Unique Profile of Inflammation and Immune Activation in Pregnant People With HIV in the United States.

BACKGROUND: Little is known about inflammation/immune activation during pregnancy in people with HIV (PWH) and growth in their children who are HIV-exposed and uninfected (CHEU). METHODS: Using data from the Pediatric HIV/AIDS Cohort Study and an HIV-seronegative comparison group, we assessed associations of (1) HIV status, mode of HIV acquisition (perinatally vs nonperinatally acquired), and type of antiretroviral therapy (ART) with inflammation/immune activation in pregnancy; and (2) inflammation/immune activation in pregnancy with growth of CHEU at 12 months. Interleukin 6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), soluble(s) TNF-α receptor 1 and 2 (sTNFR1, sTNFR2), sCD14, and sCD163 were measured between 13 and 27 weeks' gestation. Linear regression models were fit to estimate differences between groups for each log-transformed biomarker, adjusted for confounders. RESULTS: Pregnant PWH (188 total, 39 perinatally acquired, 149 nonperinatally acquired) and 76 HIV-seronegative persons were included. PWH had higher IL-6, sTNFR1, sCD14, and sCD163 and lower sTNFR2 compared to HIV-seronegative persons in adjusted models. Among PWH, sCD163 was higher in those with perinatally versus nonperinatally acquired HIV and on PI-based versus INSTI-based ART. Higher maternal concentrations of IL-6, sTNFR2, and hs-CRP were associated with poorer growth at 12 months. CONCLUSIONS: Maternal HIV status is associated with a distinct profile of inflammation/immune activation during pregnancy, which may influence child growth.

Distinct cord blood C-peptide, adipokine, and lipidomic signatures by in utero HIV exposure.

BACKGROUND: Early-life metabolic derangements in HIV-exposed uninfected (HEU) infants have been reported. METHODS: Pregnant women with HIV and HIV-uninfected pregnant women were enrolled with their newborns in a US cohort from 2011 to 2015. We measured cord insulin, C-peptide, and metabolic cytokines of HEU and HIV-unexposed uninfected (HUU) newborns using ELISA and metabolites, lipid subspecies, and eicosanoids via liquid chromatography/mass spectrometry. Linear regression was employed to assess the association of intrauterine HIV/ART with insulin and C-peptide. Graphical lasso regression was used to identify differences between metabolite/lipid subspecies networks associated with C-peptide. RESULTS: Of 118 infants, 56 were HEU, ART exposed. In adjusted analyses, mean cord insulin (ß = 0.295, p = 0.03) and C-peptide (ß = 0.522, p < 0.01) were significantly higher in HEU vs. HUU newborns. HEU neonates exhibited primarily positive associations between complex lipids and C-peptide, indicative of fuel storage, and augmented associations between cord eicosanoids and cytokines. HUU neonates exhibited negative associations with lipids and C-peptide indicative of increased fuel utilization. CONCLUSION: Higher cord insulin and C-peptide in HEU vs. HUU newborns as well as differences in cord metabolites, metabolic-related cytokines, and eicosanoids may reflect a propensity for fuel storage and an inflammatory milieu suggestive of fetal metabolic changes associated with in utero HIV/ART exposure. IMPACT: There is a paucity of studies assessing cord blood and neonatal metabolic health in HIV-exposed uninfected (HEU) newborns, an increasing population worldwide. Compared to HIV-unexposed uninfected (HUU) newborns, HEU newborns exhibit alterations in fuel homeostasis and an inflammatory milieu associated with in utero HIV/antiretroviral therapy (ART) exposure. The long-term implications of these neonatal findings are as yet unknown, but merit continued evaluation as this important and growing population ages into adulthood.

SARS-CoV-2 during pregnancy and associated outcomes: Results from an ongoing prospective cohort.

