Safety and efficacy of PfSPZ Vaccine against malaria in healthy adults and women anticipating pregnancy in Mali: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials.

BACKGROUND: Plasmodium falciparum parasitaemia during pregnancy causes maternal, fetal, and infant mortality. Poor pregnancy outcomes are related to blood-stage parasite sequestration and the ensuing inflammatory response in the placenta, which decreases over successive pregnancies. A radiation-attenuated, non-replicating, whole-organism vaccine based on P falciparum sporozoites (PfSPZ Vaccine) has shown efficacy at preventing infection in African adults. Here, we aimed to examine vaccine safety and efficacy of the PfSPZ Vaccine in adults and women who anticipated conception. METHODS: Two randomised, double-blind, placebo-controlled trials (phase 1 MLSPZV3 and phase 2 MLSPZV4) were conducted at a clinical research centre in Mali. MLSPZV3 included adults aged 18-35 years and MLSPZV4 included non-pregnant women aged 18-38 years who anticipated conception within a year of enrolment. In MLSPZV3, participants were stratified by village and randomly assigned (2:1) using block randomisation to receive three doses of 9 × 105 PfSPZ Vaccine or saline placebo at weeks 0, 1, and 4 (4-week schedule) or at weeks 0, 8, and 16 (16-week schedule) and a booster dose around 1 year later. In MLSPZV4, women received presumptive artemether-lumefantrine twice per day for 3 days 2 weeks before dose one and were randomly assigned (1:1:1) using block randomisation to receive three doses of 9 × 105 or 1·8 × 106 PfSPZ Vaccine or saline placebo all administered at weeks 0, 1, and 4 (4-week schedule). Participants in both studies received artemether-lumefantrine 2 weeks before dose three and additionally 2 weeks before dose four (booster dose) in MLSPZV3. Investigators and participants were masked to group assignment. The primary outcome, assessed in the as-treated population, was PfSPZ Vaccine safety and tolerability within 7 days after each dose. The secondary outcome, assessed in the modified intention-to-treat population, was vaccine efficacy against P falciparum parasitaemia (defined as the time-to-first positive blood smear) from dose three until the end of transmission season. In exploratory analyses, MLSPZV4 evaluated incidence of maternal obstetric and neonatal outcomes as safety outcomes, and vaccine efficacy against P falciparum parasitaemia during pregnancy (defined as time-to-first positive blood smear post-conception). In MLSPZV4, women were followed at least once a month with human chorionic gonadotropin testing, and those who became pregnant received standard of care (including intermittent presumptive sulfadoxine-pyrimethamine antimalarial drugs after the first trimester) during routine antenatal visits. These studies are registered with ClinicalTrials.gov, NCT03510481 and NCT03989102. FINDINGS: Participants were enrolled for vaccination during the onset of malaria seasons for two sequential studies conducted from 2018 to 2019 for MLSPZV3 and from 2019 to 2021 for MLSPZV4, with follow-up during malaria seasons across 2 years. In MLSPZV3, 478 adults were assessed for eligibility, of whom 220 were enrolled between May 30 and June 12, 2018, and then between Aug 13 and Aug 18, 2018, and 210 received dose one. 66 (96%) of 69 participants who received the 16-week schedule and 68 (97%) of 70 who received the 4-week schedule of the 9 × 105 PfSPZ Vaccine and 70 (99%) of 71 who received saline completed all three doses in year 1. In MLSPZV4, 407 women were assessed for eligibility, of whom 324 were enrolled from July 3 to July 27, 2019, and 320 received dose one of presumptive artemether-lumefantrine. 300 women were randomly assigned with 100 per group (PfSPZ Vaccine 9 × 105, 1·8 × 106, or saline) receiving dose one. First trimester miscarriages were the most commonly reported serious adverse event but occurred at a similar rate across study groups (eight [15%] of 54 with 9 × 105 PfSPZ Vaccine, 12 [21%] of 58 with 1·8 × 106 PfSPZ Vaccine, and five [12%] of 43 with saline). One unrelated maternal death occurred 425 days after the last vaccine dose in the 1·8 × 106 PfSPZ Vaccine group due to peritonitis shortly after childbirth. Most related adverse events reported in MLSPZV3 and MLSPZV4 were mild (grade 1) and frequency of adverse events in the PfSPZ Vaccine groups did not differ from that in the saline group. Two unrelated serious adverse events occurred in MLSPZV3 (one participant had appendicitis in the 9 × 105 PfSPZ Vaccine group and the other in the saline group died due to a road traffic accident). In MLSPZV3, the 9 × 105 PfSPZ Vaccine did not show vaccine efficacy against parasitaemia with the 4-week (27% [95% CI -18 to 55] in year 1 and 42% [-5 to 68] in year 2) and 16-week schedules (16% [-34 to 48] in year 1 and -14% [-95 to 33] in year 2); efficacies were similar or worse against clinical malaria compared with saline. In MLSPZV4, the PfSPZ Vaccine showed significant efficacy against parasitaemia at doses 9 × 105 (41% [15 to 59]; p=0·0069 in year 1 and 61% [36 to 77]; p=0·0011 in year 2) and 1·8 × 106 (54% [34 to 69]; p<0·0001 in year 1 and 45% [13 to 65]; p=0·029 in year 2); and against clinical malaria at doses 9 × 105 (47% [20 to 65]; p=0·0045 in year 1 and 56% [22 to 75]; p=0·0081 in year 2) and 1·8 × 106 (48% [22 to 65]; p=0·0013 in year 1 and 40% [2 to 64]; p=0·069 in year 2). Vaccine efficacy against post-conception P falciparum parasitaemia during first pregnancies that arose in the 2-year follow-up was 57% (14 to 78; p=0·017) in the 9 × 105 PfSPZ Vaccine group versus 49% (3 to 73; p=0·042) in the 1·8 × 106 PfSPZ Vaccine group. Among 55 women who became pregnant within 24 weeks after dose three, vaccine efficacy against parasitaemia was 65% (23 to 84; p=0·0088) with the 9 × 105 PfSPZ Vaccine and 86% (64 to 94; p<0·0001) with the 1·8 × 106 PfSPZ Vaccine. When combined in a post-hoc analysis, women in the PfSPZ Vaccine groups had a non-significantly reduced time-to-first pregnancy after dose one compared with those in the saline group (log-rank test p=0·056). Exploratory maternal obstetric and neonatal outcomes did not differ significantly between vaccine groups and saline. INTERPRETATION: PfSPZ Vaccine was safe and well tolerated in adults in Mali. The 9 × 105 and 1·8 × 106 doses of PfSPZ Vaccine administered as per the 4-week schedule, which incorporated presumptive antimalarial treatment before the first vaccine dose, showed significant efficacy against P falciparum parasitaemia and clinical malaria for two malaria transmission seasons in women of childbearing age and against pregnancy malaria. PfSPZ Vaccine without presumptive antimalarial treatment before the first vaccine dose did not show efficacy. FUNDING: National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Sanaria.

