RSV Prefusion F Protein-Based Maternal Vaccine - Preterm Birth and Other Outcomes.

BACKGROUND: Vaccination against respiratory syncytial virus (RSV) during pregnancy may protect infants from RSV disease. Efficacy and safety data on a candidate RSV prefusion F protein-based maternal vaccine (RSVPreF3-Mat) are needed. METHODS: We conducted a phase 3 trial involving pregnant women 18 to 49 years of age to assess the efficacy and safety of RSVPreF3-Mat. The women were randomly assigned in a 2:1 ratio to receive RSVPreF3-Mat or placebo between 24 weeks 0 days and 34 weeks 0 days of gestation. The primary outcomes were any or severe medically assessed RSV-associated lower respiratory tract disease in infants from birth to 6 months of age and safety in infants from birth to 12 months of age. After the observation of a higher risk of preterm birth in the vaccine group than in the placebo group, enrollment and vaccination were stopped early, and exploratory analyses of the safety signal of preterm birth were performed. RESULTS: The analyses included 5328 pregnant women and 5233 infants; the target enrollment of approximately 10,000 pregnant women and their infants was not reached because enrollment was stopped early. A total of 3426 infants in the vaccine group and 1711 infants in the placebo group were followed from birth to 6 months of age; 16 and 24 infants, respectively, had any medically assessed RSV-associated lower respiratory tract disease (vaccine efficacy, 65.5%; 95% credible interval, 37.5 to 82.0), and 8 and 14, respectively, had severe medically assessed RSV-associated lower respiratory tract disease (vaccine efficacy, 69.0%; 95% credible interval, 33.0 to 87.6). Preterm birth occurred in 6.8% of the infants (237 of 3494) in the vaccine group and in 4.9% of those (86 of 1739) in the placebo group (relative risk, 1.37; 95% confidence interval [CI], 1.08 to 1.74; P = 0.01); neonatal death occurred in 0.4% (13 of 3494) and 0.2% (3 of 1739), respectively (relative risk, 2.16; 95% CI, 0.62 to 7.56; P = 0.23), an imbalance probably attributable to the greater percentage of preterm births in the vaccine group. No other safety signal was observed. CONCLUSIONS: The results of this trial, in which enrollment was stopped early because of safety concerns, suggest that the risks of any and severe medically assessed RSV-associated lower respiratory tract disease among infants were lower with the candidate maternal RSV vaccine than with placebo but that the risk of preterm birth was higher with the candidate vaccine. (Funded by GlaxoSmithKline Biologicals; ClinicalTrials.gov number, NCT04605159.).

A Phase 2 Clinical Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of Different Prime-Boost Vaccination Schedules of 2013 and 2017 A(H7N9) Inactivated Influenza Virus Vaccines Administered With and Without AS03 Adjuvant in Healthy US Adults.

INTRODUCTION: A surge of human influenza A(H7N9) cases began in 2016 in China from an antigenically distinct lineage. Data are needed about the safety and immunogenicity of 2013 and 2017 A(H7N9) inactivated influenza vaccines (IIVs) and the effects of AS03 adjuvant, prime-boost interval, and priming effects of 2013 and 2017 A(H7N9) IIVs. METHODS: Healthy adults (n = 180), ages 19-50 years, were enrolled into this partially blinded, randomized, multicenter phase 2 clinical trial. Participants were randomly assigned to 1 of 6 vaccination groups evaluating homologous versus heterologous prime-boost strategies with 2 different boost intervals (21 vs 120 days) and 2 dosages (3.75 or 15 µg of hemagglutinin) administered with or without AS03 adjuvant. Reactogenicity, safety, and immunogenicity measured by hemagglutination inhibition and neutralizing antibody titers were assessed. RESULTS: Two doses of A(H7N9) IIV were well tolerated, and no safety issues were identified. Although most participants had injection site and systemic reactogenicity, these symptoms were mostly mild to moderate in severity; injection site reactogenicity was greater in vaccination groups receiving adjuvant. Immune responses were greater after an adjuvanted second dose, and with a longer interval between prime and boost. The highest hemagglutination inhibition geometric mean titer (95% confidence interval) observed against the 2017 A(H7N9) strain was 133.4 (83.6-212.6) among participants who received homologous, adjuvanted 3.75 µg + AS03/2017 doses with delayed boost interval. CONCLUSIONS: Administering AS03 adjuvant with the second H7N9 IIV dose and extending the boost interval to 4 months resulted in higher peak antibody responses. These observations can broadly inform strategic approaches for pandemic preparedness. Clinical Trials Registration. NCT03589807.

A Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus Infection.

