Influence of Neighborhood Socioeconomic Status on Adverse Outcomes in Pregnancy.

PURPOSE: To evaluate whether ZIP-code level neighborhood socioeconomic status (SES) is associated with adverse pregnancy outcomes. METHODS: A retrospective study of 2009-2014 Oregon Health and Science University (OHSU) births with maternal ZIP codes in one of 89 Portland metropolitan area ZIP codes. Deliveries with ZIP codes outside of the Portland metro area were excluded. Deliveries were stratified by SES based on ZIP code median household income: low (below 10th percentile), medium (11th-89th percentile), and high (above 90th percentile). Univariate analysis and multivariable logistic regression with medium SES as the reference group evaluated perinatal outcomes and strength of association between SES and adverse events. RESULTS: This study included 8118 deliveries with 1654 (20%) classified as low SES, 5856 (72%) medium SES, and 608 (8%) high SES. The low SES group was more likely to be younger, have a higher maternal BMI, have increased tobacco use, identify as Hispanic or Black, and less likely to have private insurance. Low SES was associated with a significantly increased risk of preeclampsia (RR 1.23 95% CI 1.01-1.49), but this was no longer significant after adjusting for confounders (aRR 1.23 95% CI .971-1.55). High SES was negatively associated with gestational diabetes mellitus (GDM), even after adjusting for confounders (aRR 0.710, 95% CI 0.507-0.995). CONCLUSION: In the Portland metropolitan area, high SES was associated with a lower risk of GDM. Low SES was associated with a higher risk of preeclampsia before accounting for covariates. ZIP code-based risk assessment may be a useful indicator in detecting healthcare disparities.

Adverse Perinatal and Neonatal Outcomes among Adolescent Pregnancies in the United States.

OBJECTIVE: Despite a downward trend in recent years, adolescent pregnancies in the United States remain higher than any other western country. Adolescent pregnancies have been inconsistently associated with adverse perinatal outcomes. The objective of this study is to investigate the association between adolescent pregnancies and adverse perinatal and neonatal outcomes in the United States. STUDY DESIGN: This is a retrospective cohort study of singleton births in the United States from 2014 to 2020 using national vital statistics data. Perinatal outcomes included gestational diabetes, gestational hypertension, preterm delivery <37 weeks (preterm birth [PTB]), cesarean delivery (CD), chorioamnionitis, small for gestational age (SGA), large for gestational age (LGA), and neonatal composite outcome. Chi-square tests were used to compare outcomes among adolescent (13-19 years) versus adult (20-29 years) pregnancies. Multivariable logistic regression models were used to examine association of adolescent pregnancies with perinatal outcomes. For each outcome, we utilized three models: unadjusted logistic regression, adjusted for demographics, and adjusted for demographics and medical comorbidities. Similar analyses were used to compare younger (13-17 years) and older (18-19 years) adolescent pregnancies to adults. RESULTS: In a cohort of 14,014,078 pregnancies, we found that adolescents were at an increased risk of PTB (adjusted odds ratio [aOR]: 1.12, 99% confidence interval (CI): 1.12-1.13) and SGA (aOR: 1.02, 99% CI: 1.01-1.03) compared with adult pregnancies. We also found that multiparous adolescents with a prior history of CD were at an increased risk of CD, compared with adults. For all other outcomes, adult pregnancies were at higher risk for adverse outcomes in the adjusted models. When comparing birth outcomes among adolescents, we found that older adolescents are at an increased risk of PTB, whereas younger adolescents are at an increased risk of both PTB and SGA. CONCLUSION: After adjusting for confounders, our study demonstrates adolescents have an increased risk of PTB and SGA, compared with adults. KEY POINTS: · Adolescents as a whole subgroup have an increased risk of PTB and SGA compared with adults.. · Younger adolescents have a risk of PTB and SGA, whereas older adolescents have a risk of PTB only.. · Adverse birth outcomes in adults are gestational diabetes, chorioamnionitis, LGA, and worse neonatal composite score..

Hyperglycemia and gestational diabetes suppress placental glycolysis and mitochondrial function and alter lipid processing.