Malaria in Pregnancy, Current Challenges, and Emerging Prevention Strategies in a Warming Climate.

Malaria still presents a grave threat to the health of pregnancies worldwide with prevention currently stalling as traditional control and prevention strategies are limited by both insecticide and drug resistance. Furthermore, climate change is bringing malaria to locations where it was once eradicated and intensifying malaria in other areas. Even where malaria is not currently common, obstetricians will need to understand the pathogenesis of the disease, how it is transmitted, methods for prevention and treatment in pregnancy, and promising emerging strategies such as vaccines. A renewed global response is needed for this age-old disease in which pregnancy poses specific susceptibility.

The impact of reference growth standards on small- and large-for-gestational age outcomes among pregnancies conceived by fresh and frozen embryo transfers.

Objective: To describe differences in the frequency of small-for-gestational age (SGA) and large-for-gestational age (LGA) driven by different birth weight curves in assisted reproductive technology (ART)-conceived pregnancies. Design: Retrospective cohort study. Setting: Single academic medical center. Patients: Singleton live births between the gestational ages of 36 weeks and 0 days and 42 weeks and 6 days from fresh or frozen embryo transfer (ET). Interventions: None. Main Outcome Measures: SGA (<10th percentile) and LGA (>90th percentile) classified by Fenton, INTERGROWTH-21, World Health Organization, Duryea, and Oken curves. Results: The median birth weight and gestational age at birth among fresh ET pregnancies were 3,289g (interquartile range [IQR], 2,977-3,600g) and 39.4 (IQR, 38.6-40.3) weeks, respectively, and those among frozen ET pregnancies were 3,399g (IQR, 3,065-3,685g) and 39.4 (IQR, 38.7-40.1) weeks, respectively. The frequencies of SGA neonates using each birth weight standard ranged from 5.8% to 13.4% for fresh ET and from 3.5% to 8.7% for frozen ET. Those of LGA neonates ranged from 5.3% to 14.3% for fresh ET and from 6.6% to 21.2% for frozen ET. Conclusion: The frequency of SGA and LGA neonates among ART-conceived gestations is partially driven by the birth weight standard. Selecting an appropriate standard that best reflects the patient population is critical to quantifying the risk of ART-conceived pregnancies.