BACKGROUND: Primary cytomegalovirus (CMV) infection during pregnancy carries a risk of congenital infection and possible severe sequelae. There is no established intervention for preventing congenital CMV infection. METHODS: In this multicenter, double-blind trial, pregnant women with primary CMV infection diagnosed before 24 weeks' gestation were randomly assigned to receive a monthly infusion of CMV hyperimmune globulin (at a dose of 100 mg per kilogram of body weight) or matching placebo until delivery. The primary outcome was a composite of congenital CMV infection or fetal or neonatal death if CMV testing of the fetus or neonate was not performed. RESULTS: From 2012 to 2018, a total of 206,082 pregnant women were screened for primary CMV infection before 23 weeks of gestation; of the 712 participants (0.35%) who tested positive, 399 (56%) underwent randomization. The trial was stopped early for futility. Data on the primary outcome were available for 394 participants; a primary outcome event occurred in the fetus or neonate of 46 of 203 women (22.7%) in the group that received hyperimmune globulin and of 37 of 191 women (19.4%) in the placebo group (relative risk, 1.17; 95% confidence interval [CI] 0.80 to 1.72; P = 0.42). Death occurred in 4.9% of fetuses or neonates in the hyperimmune globulin group and in 2.6% in the placebo group (relative risk, 1.88; 95% CI, 0.66 to 5.41), preterm birth occurred in 12.2% and 8.3%, respectively (relative risk, 1.47; 95% CI, 0.81 to 2.67), and birth weight below the 5th percentile occurred in 10.3% and 5.4% (relative risk, 1.92; 95% CI, 0.92 to 3.99). One participant in the hyperimmune globulin group had a severe allergic reaction to the first infusion. Participants who received hyperimmune globulin had a higher incidence of headaches and shaking chills while receiving infusions than participants who received placebo. CONCLUSIONS: Among pregnant women, administration of CMV hyperimmune globulin starting before 24 weeks' gestation did not result in a lower incidence of a composite of congenital CMV infection or perinatal death than placebo. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Center for Advancing Translational Sciences; ClinicalTrials.gov number, NCT01376778.).

Prenatal Vaccination Patterns among Birthing Individuals with History of Preterm Birth in the Pre- and Post-COVID Era.

OBJECTIVE: This study aims to explore vaccination acceptance among individuals with a history of preterm birth between March and June during the pre-COVID (2019), early-COVID (2020), and late-COVID (2021) periods. STUDY DESIGN: This is a cross-sectional, retrospective cohort study of pregnant individuals with a history of preterm birth (<37 weeks' gestation) who initiated care of a subsequent pregnancy during pre-COVID (March-June 2019), early-COVID (March-June 2020), or late-COVID (March-June 2021). The primary outcome of interest was vaccination status for influenza, Tdap, and COVID-19 vaccines. Fisher's exact and chi-square tests were used to investigate association between vaccination status and time periods, race/ethnicity, and insurance. RESULTS: Among 293 pregnancies, influenza vaccination rate was highest in early-COVID (p < 0.05). There was no statistically significant difference in Tdap or COVID-19 vaccination between time periods. COVID-19 vaccination was highest in individuals with private insurance (p < 0.05). There was no statistically significant difference in vaccination status by race/ethnicity. CONCLUSION: In this study on high-risk pregnant individuals, the majority of our cohort remained unvaccinated against COVID-19 into the late-COVID period. Additionally, their influenza vaccination rates were greater than the national average in early-COVID and substantially lower than the national average in late-COVID. This shift in influenza vaccination acceptance may have been sparked by COVID-19 vaccine distribution beginning in January 2021 leading to overall vaccination hesitancy. Standardized guidelines and counseling concerning prenatal safety in recommended immunizations may serve as important tools of reassurance and health promotion. KEY POINTS: · Maternal infections during pregnancy are a risk factor for preterm birth.. · High-risk cohort had low influenza vaccination post-COVID possibly due to COVID-19 vaccine hesitancy.. · Vaccination education may be a uniquely important tool among high-risk pregnant patients..

Neurodevelopmental Outcomes After Late Preterm Antenatal Corticosteroids: The ALPS Follow-Up Study.