The degree that maternal glycemia affects placental metabolism of trophoblast cell types [cytotrophoblast (CTB) and syncytiotrophoblast (SCT)] in pregnant persons with gestational diabetes mellitus (GDM) is unknown. We tested the hypotheses that (a) hyperglycemia suppresses the metabolic rates of CTB and SCT; and (b) low placental metabolic activity from GDM placentas is due to decreased oxygen consumption of CTB. Trophoblast cells isolated from GDM and non-GDM term placentas were cultured for 8-hour (CTB) and following syncytialization at 72-hour (SCT) in 5 mM of glucose or 25 mM of glucose. Oxygen consumption rates, glycolysis, ATP levels, and lipid droplet morphometries were determined in CTB and SCT. In CTB from GDM placentas compared to control CTB: (a) oxidative phosphorylation was decreased by 44% (41.8 vs 74.2 pmol O2 /min/100 ng DNA, P = .002); (b) ATP content was 39% lower (1.1 × 10-7 vs 1.8 × 10-7  nM/ng DNA, P = .046); and (c) lipid droplets were two times larger (31.0 vs 14.4 µm2 /cell, P < .001) and 1.7 times more numerous (13.5 vs 7.9 lipid droplets/cell, P < .001). Hyperglycemia suppressed CTB glycolysis by 55%-60% (mean difference 20.4 [GDM, P = .008] and 15.4 [non-GDM, P = .029] mpH/min/100 ng DNA). GDM SCT was not metabolically different from non-GDM SCT. However, GDM SCT had significantly decreased expression of genes associated with differentiation including hCG, GCM1, and syncytin-1. We conclude that suppressed metabolic activity by the GDM placenta is attributable to metabolic dysfunction of CTB, not SCT. Critical placental hormone expression and secretion are decreased in GDM trophoblasts.

Strategies for Prevention or Treatment of Tobacco and Cannabis Use Disorder.

Tobacco and cannabis use in pregnancy are associated with increased adverse perinatal and long-term offspring outcomes. Products for both have evolved with various forms available on the market, challenging accurate counseling of risks and quantification of tobacco and cannabis usage during the perinatal period. Health care providers are recommended to screen for any type of use, provide consistent messaging of harms of tobacco and cannabis use in pregnancy, and offer individualized interventions. The journey to cessation can be complicated by barriers and triggers, lack of social supports, and mental health challenges that should be addressed to prevent relapse and withdrawals.

The Risk of Perinatal Mortality in Nulliparous Women Compared to Primiparous Women at Term.

OBJECTIVE: The aim of this study was to determine the rate of perinatal mortality among nulliparous women compared with primiparous women at term and further characterize the risk of stillbirth by each week of gestation. STUDY DESIGN: This is a retrospective cohort study of all term, singleton, nonanomalous births comparing perinatal mortality (stillbirth and neonatal death [NND]) between primiparous (parity = 1, with no history of abortion) and nulliparous (parity = 0) women who delivered in California between 2007 and 2011. Chi-squared tests and multivariable logistic regression analyses were performed to determine the frequencies and strength of association of perinatal mortality with parity, adjusting for maternal age, race, body mass index, pregestational diabetes, chronic hypertension, fetal sex, smoking status, and socioeconomic status. The risk of stillbirth at each gestational age at term was calculated using a pregnancies-at-risk life table method. A p-value less than 0.05 was used to indicate statistical significance. RESULTS: Of 1,317,761 total deliveries, 765,995 (58.1%) were to nulliparous women and 551,766 (41.9%) were to primiparous women with one prior birth. Nulliparous women had increased odds of stillbirth (adjusted odds ratio [aOR], 3.30; 95% confidence interval [CI], 2.93-3.72) and NND (aOR, 1.54; 95% CI, 1.19-1.98) compared with primiparous women. The risk of stillbirth in nulliparous women was greater at every gestational age between 370/7 and 410/7 weeks compared with primiparous women. Nulliparous women also had increased odds of small for gestational age infants at less than 10% birth weight (aOR, 1.76; 95% CI, 1.72-1.79), less than 5% birth weight (aOR, 1.91; 95% CI, 1.86-1.98), and less than 3% birth weight (aOR, 2.02; 95% CI, 1.93-2.11). CONCLUSION: Perinatal mortality is significantly greater in nulliparous women compared with primiparous women with term deliveries. These findings suggest that low-risk nulliparous women may require increased surveillance. There may be a role in improving maternal health by maximizing physiologic adaptation in nulliparous women. KEY POINTS: · Parity is associated with perinatal mortality.. · Perinatal mortality is significantly greater in nulliparous women compared with primiparous women.. · The risk of stillbirth in nulliparous women is greater at every gestational age compared with primiparous women..