Polybrominated diphenyl ethers and gestational weight gain: a multi-center prospective cohort study.

OBJECTIVE: To evaluate the associations of plasma polybrominated diphenyl ether (PBDE) concentrations in early pregnancy with gestational weight gain (GWG). DESIGN: Prospective cohort study. SETTING: US-based, multicentre cohort of pregnant women. POPULATION: We used data from 2052 women without obesity and 397 women with obesity participating in the NICHD Fetal Growth Studies - Singleton Cohort, with first-trimester plasma PBDE concentrations and weight measurements throughout pregnancy. METHODS: We applied generalised linear models and Bayesian kernel machine regression (BKMR) to evaluate both the individual and joint associations of PBDEs with measures of GWG, adjusting for potential confounders. MAIN OUTCOME MEASURES: Total GWG (kg), total and trimester-specific GWG velocities (kg/week), and GWG categories and trajectory groups. RESULTS: Mean pre-pregnancy BMIs were 23.6 and 34.5 kg/m2 for women without and with obesity, respectively. Among women without obesity, there were no associations of PBDEs with any GWG measure. Among women with obesity, one standard deviation increase in log-transformed PBDE 47 was associated with a 1.87 kg higher total GWG (95% CI 0.39-3.35) and a 0.05 kg/week higher total GWG velocity (95% CI 0.01-0.09). Similar associations were found for PBDE 47 in BKMR among women with obesity, and PBDE 47, 99 and 100 were associated with lower odds of being in the low GWG trajectory group. CONCLUSIONS: PBDEs were not associated with GWG among individuals without obesity. Among those with obesity, only PBDE 47 showed consistent positive associations with GWG measures across multiple statistical methods. Further research is needed to validate this association and explore potential mechanisms.

Plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio of 11.5 multiples of median predicts preeclampsia with severe features within 2 weeks of testing.

BACKGROUND: Angiogenic imbalances, characterized by an excess of antiangiogenic factors (soluble fms-like tyrosine kinase 1) and reduced angiogenic factors (vascular endothelial growth factor and placental growth factor), contribute to the mechanisms of disease in preeclampsia. The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor has been used as a biomarker for preeclampsia, but the cutoff values may vary with gestational age and assay platform. OBJECTIVE: This study aimed to compare multiples of the median of the maternal plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio, soluble fms-like tyrosine kinase 1, placental growth factor, and conventional clinical and laboratory values in their ability to predict preeclampsia with severe features. STUDY DESIGN: We conducted a cohort study across 18 United States centers involving hospitalized individuals with hypertension between 23 and 35 weeks' gestation. Receiver operating characteristic curve analyses of maternal plasma biomarkers, highest systolic or diastolic blood pressures, and laboratory values at enrollment were performed for the prediction of preeclampsia with severe features. The areas under the curve were compared, and quasi-Poisson regression models were fitted to estimate relative risks. The primary outcome was preeclampsia with severe features within 2 weeks of enrollment. Secondary outcomes were a composite of severe adverse maternal outcomes (elevated liver enzymes, low platelets count, placental abruption, eclampsia, disseminated intravascular coagulation, and pulmonary edema) and a composite of severe adverse perinatal outcomes (birth weight below the third percentile, very preterm birth [<32 weeks' gestation], and fetal or neonatal death). RESULTS: Of the 543 individuals included in the study, preeclampsia with severe features within 2 weeks was observed in 33.1% (n=180) of them. A receiver operating characteristic curve-derived cutoff of 11.5 multiples of the median for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio provided good sensitivity (90.6%), specificity (76.9%), positive predictive value (66.0%), negative predictive value (94.3%), positive likelihood ratio (3.91), negative likelihood ratio (0.12), and accuracy (81.4%) for preeclampsia with severe features within 2 weeks. This cutoff was used to compare test positive cases (≥ cutoff) and test negative cases (< cutoff). Preeclampsia with severe features (66.0% vs 5.7%; P<.001) and composites of severe adverse maternal (8.11% vs 2.7%; P=.006) or perinatal (41.3% vs 10.14%; P=.001) outcomes within 2 weeks were more frequent in test positive cases than in test negative cases. A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the median was independently associated with preeclampsia with severe features (adjusted incidence rate ratio, 9.08; 95% confidence interval, 6.11-14.06; P<.001) and a composite of severe adverse perinatal outcomes (adjusted incidence rate ratio, 9.42; 95% confidence interval, 6.36-14.53; P<.001) but not with a composite of severe adverse maternal outcomes (adjusted incidence rate ratio, 2.20; 95% confidence interval, 0.95-5.54; P=.08). The area under the curve for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio in multiples of the median (0.91; 95% confidence interval, 0.89-0.94) for preeclampsia with severe features within 2 weeks was significantly higher (P<.001 for all comparisons) than either plasma biomarker alone or any other parameter with the exception of absolute soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio values. CONCLUSION: A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the mean among hospitalized patients with hypertension between 23 and 35 week's gestation predicts progression to preeclampsia with severe features and severe adverse perinatal outcomes within 2 weeks.