Importance: The Antenatal Late Preterm Steroids (ALPS) trial changed clinical practice in the United States by finding that antenatal betamethasone at 34 to 36 weeks decreased short-term neonatal respiratory morbidity. However, the trial also found increased risk of neonatal hypoglycemia after betamethasone. This follow-up study focused on long-term neurodevelopmental outcomes after late preterm steroids. Objective: To evaluate whether administration of late preterm (34-36 completed weeks) corticosteroids affected childhood neurodevelopmental outcomes. Design, Setting, and Participants: Prospective follow-up study of children aged 6 years or older whose birthing parent had enrolled in the multicenter randomized clinical trial, conducted at 13 centers that participated in the Maternal-Fetal Medicine Units (MFMU) Network cycle from 2011-2016. Follow-up was from 2017-2022. Exposure: Twelve milligrams of intramuscular betamethasone administered twice 24 hours apart. Main Outcome and Measures: The primary outcome of this follow-up study was a General Conceptual Ability score less than 85 (-1 SD) on the Differential Ability Scales, 2nd Edition (DAS-II). Secondary outcomes included the Gross Motor Function Classification System level and Social Responsiveness Scale and Child Behavior Checklist scores. Multivariable analyses adjusted for prespecified variables known to be associated with the primary outcome. Sensitivity analyses used inverse probability weighting and also modeled the outcome for those lost to follow-up. Results: Of 2831 children, 1026 enrolled and 949 (479 betamethasone, 470 placebo) completed the DAS-II at a median age of 7 years (IQR, 6.6-7.6 years). Maternal, neonatal, and childhood characteristics were similar between groups except that neonatal hypoglycemia was more common in the betamethasone group. There were no differences in the primary outcome, a general conceptual ability score less than 85, which occurred in 82 (17.1%) of the betamethasone vs 87 (18.5%) of the placebo group (adjusted relative risk, 0.94; 95% CI, 0.73-1.22). No differences in secondary outcomes were observed. Sensitivity analyses using inverse probability weighting or assigning outcomes to children lost to follow-up also found no differences between groups. Conclusion and Relevance: In this follow-up study of a randomized clinical trial, administration of antenatal corticosteroids to persons at risk of late preterm delivery, originally shown to improve short-term neonatal respiratory outcomes but with an increased rate of hypoglycemia, was not associated with adverse childhood neurodevelopmental outcomes at age 6 years or older.

Safety and Immunogenicity of Influenza A/H5N8 Virus Vaccine in Healthy Adults: Durability and Cross-reactivity of Antibody Responses.

BACKGROUND: Influenza A/H5N8 viruses infect poultry and wild birds in many countries. In 2021, the first human A/H5N8 cases were reported. METHODS: We conducted a phase I, cohort-randomized, double-blind, controlled trial of inactivated influenza A/H5N8 vaccine (clade 2.3.4.4c) administered with or without adjuvant. Cohort 1 subjects received either two doses of AS03-adjuvanted vaccine containing 3.75 µg or 15 µg hemagglutinin (HA); two doses of 15 µg HA unadjuvanted vaccine; or one dose of AS03-adjuvanted vaccine (3.75 µg or 15 µg HA), followed by one dose of non-adjuvanted vaccine (same HA content). Cohort 2 subjects received two doses of MF59-adjuvanted vaccine containing 3.75 µg or 15 µg HA, or 15 µg HA of non-adjuvanted vaccine. Subjects were followed for 13 months for safety and immunogenicity. RESULTS: We enrolled 386 adult subjects in good health. Solicited adverse events were generally mild and more common among subjects who received adjuvanted vaccines. Antibody responses (hemagglutination inhibition or microneutralization assays) were highest in the two-dose AS03 group, followed by the one-dose AS03 group, the MF59 groups, and the non-adjuvanted groups. Antibody levels returned to baseline 12 months after the second vaccination in all groups except the 15 µg AS03-adjuvanted group. Cross-reactive antibodies to clade 2.3.4.4b strains isolated from recent human cases were demonstrated in a subset of both 15 µg adjuvanted groups. CONCLUSIONS: Two doses of influenza A/H5N8 vaccine were well-tolerated. Immunogenicity improved with receipt of two doses of adjuvanted vaccine and higher antigen content. (Funded by the National Institute of Allergy and Infectious Diseases.

Respiratory Syncytial Virus Vaccination during Pregnancy and Effects in Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is the dominant cause of severe lower respiratory tract infection in infants, with the most severe cases concentrated among younger infants. METHODS: Healthy pregnant women, at 28 weeks 0 days through 36 weeks 0 days of gestation, with an expected delivery date near the start of the RSV season, were randomly assigned in an overall ratio of approximately 2:1 to receive a single intramuscular dose of RSV fusion (F) protein nanoparticle vaccine or placebo. Infants were followed for 180 days to assess outcomes related to lower respiratory tract infection and for 364 days to assess safety. The primary end point was RSV-associated, medically significant lower respiratory tract infection up to 90 days of life, and the primary analysis of vaccine efficacy against the primary end point was performed in the per-protocol population of infants (prespecified criterion for success, lower bound of the 97.52% confidence interval [CI] of ≥30%). RESULTS: A total of 4636 women underwent randomization, and there were 4579 live births. During the first 90 days of life, the percentage of infants with RSV-associated, medically significant lower respiratory tract infection was 1.5% in the vaccine group and 2.4% in the placebo group (vaccine efficacy, 39.4%; 97.52% CI, -1.0 to 63.7; 95% CI, 5.3 to 61.2). The corresponding percentages for RSV-associated lower respiratory tract infection with severe hypoxemia were 0.5% and 1.0% (vaccine efficacy, 48.3%; 95% CI, -8.2 to 75.3), and the percentages for hospitalization for RSV-associated lower respiratory tract infection were 2.1% and 3.7% (vaccine efficacy, 44.4%; 95% CI, 19.6 to 61.5). Local injection-site reactions among the women were more common with vaccine than with placebo (40.7% vs. 9.9%), but the percentages of participants who had other adverse events were similar in the two groups. CONCLUSIONS: RSV F protein nanoparticle vaccination in pregnant women did not meet the prespecified success criterion for efficacy against RSV-associated, medically significant lower respiratory tract infection in infants up to 90 days of life. The suggestion of a possible benefit with respect to other end-point events involving RSV-associated respiratory disease in infants warrants further study. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov NCT02624947.).