BACKGROUND: The COVID-19 pandemic is an ongoing global health threat, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Questions remain about how SARS-CoV-2 impacts pregnant individuals and their children. OBJECTIVE: To expand our understanding of the effects of SARS-CoV-2 infection during pregnancy on pregnancy outcomes, regardless of symptomatology, by using serological tests to measure IgG antibody levels. METHODS: The Generation C Study is an ongoing prospective cohort study conducted at the Mount Sinai Health System. All pregnant individuals receiving obstetrical care at the Mount Sinai Healthcare System from 20 April 2020 onwards are eligible for participation. For the current analysis, we included participants who had given birth to a liveborn singleton infant on or before 22 September 2020. For each woman, we tested the latest prenatal blood sample available to establish seropositivity using a SARS-CoV-2 serologic enzyme-linked immunosorbent assay. Additionally, RT-PCR testing was performed on a nasopharyngeal swab taken during labour. Pregnancy outcomes of interest (i.e., gestational age at delivery, preterm birth, small for gestational age, Apgar scores, maternal and neonatal intensive care unit admission, and length of neonatal hospital stay) and covariates were extracted from medical records. Excluding individuals who tested RT-PCR positive at delivery, we conducted crude and adjusted regression models to compare antibody positive with antibody negative individuals at delivery. We stratified analyses by race/ethnicity to examine potential effect modification. RESULTS: The SARS-CoV-2 seroprevalence based on IgG measurement was 16.4% (95% confidence interval 13.7, 19.3; n=116). Twelve individuals (1.7%) were SARS-CoV-2 RT-PCR positive at delivery. Seropositive individuals were generally younger, more often Black or Hispanic, and more often had public insurance and higher pre-pregnancy BMI compared with seronegative individuals. None of the examined pregnancy outcomes differed by seropositivity, overall or stratified by race/ethnicity. CONCLUSION: Seropositivity for SARS-CoV-2 without RT-PCR positivity at delivery (suggesting that infection occurred earlier during pregnancy) was not associated with selected adverse maternal or neonatal outcomes among live births in a cohort sample from New York City.

Birth Weight and Preterm Delivery Outcomes of Perinatally vs Nonperinatally Human Immunodeficiency Virus-Infected Pregnant Women in the United States: Results From the PHACS SMARTT Study and IMPAACT P1025 Protocol.

BACKGROUND: Pregnancy outcomes of perinatally human immunodeficiency virus-infected women (PHIV) are poorly defined. METHODS: We compared preterm delivery and birth weight (BW) outcomes (low BW [LBW], <2500 g), small-for-gestational-age [SGA], and BW z scores [BWZ]) in HIV-exposed uninfected infants of PHIV vs nonperinatally HIV-infected (NPHIV) pregnant women in the Pediatric HIV/AIDS Cohort Study Surveillance Monitoring of ART Toxicities or International Maternal Pediatric Adolescent AIDS Clinical Trials P1025 studies. Mixed effects models and log binomial models were used to assess the association of maternal PHIV status with infant outcomes. Age-stratified analyses were performed. RESULTS: From 1998 to 2013, 2270 HIV-infected pregnant women delivered 2692 newborns (270 born to PHIV and 2422 to NPHIV women). PHIV women were younger, (mean age 21 vs 25 years, P < .01) and more likely to have a pregnancy CD4 count <200 cells/mm3 (19% vs 11%, P = .01). No associations between maternal PHIV status and preterm delivery, SGA, or LBW were observed. After adjustment, BWZ was 0.12 lower in infants of PHIV vs NPHIV women (adjusted mean, -0.45 vs -0.33; P = .04). Among women aged 23-30 years (n = 1770), maternal PHIV was associated with LBW (aRR = 1.74; 95% confidence interval, 1.18, 2.58; P < .01). CONCLUSION: The overall lack of association between maternal PHIV status and preterm delivery or infant BW outcomes is reassuring. The higher rates of LBW observed in PHIV women aged 23-30 years warrants further mechanism-based investigations as this is a rapidly growing and aging population worldwide. CLINICAL TRIALS REGISTRATION: PHACS SMARTT study, NCT01310023. CLINICAL TRIALS REGISTRATION: IMPAACT 1025, NCT00028145.

Severe Vitamin D Deficiency in Human Immunodeficiency Virus-Infected Pregnant Women is Associated with Preterm Birth.