Antithrombotic Therapy in Patients With Atrial Fibrillation and Coronary Artery Disease With Recent or Remote Events: Systematic Review and Meta-analysis.

Background: Ongoing debate remains regarding optimal antithrombotic therapy in patients with atrial fibrillation (AF) and coronary artery disease. Methods: We performed a systematic review and meta-analysis to synthesize randomized controlled trials (RCTs) comparing the following: (i) dual-pathway therapy (DPT; oral anticoagulant [OAC] plus antiplatelet) vs triple therapy (OAC and dual-antiplatelet therapy) after percutaneous coronary intervention (PCI) or acute coronary syndrome (ACS), and (iii) OAC monotherapy vs DPT at least 1 year after PCI or ACS. Following a 2-stage process, we identified systematic reviews published between 2019 and 2022 on these 2 clinical questions, and we updated the most comprehensive search for additional RCTs published up to October 2022. Outcomes of interest were major adverse cardiovascular events (MACE), death, stent thrombosis, and major bleeding. We estimated risk ratios (RRs) and 95% confidence intervals (CIs) using a random-effects model. Results: Based on 6 RCTs (n = 10,435), DPT reduced major bleeding (RR 0.62, 95% CI 0.52-0.73) and increased stent thrombosis (RR 1.55, 95% CI 1.02-2.36), vs triple therapy after PCI or medically-managed ACS, with no significant differences in MACE and death. In 2 RCTs (n = 2905), OAC monotherapy reduced major bleeding (RR 0.66, 95% CI 0.49-0.91) vs DPT in AF patients with remote PCI or ACS, with no significant differences in MACE or death. Conclusions: In patients with AF and coronary artery disease, using less-aggressive antithrombotic treatment (DPT after PCI or ACS, and OAC alone after remote PCI or ACS) reduced major bleeding, with an increase in stent thrombosis with recent PCI. These results support a minimalist yet personalized antithrombotic strategy for these patients.