Factors Associated with Guideline Concordant Clinician Counseling about Low-Dose Aspirin to Prevent Preeclampsia in Nulliparous Patients.

OBJECTIVE: The primary aim of this study was to examine the United States Preventative Services Task Force (USPSTF) guidelines concordant low-dose aspirin (LDA) counseling and factors associated with counseling in nulliparous birthing individuals. STUDY DESIGN: We conducted a retrospective cohort study of nulliparous birthing individuals who delivered between January 1, 2019 and June 30, 2020 and received prenatal care at the Duke High Risk Obstetrical Clinics (HROB). All nulliparous patients over 18 years old who established or transferred care to HROB by 16 weeks, 6 days were included in the analysis. We excluded patients with more than two previous first-trimester pregnancy losses, multiple gestation, a known contraindication to LDA, initiation of LDA prior to their prenatal care, or documented medical history of coagulation disorder. Bivariate associations between demographic/medical characteristics and our primary outcome, receipt of counseling (yes/no), were assessed using two-sample t-tests for continuous variables and chi-square or Fisher's exact test for categorical variables. Factors significantly associated with the primary outcome (p < 0.05) were entered into the multivariable logistic regression model. RESULTS: Among 391 birthing individuals included in the final analysis cohort, 51.7% of eligible patients received guideline consistent LDA counseling. Factors associated with increased odds of LDA counseling were advanced maternal age (adjusted odds ratio [aOR]: 1.05, 95% confidence interval [CI]: 1.01-1.09), Black race compared with White race (aOR:1.75, 95% CI: 1.03-2.98), chronic hypertension (aOR: 4.17, 95% CI: 1.82-9.55), and obesity (aOR: 5.02, 95% CI: 3.12-8.08). CONCLUSION: Approximately half of all nulliparous birthing individuals had appropriately documented LDA counseling. The USPSTF guidelines on LDA for preeclampsia risk reduction are complex, which may lead to ineffective provider adherence. Efforts to simplify guidelines and improve LDA counseling are vital to ensuring this low-cost, evidence-based preeclampsia prevention is used in a consistent and equitable manner. KEY POINTS: · A total of 51.7% of eligible patients received guideline consistent LDA counseling.. · Advanced maternal age , body mass index > 30, Black race, and chronic hypertension associated with increased odds of counseling.. · Among patients most likely to be counseled, high numbers did not receive LDA counseling..

Maternal and Neonatal Outcomes in Nulliparous Participants Undergoing Labor Induction by Cervical Ripening Method.

OBJECTIVE: This study aimed to evaluate maternal and neonatal outcomes by method of cervical ripening for labor induction among low-risk nulliparous individuals. STUDY DESIGN: This is a secondary analysis of a multicenter randomized trial of labor induction at 39 weeks versus expectant management in low-risk nulliparous participants. Participants undergoing cervical ripening for labor induction in either group were included. Participants were excluded for preripening membrane rupture, abruption, chorioamnionitis, fetal demise, or cervical dilation ≥3.5 cm. Cervical ripening was defined by the initial method used: prostaglandin only (PGE; referent), Foley with concurrent prostaglandin (Foley-PGE), Foley only (Foley), and Foley with concurrent oxytocin (Foley-oxytocin). Coprimary outcomes were adverse maternal and neonatal composites. Secondary outcomes included cesarean delivery and length of labor and delivery (L&D) stay. Multivariable analysis was used to adjust for patient characteristics. RESULTS: Of 6,106 participants included in the trial, 2,376 (38.9%) met criteria for this analysis. Of these, 1,247 (52.4%) had cervical ripening with PGE, 290 (12.2%) had Foley-PGE, 385 (16.2%) had Foley, and 454 (19.1%) had Foley-oxytocin. The maternal composite outcome was similar among participants who received Foley-PGE (24.1%, adjusted relative risk [aRR] = 1.21, 95% confidence interval [CI]: 0.96-1.52), Foley (21.3%, aRR = 1.16, 95% CI: 0.92-1.45), or Foley-oxytocin (19.4%, aRR = 1.04, 95% CI: 0.83-1.29), compared with PGE (19.7%). The neonatal composite outcome was less frequent in participants who received the Foley-PGE (2.4%, aRR = 0.35, 95% CI: 0.16-0.75) or Foley (3.6%, aRR = 0.51, 95% CI: 0.29-0.89) but did not reach statistical significance for participants who received Foley-oxytocin (4.6%, aRR = 0.63, 95% CI: 0.40-1.01) compared with PGE only (6.8%). Participants who received Foley-PGE or Foley-oxytocin had a shorter L&D stay (adjusted mean difference = -1.97 hours, 95% CI: -3.45 to -0.49 and -5.92 hours, 95% CI: -7.07 to -4.77, respectively), compared with PGE. CONCLUSION: In term low-risk nulliparous participants, Foley alone or concurrent with PGE is associated with a lower risk of adverse neonatal outcomes than with PGE alone. Length of L&D stay was the shortest with concurrent Foley-oxytocin. KEY POINTS: · Adverse maternal outcomes are similar among different methods of cervical ripening in low-risk women.. · Adverse neonatal outcomes are less frequent with use of Foley alone or in combination with PGE.. · The use of Foley alone, or in combination with other agents, appears to be beneficial..