Background Low maternal vitamin D has been associated with preterm birth (PTB). Human immunodeficiency virus (HIV)-infected pregnant women are at risk for PTB, but data on maternal vitamin D and PTB in this population are scarce. Methods In a cohort of Latin American HIV-infected pregnant women from the National Institute of Child Health and Human Development International Site Development Initiative protocol, we examined the association between maternal vitamin D status and PTB. Vitamin D status was defined as the following 25-hydroxyvitamin D levels: severe deficiency (< 10 ng/mL), deficiency (10-20 ng/mL), insufficiency (21-29 ng/mL), and sufficiency (≥30 ng/mL). PTB was defined as delivery at < 37 weeks' gestational age (GA). Logistic regression was used to assess the association between maternal vitamin D status and PTB. Results Of 715 HIV-infected pregnant women, 13 (1.8%) were severely vitamin D deficient, 224 (31.3%) were deficient, and 233 were (32.6%) insufficient. Overall, 23.2% (166/715) of pregnancies resulted in PTB (median GA of PTBs = 36 weeks [interquartile range: 34-36]). In multivariate analysis, severe vitamin D deficiency was associated with PTB (odds ratio = 4.7, 95% confidence interval: 1.3-16.8]). Conclusion Severe maternal vitamin D deficiency is associated with PTB in HIV-infected Latin American pregnant women. Further studies are warranted to determine if vitamin D supplementation in HIV-infected women may impact PTB.

Impact of prenatal COVID-19 vaccination on delivery and neonatal outcomes: Results from a New York City cohort.

Research suggest prenatal vaccination against coronavirus disease-19 (COVID-19) is safe. However, previous studies utilized retrospectively collected data or examined late pregnancy vaccinations. We investigated the associations of COVID-19 vaccination throughout pregnancy with delivery and neonatal outcomes. We included 1,794 mother-neonate dyads enrolled in the Generation C Study with known prenatal COVID-19 vaccination status and complete covariate and outcome data. We used multivariable quantile regressions to estimate the effect of prenatal COVID-19 vaccination on birthweight, delivery gestational age, and blood loss at delivery; and Poisson generalized linear models for Caesarean delivery (CD) and Neonatal Intensive Care Unit (NICU) admission. Using the above methods, we estimated effects of trimester of vaccine initiation on these outcomes. In our sample, 13.7% (n = 250) received at least one prenatal dose of any COVID-19 vaccine. Vaccination was not associated with birthweight (ß = 12.42 g [-90.5, 114.8]), gestational age (ß = 0.2 days [-1.1, 1.5]), blood loss (ß = -50.6 ml [-107.0, 5.8]), the risks of CD (RR = 0.8; [0.6, 1.1]) or NICU admission (RR = 0.9 [0.5, 1.7]). Trimester of vaccine initiation was also not associated with these outcomes. Our findings suggest that there is no associated risk between prenatal COVID-19 vaccination and adverse delivery and neonatal outcomes in a cohort sample from NYC.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibody Titer Levels in Pregnant Individuals After Infection, Vaccination, or Both.

We examined differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody responses in pregnant individuals with natural, vaccine-induced, or combined immunity. Participants had live or nonlive births between 2020 and 2022, were seropositive (SARS-CoV-2 spike protein, anti-S), and had available mRNA vaccination and infection information (n=260). We compared titer levels among three immunity profiles: 1) natural immunity (n=191), 2) vaccine-induced immunity (n=37), and 3) combined immunity (ie, natural and vaccine-induced immunity; n=32). We applied linear regression to compare anti-S titers between the groups, controlling for age, race and ethnicity, and time between vaccination or infection (whichever came last) and sample collection. Anti-S titers were 57.3% and 94.4% lower among those with vaccine-induced and natural immunity, respectively, compared with those with combined immunity ( P <.001, P =.005).

Characterizing the pregnancy immune phenotype: results of the viral immunity and pregnancy (VIP) study.