A cautionary response to SMFM statement: pharmacological treatment of gestational diabetes.

Use of oral agents to treat gestational diabetes mellitus remains controversial. Recent recommendations from the Society for Maternal-Fetal Medicine assert that metformin may be a safe first-line alternative to insulin for gestational diabetes mellitus treatment and preferable to glyburide. However, several issues should give pause to the widespread adoption of metformin use during pregnancy. Fetal concentrations of metformin are equal to maternal, and metformin can inhibit growth, suppress mitochondrial respiration, have epigenetic modifications on gene expression, mimic fetal nutrient restriction, and alter postnatal gluconeogenic responses. Because both the placenta and fetus express metformin transporters and exhibit high mitochondrial activity, these properties raise important questions about developmental programming of metabolic disease in offspring. Animal studies have demonstrated that prenatal metformin exposure results in adverse long-term outcomes on body weight and metabolism. Two recent clinical randomized controlled trials in women with gestational diabetes mellitus or polycystic ovary syndrome provide evidence that metformin exposure in utero may produce a metabolic phenotype that increases childhood weight or obesity. These developmental programming effects challenge the conclusion that metformin is equivalent to insulin. Although the Society for Maternal-Fetal Medicine statement endorsed metformin over glyburide if oral agents are used, there are few studies directly comparing the 2 agents and it is not clear that metformin alone is superior to glyburide. Moreover, it should be noted that prior clinical studies have dosed glyburide in a manner inconsistent with its pharmacokinetic properties, resulting in poor glycemic control and high rates of maternal hypoglycemia. We concur with the American Diabetes Association and American Congress of Obstetricians and Gynecologists, which recommend insulin as the preferred agent, but we believe that it is premature to embrace metformin as equivalent to insulin or superior to glyburide. Due to the uncertainty of the long-term metabolic risks of either metformin or glyburide, we call for carefully controlled studies that optimize oral medication dosing according to their pharmacodynamic and pharmacokinetic properties in pregnancy, appropriately target medications based on individual patterns of hyperglycemia, and follow the offspring long-term for metabolic risk.

Comprehensive Management of Type 2 Diabetes During Pregnancy.

This JAMA Insights Clinical Update discusses a comprehensive approach to treating pregnant patients with type 2 diabetes to reduce adverse perinatal and neonatal outcomes.

Accuracy of Sonographically Estimated Fetal Weight Near Delivery in Pregnancies Complicated With Diabetes Mellitus.

OBJECTIVES: The purpose of this study was to evaluate the accuracy of sonographic estimations of fetal weight (FW) and signed percent error between pregnant patients with and without diabetes mellitus (DM). METHODS: We conducted a retrospective cohort study of all singleton nonanomalous live births who delivered after 34 weeks and received a sonographic estimation of FW within 2 weeks of delivery at the University of Cincinnati Medical Center between 2008 and 2011. Our primary outcome compared the ΔFW and signed percent error between DM and non-DM pregnancies. Sensitivity and specificity were calculated for the prediction of FW greater than 4000 g in each study group. Linear regression analysis assessed correlation coefficients, R2 values, and variance of the ΔFW by live birth weight. RESULTS: The mean ΔFWs were 62 and 103 g for non-DM and DM pregnancies, respectively (P = .04). However, the signed percent error (mean ± SD, 1.7% ± 9.8% versus 2.6% ± 9.9%; P = .15) was similar between the study groups. Linear regression comparing the ΔFW to the live birth weight revealed a weak correlation in DM (r = 0.34; R2 = 0.11) and non-DM pregnancies, (r = 0.17; R2 = 0.03) pregnancies. Overall sensitivity for the prediction of FW greater than 4000 g was poor (0.41 and 0.62 in non-DM and DM pregnancies). However, the specificity was high (0.97 and 0.99 for both groups). CONCLUSIONS: Although DM alters the biometric measurements of the fetus with increasing thoracoabdominal size, there are no clinically significant alterations in the accuracy of sonography for FW prediction when performed near delivery. Sonography is highly specific for birth weight greater than 4000 g, which is helpful for delivery planning and management.