Evaluation of Hypoglycemia in Neonates of Women at Risk for Late Preterm Delivery: An Antenatal Late Preterm Steroids Trial Cohort Study.

OBJECTIVE: In the antenatal late preterm steroids (ALPS) trial betamethasone significantly decreased short-term neonatal respiratory morbidity but increased the risk of neonatal hypoglycemia, diagnosed only categorically (<40 mg/dL). We sought to better characterize the nature, duration, and treatment for hypoglycemia. STUDY DESIGN: Secondary analysis of infants from ALPS, a multicenter trial randomizing women at risk for late preterm delivery to betamethasone or placebo. This study was a reabstraction of all available charts from the parent trial, all of which were requested. Unreviewed charts included those lost to follow-up or from sites not participating in the reabstraction. Duration of hypoglycemia (<40 mg/dL), lowest value and treatment, if any, were assessed by group. Measures of association and regression models were used where appropriate. RESULTS: Of 2,831 randomized, 2,609 (92.2%) were included. There were 387 (29.3%) and 223 (17.3%) with hypoglycemia in the betamethasone and placebo groups, respectively (relative risk [RR]: 1.69, 95% confidence interval [CI]: 1.46-1.96). Hypoglycemia generally occurred in the first 24 hours in both groups: 374/385 (97.1%) in the betamethasone group and 214/222 (96.4%) in the placebo group (p = 0.63). Of 387 neonates with hypoglycemia in the betamethasone group, 132 (34.1%) received treatment, while 73/223 (32.7%) received treatment in placebo group (p = 0.73). The lowest recorded blood sugar was similar between groups. Most hypoglycemia resolved by 24 hours in both (93.0 vs. 89.3% in the betamethasone and placebo groups, respectively, p = 0.18). Among infants with hypoglycemia in the first 24 hours, the time to resolution was shorter in the betamethasone group (2.80 [interquartile range: 2.03-7.03) vs. 3.74 (interquartile range: 2.15-15.08) hours; p = 0.002]. Persistence for >72 hours was rare and similar in both groups, nine (2.4%, betamethasone) and four (1.9%, placebo, p = 0.18). CONCLUSION: In this cohort, hypoglycemia was transient and most received no treatment, with a quicker resolution in the betamethasone group. Prolonged hypoglycemia was uncommon irrespective of steroid exposure. KEY POINTS: · Hypoglycemia was transient and approximately two-thirds received no treatment.. · Neonates in the ALPS trial who received betamethasone had a shorter time to resolution than those with hypoglycemia in the placebo group.. · Prolonged hypoglycemia occurred in approximately 2 out of 100 late preterm newborns, irrespective of antenatal steroid exposure..

Exosomes in the visual system: New avenues in ocular diseases.

Exosomes are a subgroup of membrane-bound extracellular vesicles secreted by all cell types and present virtually in all biological fluids. The composition of exosomes in the same cell type varies in healthy and disease conditions. Hence, exosomes research is a prime focus area for clinical research in cancer and numerous age-related metabolic syndromes. Functions of exosomes include crucial cell-to-cell communication that mediates complex cellular processes, such as antigen presentation, stem cell differentiation, and angiogenesis. However, very few studies reported the presence and role of exosomes in normal physiological and pathological conditions of specialized ocular tissues of the eye and ocular cancers. The eye being a protected sense organ with unique connectivity with the rest of the body through the blood and natural passages, we believe that the role of exosomes in ocular tissues will significantly improve our understanding of ocular diseases and their interactions with the rest of the body. We present a review that highlights the existence and function of exosomes in various ocular tissues, their role in the progression of some of the neoplastic and non-neoplastic conditions of the eyes.

Hypertension in pregnancy and adverse outcomes among low-risk nulliparous women expectantly managed at or after 39 weeks: a secondary analysis of a randomised controlled trial.

