatal risks associated with delivery timing.

Cancer diagnosis among women with recurrent pregnancy loss: a retrospective cohort study.

RESEARCH QUESTION: What is relationship between unexplained recurrent pregnancy loss (RPL) and risk of cancer morbidity? DESIGN: A retrospective observational cohort study was conducted, based on data from a tertiary medical centre. RPL cases (exposed) were defined as women presenting with three or more unexplained confirmed pregnancy losses at 5-24 weeks, whose first visit to the RPL clinic was between 1990 and 2010. The unexposed group included women giving birth who were not RPL patients; these were matched by age and year of giving birth/admission (1:5 ratio). Data from the RPL and the live birth registries were cross-linked to the Israeli national cancer registry according to the unique ID number and merged into one database. RESULTS: The study group comprised 937 RPL patients who were matched by maternal age (P = 1.0) and admission date (P = 0.84) to 4685 women achieving a live birth. There was no difference in overall cancer incidence between groups (adjusted odds ratio [OR] 0.76, 95% confidence interval [CI] 0.55-1.03; P = 0.08). The secondary RPL group showed a trend towards decreased cancer morbidity incidence compared with primary RPL (adjusted OR 0.65, 95% CI 0.41-1.03; P = 0.07). Analysis by cancer type showed a similar risk for breast cancer among women with RPL compared with live birth, but a significantly lower risk for gynaecological cancers among women with RPL (adjusted OR 0.25, 95% CI 0.08-0.79; P = 0.018). CONCLUSIONS: Unexplained RPL may be related to a lower risk of gynaecological cancers, possibly explained by hyper-responsive immunological mechanisms involving uterine natural killer cells.

Thromboembolic events in pregnant and puerperal women after COVID-19 lockdowns: A retrospective cohort study.

OBJECTIVE: To explore the indirect impact of the COVID-19 pandemic on patterns of pregnancy-related venous thromboembolism (VTE) events, mediated by population mobility restrictions during lockdown periods. METHODS: Pregnancy-related VTE hospitalizations were identified through a code-targeted search of the Hadassah Medical Center's computerized database. A manual analysis of relevant medical records was performed, and cases diagnosed throughout the year 2020 were compared to those diagnosed during 2019 and 2018. Statistical analyses studied obstetrical outcomes, as well as the extent and treatment of VTE events during the COVID-19 pandemic compared to those of preceding years, stratified by pre-, intra-, and post-lockdown periods. RESULTS: The incidence of pregnancy-related thromboembolic events during 2020 was 0.16% of all deliveries, significantly higher than in 2018 and 2019 (0.06% and 0.1%, respectively; P < 0.05). Higher rates of VTE events were found during post-lockdown periods in 2020, compared with corresponding time periods in 2019 and 2018. CONCLUSION: The present data suggest that lockdown periods impact pregnancy-related VTE hospitalizations, possibly as a result of restricted population mobility. Increased awareness of this undesirable outcome may aid health policymakers in the continuing struggle with epidemics.

The association between Müllerian anomalies and perinatal outcome.

INTRODUCTION: Deviation in the development of the female reproductive organs from the normal anatomy has been shown to have an impact on obstetrical outcomes and neonatal morbidity. MATERIAL AND METHODS: In this retrospective population-based cohort study, short-term neonatal morbidity and mortality were compared in pregnancies of women with and without uterine anomalies. The analysis included deliveries that occurred between the years 1991 and 2013 in a tertiary medical center. Statistical analysis included multiple logistic regression models. RESULTS: During the study period, 256,299 deliveries met the inclusion criteria; 0.49% (n = 1251) of which occurred in women diagnosed with Müllerian anomalies. In the regression model, Müllerian anomalies were noted as an independent risk factor for placental abruption (adjusted odds ratio, 1.9; 95% confidence interval, 1.3-2.8; p = .001), intrauterine growth restriction (adjusted odds ratio, 1.9; 95% confidence interval, 1.5-2.4; p < .001), pathological presentation (adjusted odds ratio, 13.5; 95% confidence interval, 11.9-15.1; p < .001) and cesarean delivery (adjusted odds ratio, 13.4; 95% confidence interval, 11.5-15.6; p < .001) while controlling for multiple confounders. Perinatal mortality, however, was not found to be increased in the exposed group in a model controlled for gestational age and weight (adjusted odds ratio, 0.6; 95% confidence interval, 0.4-1.02; p = .061). CONCLUSION: Women with Müllerian anomalies are at an increased risk for multiple adverse pregnancy outcomes, including preterm delivery and intrauterine growth restriction. Perinatal mortality, however, is not increased when controlled for gestational age and weight suggesting that mortality in these pregnancies is mediated by preterm delivery and small for gestational age.

Maternal müllerian anomalies and future health of the offspring.

OBJECTIVE: To evaluate whether offspring of women with müllerian anomalies are at an increased risk for long-term pediatric morbidity. STUDY DESIGN: A population-based cohort study compared the incidence of long-term (up to the age of 18 years for offspring) hospitalizations due to cardiovascular, endocrine, neurological, hematological, respiratory and urinary morbidity of offspring to mothers diagnosed with uterine anomalies. Deliveries occurred between the years 1991 and 2013 in a tertiary medical center. Multiple pregnancies, unknown gestational age, gestational age of less than 24 weeks, perinatal mortality, and fetuses with congenital malformations were excluded. Kaplan-Meier survival curves were used to compare cumulative morbidity incidence. Survival analysis for clustered data was performed for each major-system pediatric hospitalization. RESULTS: During the study period 253,808 deliveries met the inclusion criteria; 0.48% (n=1230) of which occurred in women diagnosed with müllerian anomalies. In the Kaplan-Meier survival curve, children born to mothers with müllerian anomalies did not have a significantly different cumulative incidence of any of the long-term pediatric morbidities, compared with the comparison group. In the multivariable survival analysis for clustered data, after adjustment of maternal clusters, maternal age, gestational age and birthweight, müllerian anomalies did not exhibit an independent association with long-term morbidities of the offspring. CONCLUSION: Müllerian anomalies do not appear to have an independent impact on long-term morbidity of the offspring.