Effect of Post-Cesarean Delivery Oral Cephalexin and Metronidazole on Surgical Site Infection Among Obese Women: A Randomized Clinical Trial.

Importance: The rate of obesity among US women has been increasing, and obesity is associated with increased risk of surgical site infection (SSI) following cesarean delivery. The optimal perioperative antibiotic prophylactic regimen in this high-risk population undergoing cesarean delivery is unknown. Objective: To determine rates of SSI among obese women who receive prophylactic oral cephalexin and metronidazole vs placebo for 48 hours following cesarean delivery. Design, Setting, and Participants: Randomized, double-blind clinical trial comparing oral cephalexin and metronidazole vs placebo for 48 hours following cesarean delivery for the prevention of SSI in obese women (prepregnancy BMI ≥30) who had received standard intravenous preoperative cephalosporin prophylaxis. Randomization was stratified by intact vs rupture of membranes prior to delivery. The study was conducted at the University of Cincinnati Medical Center, Cincinnati, Ohio, an academic and urban setting, between October 2010 and December 2015, with final follow-up through February 2016. Interventions: Participants were randomly assigned to receive oral cephalexin, 500 mg, and metronidazole, 500 mg (n = 202 participants), vs identical-appearing placebo (n = 201 participants) every 8 hours for a total of 48 hours following cesarean delivery. Main Outcomes and Measures: The primary outcome was SSI, defined as any superficial incisional, deep incisional, or organ/space infections within 30 days after cesarean delivery. Results: Among 403 randomized participants who were included (mean age, 28 [SD, 6] years; mean BMI, 39.7 [SD, 7.8]), 382 (94.6%) completed the trial. The overall rate of SSI was 10.9% (95% CI, 7.9%-14.0%). Surgical site infection was diagnosed in 13 women (6.4%) in the cephalexin-metronidazole group vs 31 women (15.4%) in the placebo group (difference, 9.0% [95% CI, 2.9%-15.0%]; relative risk, 0.41 [95% CI, 0.22-0.77]; P = .01). There were no serious adverse events, including allergic reaction, reported in either the antibiotic group or the placebo group. Conclusions and Relevance: Among obese women undergoing cesarean delivery who received the standard preoperative cephalosporin prophylaxis, a postoperative 48-hour course of oral cephalexin and metronidazole, compared with placebo, reduced the rate of SSI within 30 days after delivery. For prevention of SSI among obese women after cesarean delivery, prophylactic oral cephalexin and metronidazole may be warranted. Trial Registration: clinicaltrials.gov Identifier: NCT01194115.

Regulatory T cells: new keys for further unlocking the enigma of fetal tolerance and pregnancy complications.

The immunological alterations required for successful pregnancy in eutherian placental mammals have remained a scientific enigma since the discovery of MHC haplotype diversity and unique immune signatures among individuals. Within the past 10 years, accumulating data suggest that immune-suppressive regulatory T cells (Tregs) confer essential protective benefits in sustaining tolerance to the semiallogeneic fetus during pregnancy, along with their more established roles in maintaining tolerance to self and "extended self" commensal Ags that averts autoimmunity. Reciprocally, many human pregnancy complications stemming from inadequacies in fetal tolerance have been associated with defects in maternal Tregs. Thus, further elucidating the immunological shifts during pregnancy not only have direct translational implications for improving perinatal health, they have enormous potential for unveiling new clues about how Tregs work in other biological contexts. In this article, epidemiological data in human pregnancy and complementary animal studies implicating a pivotal protective role for maternal Tregs are summarized.