OBJECTIVE: To evaluate whether hypertensive disorders of pregnancy (HDP) among low-risk nulliparous women expectantly managed at or after 39 weeks of gestation are associated with adverse outcomes. DESIGN: Secondary analysis of a randomised trial. SETTING: Multicentre, USA. POPULATION: Individuals in the expectantly managed group who delivered on or after 39 weeks. METHODS: Multivariable analysis to estimate adjusted relative risks (aRR) for binomial outcomes, adjusted odds ratios (aOR) for multinomial outcomes and 95% CI. MAIN OUTCOME MEASURES: Composite adverse maternal outcome including placental abruption, pulmonary oedema, postpartum haemorrhage, postpartum infection, venous thromboembolism or intensive care unit admission. Secondary outcomes included a composite of perinatal death or severe neonatal complications, mode of delivery, small and large for gestational age and neonatal intermediate or intensive unit length of stay. RESULTS: Of the 3044 women randomised to expectant management in the original trial, 2718 (89.3%) were eligible for this analysis, of whom 373 (13.7%) developed HDP. Compared with participants who remained normotensive, those who developed HDP were more likely to experience the maternal composite (12% versus 6%, aRR 1.84, 95% CI 1.33-2.54) and caesarean delivery (29% versus 23%, aOR 1.32, 95% CI 1.01-1.71). Differences between the two groups were not significantly different for the adverse perinatal composite (7% versus 5%, aRR 1.38, 95% CI 0.92-2.07) or for other secondary outcomes. CONCLUSION: Almost 14% of low-risk nulliparous individuals expectantly managed at 39 weeks developed HDP, and were more likely to experience adverse maternal outcomes compared with those who did not develop HDP. TWEETABLE ABSTRACT: Almost 14% of low-risk nulliparous individuals expectantly managed at 39 weeks developed hypertensive disorders of pregnancy, and were more likely to experience adverse maternal outcomes compared with those who did not develop hypertensive disorders.

Effects of Smoking Reduction and Cessation on Birth Outcomes in a Scheduled Gradual Reduction Cessation Trial.

INTRODUCTION: Smoking during pregnancy can affect infant birthweight. We tested whether an intervention that promoted scheduled gradual reduction improved birth outcomes among pregnant women who smoked. We also examined race differences in birth outcomes. METHODS: We conducted a 2-arm randomized controlled trial where pregnant women who smoked received either SMS text-delivered scheduled gradual smoking reduction (SGR) program plus support texts or support messages only throughout their pregnancy. The outcomes for this paper were birth outcomes including birth weight and gestational age obtained from chart review. Analyses were conducted using chi-square and t-tests in SAS. RESULTS: We approached 2201 pregnant women with smoking history. Of the 314 women recruited into the study, 290 completed a medical release form (92%). We did not find any significant differences in birth outcomes by arm or race. The majority of participants reduced smoking by the 80%. Women who reduced more than 50% of their baseline cigarettes per day had a birth weight increase of 335 g compared to those that did not (p = 0.05). The presence of alcohol/drug use in prenatal visit notes was associated with low infant birth weight (p = 0.05). DISCUSSION: The scheduled gradual reduction intervention did not improve birth outcomes. Additional research is needed to help improve birth outcomes for pregnant women who engage in tobacco and illicit substance use. CLINICAL TRIAL #: NCT01995097.

Racial and ethnic representation in 17-hydroxyprogesterone caproate preterm birth prevention studies: a systematic review.

OBJECTIVES: The US preterm birth rate varies dramatically by race and ethnicity yet the racial and ethnic representation within studies evaluating 17-hydroxprogesterone caproate (17-P) for preterm birth prevention is unknown. The objectives of our study were to 1) examine the racial and ethnic representation of participants in 17-P preterm birth prevention studies, 2) evaluate adherence to the NIH race and ethnicity reporting guidelines and 3) compare racial and ethnic representation in research studies to national preterm birth incidence. METHODS: We systematically reviewed US studies published between January 2000 and December 2019. Study participant's race and ethnicity were reported using descriptive statistics then compared to US 2017//2018 preterm birth data using Pearson's chi-square. RESULTS: Eighteen studies met the inclusion criteria, 17 studies reported race, 11 studies reported ethnicity, and yet none of the studies followed the NIH criteria. Compared to 2017/2018 US preterm births, the proportion of black/African American study participants was significantly higher whereas the proportions of all other race categories were lower. CONCLUSIONS: More detailed reporting of race and ethnicity is needed in 17-P literature. Black women appear to be well represented while other racial and ethnic groups may be understudied.

The Association between Prenatal Nicotine Exposure and Offspring's Hearing Impairment.