Contexte: La question du traitement antithrombotique optimal chez les personnes présentant une fibrillation auriculaire (FA) et une coronaropathie demeure controversée. Méthodologie: Nous avons réalisé une revue systématique et une méta-analyse pour synthétiser les essais contrôlés randomisés ayant comparé i) la bithérapie (anticoagulant oral et antiplaquettaire) et la trithérapie (anticoagulant oral et bithérapie antiplaquettaire) après une intervention coronarienne percutanée (ICP) ou un syndrome coronarien aigu (SCA), et ii) un anticoagulant oral en monothérapie et la bithérapie au moins 1 an après une ICP ou un SCA. Nous avons procédé en 2 temps, d'abord en répertoriant les revues systématiques publiées entre 2019 et 2022 sur ces 2 questions cliniques, puis en effectuant la recherche la plus exhaustive possible pour trouver d'autres essais contrôlés randomisés publiés jusqu'en octobre 2022. Les paramètres qui nous intéressaient étaient les événements cardiovasculaires indésirables majeurs (ECIM), le décès, la thrombose de l'endoprothèse et l'hémorragie majeure. Nous avons estimé les rapports de risques (RR) et les intervalles de confiance (IC) à 95 % à l'aide d'un modèle à effets aléatoires. Résultats: D'après 6 essais contrôlés randomisés (n = 10 435), la bithérapie a réduit les hémorragies majeures (RR : 0,62; IC à 95 % : 0,52 à 0,73) et augmenté les thromboses de l'endoprothèse (RR : 1,55; IC à 95 % : 1,02 à 2,36), comparativement à la trithérapie après une ICP ou un SCA ayant fait l'objet d'une prise en charge médicale, tandis qu'aucune différence significative n'a été observée quant aux ECIM et aux décès. Dans 2 essais contrôlés randomisés (n = 2 905), un anticoagulant oral en monothérapie a réduit les hémorragies majeures (RR : 0,66; IC à 95 % : 0,49 à 0,91) comparativement à la bithérapie chez des patients présentant une FA après une ICP ou un SCA plus lointain, sans différence significative quant aux ECIM et aux décès. Conclusions: Chez les patients présentant une FA et une coronaropathie, l'utilisation d'un traitement antithrombotique moins agressif (bithérapie après un ICP ou un SCA, et anticoagulant oral en monothérapie après une ICP ou un SCA plus lointain) réduit les hémorragies majeures, mais s'accompagne d'une augmentation des thromboses de l'endoprothèse en cas d'ICP récente. Ces résultats plaident en faveur d'une stratégie antithrombotique minimaliste, mais personnalisée chez ces patients.

Shared decision-making approach to type 2 diabetes management.

OBJECTIVE: To provide an online interactive decision aid to facilitate shared decision making in the context of medication choices for patients with type 2 diabetes mellitus (T2DM). SOURCES OF INFORMATION: The best available clinical prediction model for patients with T2DM was selected based on a review of guidelines, DynaMed, and UpToDate and a search of PubMed. A list of pharmacotherapeutic options for T2DM was compiled based on a review of guidelines, narrative reviews, and expert opinion. To determine the benefits and harms of each treatment, federated search engines were searched for meta-analyses of randomized controlled trials, supplemented by individual randomized controlled trials for outcomes not reported in meta-analyses. MAIN MESSAGE: Approximately 2.1 million Canadians have T2DM, with a resulting increased risk of death, cardiovascular disease, and microvascular outcomes. While more than a dozen medication options are available, decisions regarding these medications are challenging, as patients vary in their preferences. Shared decision making has the potential to individualize these difficult decisions, but the number of diabetes-related outcomes and available treatment options have made this historically impractical. It is within this context that the PEER Diabetes Medication Decision Aid was developed. This decision aid provides patients with personalized 10-year risk estimates for 6 clinically important diabetes-related outcomes. The tool also allows patients to focus on the outcome that matters most to them and to compare the benefits and harms of up to 12 different treatment options. This information is displayed in personalized absolute numbers, along with practical considerations such as cost. CONCLUSION: The PEER Diabetes Medication Decision Aid provides a practical tool that can enable patients with T2DM to come to autonomous and well-informed medication decisions.

Cohort profile: the Environmental Reproductive and Glucose Outcomes (ERGO) Study (Boston, Massachusetts, USA) - a prospective pregnancy cohort study of the impacts of environmental exposures on parental cardiometabolic health.

PURPOSE: Pregnancy and the postpartum period are increasingly recognised as sensitive windows for cardiometabolic disease risk. Growing evidence suggests environmental exposures, including endocrine-disrupting chemicals (EDCs), are associated with an increased risk of pregnancy complications that are associated with long-term cardiometabolic risk. However, the impact of perinatal EDC exposure on subsequent cardiometabolic risk post-pregnancy is less understood. The Environmental Reproductive and Glucose Outcomes (ERGO) Study was established to investigate the associations of environmental exposures during the perinatal period with post-pregnancy parental cardiometabolic health. PARTICIPANTS: Pregnant individuals aged ≥18 years without pre-existing diabetes were recruited at <15 weeks of gestation from Boston, Massachusetts area hospitals. Participants completed ≤4 prenatal study visits (median: 12, 19, 26, 36 weeks of gestation) and 1 postpartum visit (median: 9 weeks), during which we collected biospecimens, health histories, demographic and behavioural data, and vitals and anthropometric measurements. Participants completed a postpartum fasting 2-hour 75 g oral glucose tolerance test. Clinical data were abstracted from electronic medical records. Ongoing (as of 2024) extended post-pregnancy follow-up visits occur annually following similar data collection protocols. FINDINGS TO DATE: We enrolled 653 unique pregnancies and retained 633 through delivery. Participants had a mean age of 33 years, 10% (n=61) developed gestational diabetes and 8% (n=50) developed pre-eclampsia. Participant pregnancy and postpartum urinary phthalate metabolite concentrations and postpartum glycaemic biomarkers were quantified. To date, studies within ERGO found higher exposure to phthalates and phthalate mixtures, and separately, higher exposure to radioactive ambient particulate matter, were associated with adverse gestational glycaemic outcomes. Additionally, certain personal care products used in pregnancy, notably hair oils, were associated with higher urinary phthalate metabolite concentrations, earlier gestational age at delivery and lower birth weight. FUTURE PLANS: Future work will leverage the longitudinal data collected on pregnancy and cardiometabolic outcomes, environmental exposures, questionnaires, banked biospecimens and paediatric data within the ERGO Study.