When to Deliver Women with Diabetes in Pregnancy?

The prevalence of pregestational diabetes and the incidence of gestational diabetes have both increased over recent years. One component of the management of diabetes in pregnancy is the timing of delivery in the late-preterm, early-term, or full-term periods. Recent guidance from the National Institute for Child Health and Human Development, Society for Maternal-Fetal Medicine, and American College of Obstetricians and Gynecologists has lacked specificity, for example, recommending delivery for women with pregestational diabetes with poorly controlled glucose levels to be from 34 to 39 weeks' gestation. This lack of specificity is predominant because of the large holes in existing data to guide clinical practice. This article reviews existing literature regarding diabetes in pregnancy and attempts to give an analytical framework and some clearer guidance around the timing of delivery.

Expectant management of mild preeclampsia versus superimposed preeclampsia up to 37 weeks.

OBJECTIVE: We sought to compare maternal and neonatal outcomes of expectantly managed pregnancies complicated by chronic hypertension with superimposed preeclampsia vs mild preeclampsia up to 37 weeks of gestation. STUDY DESIGN: This was a multicenter retrospective cohort study of all pregnancies complicated by chronic hypertension with superimposed preeclampsia or mild preeclampsia expectantly managed in the hospital from January 2008 through December 2011. The primary outcomes, adverse maternal and neonatal composite morbidities, were compared between these 2 groups. Frequency differences of maternal adverse outcomes were stratified by gestational age at delivery of <34 and 34-36(6/7) weeks of gestation. RESULTS: We found no significant differences in rates of neonatal composite morbidity or latency periods between women with superimposed preeclampsia and mild preeclampsia. Adverse neonatal outcomes were significantly higher at <34 compared to 34-36(6/7) weeks of gestation (97-98% vs 48-50%) in both cohorts. Maternal adverse composite outcome occurred more frequently in women with superimposed preeclampsia compared to mild preeclampsia (15% vs 5%; P = .003; relative risk, 3.0; 95% confidence interval, 1.45-6.29). CONCLUSION: Women with superimposed preeclampsia have similar neonatal outcomes but more maternal complications than women with preeclampsia without severe features who are expectantly managed <37 weeks.

Maternal Malnutrition and Elevated Disease Risk in Offspring.

US populations have seen dramatic increases in the prevalence of chronic disease over the past three generations. Rapid increases in type 2 diabetes and obesity have occurred in all the states but have been particularly striking in the Deep South. These increases have contributed to decreases in life expectancy and to painful elevations in health care costs. The causes of worsening population health are complex and incompletely understood. However, there is strong evidence that vulnerability to chronic conditions is determined in early life. Most chronic diseases are developmentally driven. There are specific stressors experienced in early life that influence epigenetic and structural changes during development. These include malnutrition, severe levels of social stress, toxic chemicals, and low oxygen levels. Most US populations have experienced a decrease in the quality of the food they consume as industrial foods have replaced garden-grown foods. Thus, the consumption of too few nutrients before and during pregnancy and during lactation influences the growth of the placenta and fetal organs and their level of resilience when faced with stresses in postnatal life and particularly as adults. Animal studies have shown that the effects of poor nutrition can be passed on to future generations. The most powerful way that the current epidemics of obesity and insulin resistance can be reversed is by providing key nutrients to prospective mothers and those already pregnant.

Insulin Management for Gestational and Type 2 Diabetes in Pregnancy.