OBJECTIVE: The objective of this study is to evaluate whether there is an association between in-utero exposure to nicotine and subsequent hearing dysfunction. PATIENTS AND METHODS: Secondary analysis of a multicenter randomized trial to prevent congenital cytomegalovirus (CMV) infection among gravidas with primary CMV infection was conducted. Monthly intravenous immunoglobulin hyperimmune globulin therapy did not influence the rate of congenital CMV. Dyads with missing urine, fetal or neonatal demise, infants diagnosed with a major congenital anomaly, congenital CMV infection, or with evidence of middle ear dysfunction were excluded. The primary outcome was neonatal hearing impairment in one or more ears defined as abnormal distortion product otoacoustic emissions (DPOAEs; 1 to 8 kHz) that were measured within 42 days of birth. DPOAEs were interpreted using optimized frequency-specific level criteria. Cotinine was measured via enzyme-linked immunosorbent assay kits in maternal urine collected at enrollment and in the third trimester (mean gestational age 16.0 and 36.7 weeks, respectively). Blinded personnel ran samples in duplicates. Maternal urine cotinine >5 ng/mL at either time point was defined as in-utero exposure to nicotine. Multivariable logistic regression included variables associated with the primary outcome and with the exposure (p < 0.05) in univariate analysis. RESULTS: Of 399 enrolled patients in the original trial, 150 were included in this analysis, of whom 46 (31%) were exposed to nicotine. The primary outcome occurred in 18 (12%) newborns and was higher in nicotine-exposed infants compared with those nonexposed (15.2 vs. 10.6%, odds ratio [OR] 1.52, 95% confidence interval [CI] 0.55-4.20), but the difference was not significantly different (adjusted odds ratio [aOR] = 1.0, 95% CI 0.30-3.31). This association was similar when exposure was stratified as heavy (>100 ng/mL, aOR 0.72, 95% CI 0.15-3.51) or mild (5-100 ng/mL, aOR 1.28, 95% CI 0.33-4.95). There was no association between nicotine exposure and frequency-specific DPOAE amplitude. CONCLUSION: In a cohort of parturients with primary CMV infection, nicotine exposure was not associated with offspring hearing dysfunction assessed with DPOAEs. KEY POINTS: · Nicotine exposure was quantified from maternal urine.. · Nicotine exposure was identified in 30% of the cohort.. · Exposure was not associated with offspring hearing dysfunction..

Does Multimodal Treatment Improve Eye and Life Salvage in Adenoid Cystic Carcinoma of the Lacrimal Gland?

PURPOSE: To evaluate the efficacy of multimodal treatment in adenoid cystic carcinoma (ACC) of the lacrimal gland. METHODS: A retrospective comparative case series of 40 consecutive patients with ACC of the lacrimal gland without systemic metastasis at the initial presentation and primarily managed by one of the 3 treatment protocols-surgery + external beam radiotherapy (EBRT) (group 1), surgery + EBRT + adjuvant chemotherapy (group 2), and neoadjuvant chemotherapy + surgery + EBRT + adjuvant chemotherapy (multimodal treatment) (group 3) at a tertiary care ocular oncology center. Local tumor control, eye salvage, and systemic metastasis were the primary outcome measures. RESULTS: The age ranged from 11 to 72 (mean ± SD, 36 ± 13; median, 36) years with 26 (65%) male and 14 (35%) female patients. Twelve (30%) patients belonged to group 1, 8 (20%) to group 2, and 20 (50%) to group 3. Primary surgery included tumor excision in 36 (90%) and orbital exenteration in 4 (10%). Chemotherapy composed of cisplatin + 5 fluorouracil (5FU) for 6 cycles in 28 (70%) patients. Extended-field stereotactic EBRT with a dose of 5,000-6,000 cGy included the entire pretreatment extent of the tumor with a 10-mm margin all around, superior orbital fissure, inferior orbital fissure, cavernous sinus, and temporal fossa. Mean duration of follow up after completion of treatment was 58 ± 26 (range, 29-180; median, 60) months. In all, local tumor recurrence occurred in 10 (25%) patients at a mean of 38 ± 23 (range, 12-120; median, 24) months. Local tumor recurrence was noted in 5 (42%) patients in group 1, 2 (25%) in group 2, and 3 (15%) in group 3. Overall, eye salvage was possible in 34 (85%) patients, with visual acuity >20/40 in 28 (82%). Systemic metastasis occurred in 10 (25%) patients at a mean of 53 ± 28 (range, 12-120; median, 43) months. Eight (67%) patients in group 1, 1 (13%) in group 2, and 1 (5%) in group 3 developed systemic metastasis. Six (15%) overall, 5 (42%) in group 1 and 1 (13%) in group 2, died with systemic metastasis. CONCLUSIONS: Multimodal treatment with sequential neoadjuvant chemotherapy, followed by surgery, extended-field stereotactic EBRT, and adjuvant chemotherapy seems relatively more effective in providing local tumor control and eye salvage and in minimizing the risk of systemic metastasis in ACC of the lacrimal gland.

Labor Induction versus Expectant Management in Low-Risk Nulliparous Women.