Qualitative Analysis of Patient Decisional Needs for Medications to Treat Heart Failure.

BACKGROUND: The development of tools to support shared decision-making should be informed by patients' decisional needs and treatment preferences, which are largely unknown for heart failure (HF) with reduced ejection fraction (HFrEF) pharmacotherapy decisions. We aimed to identify patients' decisional needs when considering HFrEF medication options. METHODS: This was a qualitative study using semi-structured interviews. We recruited patients with HFrEF from 2 Canadian ambulatory HF clinics and clinicians from Canadian HF guideline panels, HF clinics, and Canadian HF Society membership. We identified themes through inductive thematic analysis. RESULTS: Participants included 15 patients and 12 clinicians. Six themes and associated subthemes emerged related to HFrEF pharmacotherapy decision-making: (1) patient decisional needs included lack of awareness of a choice or options, difficult decision timing and stage, information overload, and inadequate motivation, support and resources; (2) patients' decisional conflict varied substantially, driven by unclear trade-offs; (3) treatment attribute preferences-patients focused on both benefits and downsides of treatment, whereas clinicians centered discussion on benefits; (4) quality of life-patients' definition of quality of life depended on pre-HF activity, though most patients demonstrated adaptability in adjusting their daily activities to manage HF; (5) shared decision-making process-clinicians' described a process more akin to informed consent; (6) decision support-multimedia decision aids, virtual appointments, and primary-care comanagement emerged as potential enablers of shared decision-making. CONCLUSIONS: Patients with HFrEF have several decisional needs, which are consistent with those that may respond to decision aids. These findings can inform the development of HFrEF pharmacotherapy decision aids to address these decisional needs and facilitate shared decision-making.

Indoor Temperature and Energy Insecurity: Implications for Prenatal Health Disparities in Extreme Heat Events.

BACKGROUND: Extreme heat events are a major public health concern and are only expected to increase in intensity and severity as climate change continues to accelerate. Pregnant people are physiologically more vulnerable to the effects of extreme heat, and exposure can induce harm on both the pregnant person and the fetus. OBJECTIVES: This commentary argues that there is a need for greater epidemiological research on indoor heat exposure and energy insecurity as potential drivers of maternal and child environmental health disparities. DISCUSSION: While there is substantial evidence linking ambient (outdoor) high temperature to pregnancy-related outcomes, there is a lack of epidemiological evidence to date on pregnant people's exposure to high indoor temperature and adverse maternal and/or child health outcomes. Energy insecurity is disproportionately experienced by people with low incomes and/or people of color, and indoor temperature may play a role in shaping socioeconomic and racial/ethnic disparities in maternal and child health in the United States. Further research is needed to understand the relationship between indoor heat exposure, energy insecurity, and pregnancy outcomes in both parents and children and to inform potential policies and practices to enhance resilience and reduce maternal/child health disparities. https://doi.org/10.1289/EHP13706.

Two Randomized Trials of Low-Dose Calcium Supplementation in Pregnancy.