Insulin is preferred as the first-line agent for glucose management of gestational diabetes mellitus and type 2 diabetes in pregnancy when nutritional and lifestyle modifications are unable to achieve pregnancy-specific glucose targets. Individual heterogeneity in defects of insulin secretion or sensitivity in liver and muscle, unique genetic influences on pregnancy glycemic regulation, and variable cultural and lifestyle behaviors that affect meal, activity, sleep, and occupational schedules necessitate a personalized approach to insulin regimens. Newer insulin preparations have been developed to mimic the physiologic release of endogenous insulin, maintaining appropriate basal levels to cover hepatic gluconeogenesis and simulate the rapid, meal-related, bolus rise of insulin. Such physiologic basal-bolus dosing of insulin can be administered safely, achieving tighter glycemic control while reducing episodes of hypoglycemia. Insulin initiation and titration require understanding the pharmacodynamics of different insulin preparations in addition to a patient's glycemic profiles, effect of variable nutritional intake and mealtimes, physical activity, stress, timing of sleep cycles, and cultural habits. Educating and empowering patients to learn how their glucose responds to insulin, portion and content of meals, and physical activity can increase personal engagement in therapy, flexibility in eating patterns, and improved glycemic control. This Clinical Expert Series article is focused on optimizing insulin management (initiation, dosing, and titration) of gestational and type 2 diabetes in pregnancy.

Continuous Glucose Monitoring for Diabetes Management During Pregnancy: Evidence, Practical Tips, and Common Pitfalls.

Continuous glucose monitoring (CGM) has the potential to revolutionize diabetes management during pregnancy by providing detailed and real-time data to patients and clinicians, overcoming many of the limitations of self-monitoring of blood glucose. Although there are limited data on the role of CGM to improve pregnancy outcomes in patients with type 2 diabetes or gestational diabetes, CGM has been shown to reduce pregnancy complications in patients with type 1 diabetes. Despite the limited data in some populations, given its ease of use and recent U.S. Food and Drug Administration approval with expanding insurance coverage, CGM has gained widespread popularity among pregnant patients with all types of diabetes. It is critical for obstetric clinicians to understand how CGM can be successfully integrated into clinical practice. We present a practical, step-wise approach to CGM data interpretation that can be incorporated into diabetes management during pregnancy and common CGM pitfalls and solutions. Although technology will continue to advance with newer-generation CGM devices and diabetes technology such as automated insulin delivery (not covered here), these key principles form a basic foundation for understanding CGM technology and its utility for pregnant people.

Practical Considerations for Using Continuous Glucose Monitoring in Patients with Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is the most prevalent metabolic complication during pregnancy. GDM is associated with adverse perinatal, neonatal, and long-term health consequences. Studies have demonstrated that the use of continuous glucose monitoring (CGM) reduces the incidence of maternal and neonatal complications in pregnant women with type 1 diabetes. Although the use of CGM in GDM has not been well studied, a growing body of evidence is showing potential benefits in the GDM population. This article discusses the advantages and challenges of CGM and provides practical guidelines for using this technology in the GDM population.

Performance of the Dexcom G7 Continuous Glucose Monitoring System in Pregnant Women with Diabetes.

Background: We evaluated accuracy and safety of a seventh-generation real-time continuous glucose monitoring (CGM) system during pregnancy. Materials and Methods: Evaluable data for accuracy analysis were obtained from 96 G7 sensors (Dexcom, Inc.) worn by 96 of 105 enrolled pregnant women with type 1 (n = 59), type 2 (n = 21), or gestational diabetes (n = 25). CGM values were compared with arterialized venous glucose values from the YSI comparator instrument during 6-h clinic sessions at different time points throughout the sensors' 10-day wear period. The primary endpoint was the proportion of CGM values in the 70-180 mg/dL range within 15% of comparator glucose values. Secondary endpoints included the proportion of CGM values within 20% or 20 mg/dL of comparator values ≥ or <100 mg/dL, respectively (the %20/20 agreement rate). Results: Of the 1739 pairs with CGM in the 70-180 mg/dL range, 83.2% were within 15% of comparator values. The lower bound of the 95% confidence interval was 79.8%. Of the 2102 pairs with CGM values in the 40-400 mg/dL range, the %20/20 agreement rate was 92.5%. Of the 1659 pairs with comparator values in the 63-140 mg/dL range, the %20/20 agreement rate was 92.3%. The %20/20 agreement rates on days 1, 4 and 7, and 10 were 78.6%, 96.3%, and 97.3%, respectively. Consensus error grid analysis showed 99.8% of pairs in the clinically acceptable A and B zones. There were no serious adverse events. The sensors' 10-day survival rate was 90.3%. Conclusion: The G7 system is accurate and safe during pregnancies complicated by diabetes and does not require confirmatory fingerstick testing. Clinical Trial Registration: clinicaltrials.gov NCT04905628.

Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline.

BACKGROUND: Numerous studies demonstrate associations between serum concentrations of 25-hydroxyvitamin D (25[OH]D) and a variety of common disorders, including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases. Although a causal link between serum 25(OH)D concentrations and many disorders has not been clearly established, these associations have led to widespread supplementation with vitamin D and increased laboratory testing for 25(OH)D in the general population. The benefit-risk ratio of this increase in vitamin D use is not clear, and the optimal vitamin D intake and the role of testing for 25(OH)D for disease prevention remain uncertain. OBJECTIVE: To develop clinical guidelines for the use of vitamin D (cholecalciferol [vitamin D3] or ergocalciferol [vitamin D2]) to lower the risk of disease in individuals without established indications for vitamin D treatment or 25(OH)D testing. METHODS: A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 14 clinically relevant questions related to the use of vitamin D and 25(OH)D testing to lower the risk of disease. The panel prioritized randomized placebo-controlled trials in general populations (without an established indication for vitamin D treatment or 25[OH]D testing), evaluating the effects of empiric vitamin D administration throughout the lifespan, as well as in select conditions (pregnancy and prediabetes). The panel defined "empiric supplementation" as vitamin D intake that (a) exceeds the Dietary Reference Intakes (DRI) and (b) is implemented without testing for 25(OH)D. Systematic reviews queried electronic databases for publications related to these 14 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and guide recommendations. The approach incorporated perspectives from a patient representative and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. The process to develop this clinical guideline did not use a risk assessment framework and was not designed to replace current DRI for vitamin D. RESULTS: The panel suggests empiric vitamin D supplementation for children and adolescents aged 1 to 18 years to prevent nutritional rickets and because of its potential to lower the risk of respiratory tract infections; for those aged 75 years and older because of its potential to lower the risk of mortality; for those who are pregnant because of its potential to lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small-for-gestational-age birth, and neonatal mortality; and for those with high-risk prediabetes because of its potential to reduce progression to diabetes. Because the vitamin D doses in the included clinical trials varied considerably and many trial participants were allowed to continue their own vitamin D-containing supplements, the optimal doses for empiric vitamin D supplementation remain unclear for the populations considered. For nonpregnant people older than 50 years for whom vitamin D is indicated, the panel suggests supplementation via daily administration of vitamin D, rather than intermittent use of high doses. The panel suggests against empiric vitamin D supplementation above the current DRI to lower the risk of disease in healthy adults younger than 75 years. No clinical trial evidence was found to support routine screening for 25(OH)D in the general population, nor in those with obesity or dark complexion, and there was no clear evidence defining the optimal target level of 25(OH)D required for disease prevention in the populations considered; thus, the panel suggests against routine 25(OH)D testing in all populations considered. The panel judged that, in most situations, empiric vitamin D supplementation is inexpensive, feasible, acceptable to both healthy individuals and health care professionals, and has no negative effect on health equity. CONCLUSION: The panel suggests empiric vitamin D for those aged 1 to 18 years and adults over 75 years of age, those who are pregnant, and those with high-risk prediabetes. Due to the scarcity of natural food sources rich in vitamin D, empiric supplementation can be achieved through a combination of fortified foods and supplements that contain vitamin D. Based on the absence of supportive clinical trial evidence, the panel suggests against routine 25(OH)D testing in the absence of established indications. These recommendations are not meant to replace the current DRIs for vitamin D, nor do they apply to people with established indications for vitamin D treatment or 25(OH)D testing. Further research is needed to determine optimal 25(OH)D levels for specific health benefits.