BACKGROUND: The perinatal and maternal consequences of induction of labor at 39 weeks among low-risk nulliparous women are uncertain. METHODS: In this multicenter trial, we randomly assigned low-risk nulliparous women who were at 38 weeks 0 days to 38 weeks 6 days of gestation to labor induction at 39 weeks 0 days to 39 weeks 4 days or to expectant management. The primary outcome was a composite of perinatal death or severe neonatal complications; the principal secondary outcome was cesarean delivery. RESULTS: A total of 3062 women were assigned to labor induction, and 3044 were assigned to expectant management. The primary outcome occurred in 4.3% of neonates in the induction group and in 5.4% in the expectant-management group (relative risk, 0.80; 95% confidence interval [CI], 0.64 to 1.00). The frequency of cesarean delivery was significantly lower in the induction group than in the expectant-management group (18.6% vs. 22.2%; relative risk, 0.84; 95% CI, 0.76 to 0.93). CONCLUSIONS: Induction of labor at 39 weeks in low-risk nulliparous women did not result in a significantly lower frequency of a composite adverse perinatal outcome, but it did result in a significantly lower frequency of cesarean delivery. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ARRIVE ClinicalTrials.gov number, NCT01990612 .).

Maternal and Neonatal Outcomes Associated with Amniotomy among Nulliparous Women Undergoing Labor Induction at Term.

OBJECTIVE: The aim of the study is to evaluate the association between amniotomy at various time points during labor induction and maternal and neonatal outcomes among term, nulliparous women. STUDY DESIGN: Secondary analysis of a randomized trial of term labor induction versus expectant management in low-risk, nulliparous women (2014-2017) was conducted. Women met inclusion criteria if they underwent induction ≥38 weeks' gestation using oxytocin with documented time and type of membrane rupture. Women with antepartum stillbirth or fetal anomaly were excluded. The primary outcome was cesarean delivery. Secondary outcomes included maternal and neonatal complications. Maternal and neonatal outcomes were compared among women with amniotomy versus women with intact membranes and no amniotomy at six 2-hour time intervals: before oxytocin initiation, 0 to <2 hours after oxytocin, 2 to <4 hours after, 4 to <6 hours after, 6 to <8 hours after, and 8 to <10 hours after. Multivariable logistic regression adjusted for maternal age, body mass index, race/ethnicity, modified Bishop score on admission, treatment group, and hospital (as a random effect). RESULTS: Of 6,106 women in the parent trial, 2,854 (46.7%) women met inclusion criteria. Of these 2,340 (82.0%) underwent amniotomy, and majority of the women had amniotomy performed between 2 and <6 hours after oxytocin. Cesarean delivery was less frequent among women with amniotomy 6 to <8 hours after oxytocin compared with women without amniotomy (21.9 vs. 29.7%; adjusted odds ratio 0.61, 95% confidence interval 0.42-0.89). Amniotomy at time intervals ≥4 hours after oxytocin was associated with lower odds of labor duration >24 hours. Amniotomy at time intervals ≥2 hours and <8 hours after oxytocin was associated with lower odds of maternal hospitalization >3 days. Amniotomy was not associated with postpartum or neonatal complications. CONCLUSION: Among a contemporary cohort of nulliparous women undergoing term labor induction, amniotomy was associated with either lower or similar odds of cesarean delivery and other adverse outcomes, compared with no amniotomy.

Overexpression of metastasis-associated in colon cancer 1 in retinoblastoma.

INTRODUCTION: Metastasis-associated in colon cancer 1 (MACC1), one of the prognostic markers for colonic and other tumours was noted to be overexpressed in retinoblastoma (Rb) Y79 cancer stem cells. This prompted us to evaluate its expression in primary Rb tumour and serum samples with clinicopathologic correlation. The interacting partner, c-MET was also evaluated in primary tumour tissues to explore the activation of MACC1 signaling. METHODOLOGY: This study was done following institutional review board approval from participating institutes. Semiquantitative gene expression for MACC1 was evaluated using formalin-fixed paraffin-embedded sections and unfixed tumour samples from primary Rb cases (n = 44). Immunolocalization for MACC1 was assessed in primary Rb tumours (n = 22), bone marrow aspirates with metastasis (n = 3), and c-MET expression was also assessed in Rb tumours (n = 17). Serum MACC1 levels were analysed using enzyme-linked immunosorbent assay in samples collected from Rb patients undergoing enucleation (n = 31), Rb patients with proven clinical metastasis (n = 3), and compared to appropriate controls. Clinicopathologic correlation of MACC1 expression was analysed using the medical records with specific reference to histologic risk factors (HRF) for metastasis and differentiation. RESULTS: High expression of MACC1 gene was noted in all the tumour samples (n = 44), more so in cases with versus without HRF (p < 0.0001). In cases with HRF, MACC1 and c-MET showed diffuse nuclear and cytoplasmic staining whereas it was predominantly cytoplasmic in cases without HRF. Mean immunoreactivity score of MACC1 and c-MET tissue immunolocalization revealed that cases with HRF showed significantly higher expression compared to cases without HRF (p < 0.05). Unlike the findings in colonic tumours, serum levels of MACC1 were lower in patients compared to normal controls. CONCLUSION: Overexpression of MACC1 and c-MET in retinoblastoma tissues, specifically those with risk factors for metastasis, suggests its role in proliferation and possibly in invasion. However, the current data do not support it to be a clinical prognostic marker in retinoblastoma tumours. The inverse serum expression is an intriguing finding, which warrants further studies especially in retinoblastoma.