BACKGROUND: The World Health Organization recommends 1500 to 2000 mg of calcium daily as supplementation, divided into three doses, for pregnant persons in populations with low dietary calcium intake in order to reduce the risk of preeclampsia. The complexity of the dosing scheme, however, has led to implementation barriers. METHODS: We conducted two independent randomized trials of calcium supplementation, in India and Tanzania, to assess the noninferiority of a 500-mg daily dose to a 1500-mg daily dose of calcium supplementation. In each trial, the two primary outcomes were preeclampsia and preterm birth, and the noninferiority margins for the relative risks were 1.54 and 1.16, respectively. RESULTS: A total of 11,000 nulliparous pregnant women were included in each trial. The cumulative incidence of preeclampsia was 3.0% in the 500-mg group and 3.6% in the 1500-mg group in the India trial (relative risk, 0.84; 95% confidence interval [CI], 0.68 to 1.03) and 3.0% and 2.7%, respectively, in the Tanzania trial (relative risk, 1.10; 95% CI, 0.88 to 1.36) - findings consistent with the noninferiority of the lower dose in both trials. The percentage of live births that were preterm was 11.4% in the 500-mg group and 12.8% in the 1500-mg group in the India trial (relative risk, 0.89; 95% CI, 0.80 to 0.98), which was within the noninferiority margin of 1.16; in the Tanzania trial, the respective percentages were 10.4% and 9.7% (relative risk, 1.07; 95% CI, 0.95 to 1.21), which exceeded the noninferiority margin. CONCLUSIONS: In these two trials, low-dose calcium supplementation was noninferior to high-dose calcium supplementation with respect to the risk of preeclampsia. It was noninferior with respect to the risk of preterm live birth in the trial in India but not in the trial in Tanzania. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT03350516; Clinical Trials Registry-India number, CTRI/2018/02/012119; and Tanzania Medicines and Medical Devices Authority Trials Registry number, TFDA0018/CTR/0010/5).

Disparities in COVID-19 Hospitalization at the Intersection of Race and Ethnicity and Income.

BACKGROUND: Existing studies have elucidated racial and ethnic disparities in COVID-19 hospitalizations, but few have examined disparities at the intersection of race and ethnicity and income. METHODS: We used a population-based probability survey of non-institutionalized adults in Michigan with a polymerase chain reaction-positive SARS-CoV-2 test before November 16, 2020. We categorized respondents by race and ethnicity and annual household income: low-income (< $50,000) Non-Hispanic (NH) Black, high-income (≥ $50,000) NH Black, low-income Hispanic, high-income Hispanic, low-income NH White, and high-income NH White. We used modified Poisson regression models, adjusting for sex, age group, survey mode, and sample wave, to estimate COVID-19 hospitalization prevalence ratios by race and ethnicity and income. RESULTS: Over half of the analytic sample (n = 1593) was female (54.9%) and age 45 or older (52.5%), with 14.5% hospitalized for COVID-19. Hospitalization was most prevalent among low-income (32.9%) and high-income (31.2%) Non-Hispanic (NH) Black adults, followed by low-income NH White (15.3%), low-income Hispanic (12.9%), high-income NH White (9.6%), and high-income Hispanic adults (8.8%). In adjusted models, NH Black adults, regardless of income (low-income prevalence ratio [PR]: 1.86, 95% CI: 1.36-2.54; high-income PR: 1.57, 95% CI: 1.07-2.31), and low-income NH White adults (PR: 1.52, 95% CI: 1.12-2.07), had higher prevalence of hospitalization compared to high-income NH White adults. We observed no significant difference in the prevalence of hospitalization among Hispanic adults relative to high-income NH White adults. CONCLUSIONS: We observed disparities in COVID-19 hospitalization at the intersection of race and ethnicity and income for NH Black adults and low-income NH White adults relative to high-income NH White adults, but not for Hispanic adults.

Ambient particulate matter air pollution exposure and ovarian cancer incidence in the USA: An ecological study.

OBJECTIVE: To investigate associations between air particulate matter of ≤2.5 µm in diameter (PM2.5 ) and ovarian cancer. DESIGN: County-level ecological study. SETTING: Surveillance, epidemiology, and end results from a collection of state-level cancer registries across 744 counties. Data from the Environmental Protection Agency's network for PM2.5 monitoring was used to calculate trailing 5- and 10-year PM2.5 county-level values. County-level data on demographic characteristics were obtained from the American Community Survey. POPULATION: A total of 98 751 patients with histologically confirmed ovarian cancer as a primary malignancy from 2000 to 2016. METHODS: Generalised linear regression models were developed to estimate the association between PM2.5 and PM10 levels, over 5- and 10-year periods of exposure, and ovarian cancer risk, after accounting for county-level covariates. MAIN OUTCOME MEASURES: Risk ratios for associations between ovarian cancer (both overall and specifically epithelial ovarian cancer) and PM2.5 levels. RESULTS: For the 744 counties included, the average PM2.5 level from 1990 through 2018 was 11.75 µg/m3 (SD = 3.7) and the average PM10 level was 22.7 µg/m3 (SD = 5.7). After adjusting for county-level covariates, the overall annualised ovarian cancer incidence was significantly associated with increases in 5-year PM2.5 (RR = 1.11 per 10 units (µg/m3 ) increase, 95% CI 1.06-1.16). Similarly, when the analysis was limited to epithelial cell tumours and adjusted for county-level covariates there was a significant association with trailing 5-year PM2.5 exposure models (RR = 1.12 per 10 units increase, 95% CI 1.08-1.17). Likewise, 10-year PM2.5 exposure was associated with ovarian cancer overall and with epithelial ovarian cancer. CONCLUSIONS: Higher county-level ambient PM2.5 levels are associated with 5- and 10-year incidences of ovarian cancer, as measurable in an ecological study.

Research Note: Relative bioavailability of zinc in zinc hydroxychloride for chicks.

A chick assay was conducted to determine the effects of Zn source on performance and to establish a Zn relative bioavailability value (RBV) for a new source of Zn hydroxychloride. In the assay, 8-day-old chicks were fed a Zn-deficient soy protein concentrate diet supplemented with 0, 7, and 15 mg Zn/kg from feed grade ZnSO4 monohydrate for 14 d to establish a standard response curve. The same basal diet was supplemented with 3, 7, and 10 mg Zn/kg from a new Zn hydroxychloride (SAMZn). A second source of Zn hydroxychloride (IBZn) was supplemented at 10 mg Zn/kg as a direct comparison to the highest level of SAMZn. Weight gain increased (P < 0.05) with increasing Zn level, regardless of source. Weight gain of chicks fed 7 mg Zn/kg from SAMZn was not different (P > 0.05) from chicks fed 15 mg Zn/kg from ZnSO4. Weight gain was not different (P > 0.05) when comparing the 2 sources of Zn hydroxychloride supplemented at 10 mg Zn/kg. Tibia ash Zn and total tibia Zn were increased (P < 0.05) by all Zn sources and responded linearly (P < 0.05) to Zn supplementation from ZnSO4 and SAMZn. Total tibia Zn concentration was not different (P > 0.05) for chicks fed 10 mg Zn/kg from either source of Zn hydroxychloride. Multiple linear regression of total tibia Zn on supplemental Zn intake (R2 = 0.95) resulted in a RBV of 115% for SAMZn compared with ZnSO4 (set at 100%). The RBV of SAMZn was higher (P < 0.05) than ZnSO4. In conclusion, relative bioavailability of Zn (based on tibia Zn) in Zn hydroxychloride from SAMZn was higher than feed grade ZnSO4 based on multiple regression slope-ratio analysis and was similar to that of IBZn Zn hydroxychloride based on tibia Zn responses to 10 mg/kg supplemental dietary Zn.

Predictors of Phthalate Metabolites Exposure among Healthy Pregnant Women in the United States, 2010-2015.

Phthalate use and the concentrations of their metabolites in humans vary by geographic region, race, ethnicity, sex, product use and other factors. Exposure during pregnancy may be associated with detrimental reproductive and developmental outcomes. No studies have evaluated the predictors of exposure to a wide range of phthalate metabolites in a large, diverse population. We examined the determinants of phthalate metabolites in a cohort of racially/ethnically diverse nulliparous pregnant women. We report on urinary metabolites of nine parent phthalates or replacement compounds-Butyl benzyl phthalate (BBzP), Diisobutyl phthalate (DiBP), Diethyl phthalate (DEP), Diisononyl phthalate (DiNP), D-n-octyl phthalate (DnOP), Di-2-ethylhexyl terephthalate (DEHTP), Di-n/i-butyl phthalate (DnBP), Di-isononyl phthalate (DiNP) and Di-(2-ethylhexyl) phthalate (DEHP) from urine collected up to three times from 953 women enrolled in the Nulliparous Mothers To Be Study. Phthalate metabolites were adjusted for specific gravity. Generalized estimating equations (GEEs) were used to identify the predictors of each metabolite. Overall predictors include age, race and ethnicity, education, BMI and clinical site of care. Women who were Non-Hispanic Black, Hispanic or Asian, obese or had lower levels of education had higher concentrations of selected metabolites. These findings indicate exposure patterns that require policies to reduce exposure in specific subgroups.