PURPOSE: The increased risk of morbidity and mortality from certain microbial infections and the demonstrated improvements in the clinical course of some autoimmune diseases support the existence of pregnancy-related alterations in immune status. Elucidating the changes in innate and adaptive immunity during gestation may improve pregnancy outcomes and facilitate the development of targeted therapies for autoimmune diseases. METHOD: The Viral Immunity and Pregnancy (VIP) study evaluated over 50 subjects longitudinally at three time points during pregnancy and at two time points post-delivery. Leukocyte enumeration was performed; functional responses of NK cells and CD4 T cells were analyzed, and soluble factors such as cytokines, defensins, and steroid hormones were measured in maternal blood. RESULTS: In comparison to the post-partum period, the latter part of pregnancy was characterized by significant increases in blood phagocytes and pDCs and decreases in the number and activity of NK and T cells. Alterations were found in antimicrobial proteins and serum cytokines. CONCLUSIONS: These data show that pregnancy is not a period of immunosuppression but an alteration in immune priorities characterized by a strengthening of innate immune barriers and a concomitant reduction in adaptive/inflammatory immunity in the later stages of pregnancy.

Prenatal maternal stress and cord blood innate and adaptive cytokine responses in an inner-city cohort.

RATIONALE: Stress-elicited disruption of immunity begins in utero. OBJECTIVES: Associations among prenatal maternal stress and cord blood mononuclear cell (CBMC) cytokine responses were prospectively examined in the Urban Environment and Childhood Asthma Study (n = 557 families). METHODS: Prenatal maternal stress included financial hardship, difficult life circumstances, community violence, and neighborhood/block and housing conditions. Factor analysis produced latent variables representing three contexts: individual stressors and ecological-level strains (housing problems and neighborhood problems), which were combined to create a composite cumulative stress indicator. CBMCs were incubated with innate (lipopolysaccharide, polyinosinic-polycytidylic acid, cytosine-phosphate-guanine dinucleotides, peptidoglycan) and adaptive (tetanus, dust mite, cockroach) stimuli, respiratory syncytial virus, phytohemagglutinin, or medium alone. Cytokines were measured using multiplex ELISAs. Using linear regression, associations among increasing cumulative stress and cytokine responses were examined, adjusting for sociodemographic factors, parity, season of birth, maternal asthma and steroid use, and potential pathway variables (prenatal smoking, birth weight for gestational age). MEASUREMENTS AND MAIN RESULTS: Mothers were primarily minorities (Black [71%], Latino [19%]) with an income less than $15,000 (69%). Mothers with the highest cumulative stress were older and more likely to have asthma and deliver lower birth weight infants. Higher prenatal stress was related to increased IL-8 production after microbial (CpG, PIC, peptidoglycan) stimuli and increased tumor necrosis factor-alpha to microbial stimuli (CpG, PIC). In the adaptive panel, higher stress was associated with increased IL-13 after dust mite stimulation and reduced phytohemagglutinin-induced IFN-gamma. CONCLUSIONS: Prenatal stress was associated with altered innate and adaptive immune responses in CBMCs. Stress-induced perinatal immunomodulation may impact the expression of allergic disease in these children.

Neurodevelopment of HIV-Exposed Uninfected Infants Born to Women With Perinatally Acquired HIV in the United States.

BACKGROUND: Lifelong HIV and antiretroviral therapy may confer neurodevelopmental risk on the children of women with perinatally acquired HIV infection (PHIV). SETTING: We analyzed data from HIV-exposed uninfected (HEU) infants born to women with PHIV vs. non-perinatally acquired HIV (NPHIV) enrolled in the Surveillance Monitoring for Antiretroviral Therapy Toxicities (SMARTT) study. METHODS: Using the Bayley Scales of Infant and Toddler Development, third Ed. (Bayley-III), we compared neurodevelopmental outcomes at the age of 1 year in HEU infants born to women with PHIV vs. NPHIV. Those with valid Bayley-III data at the age of 1 year and a mother born after 1982 were included. Cognitive, language, and motor domains were assessed as continuous composite scores. Linear mixed effects models were fit to estimate the mean difference in Bayley-III scores between groups, adjusting for confounders. RESULTS: Five hundred fifty women with HIV gave birth to 678 HEU children (125 and 553 born to women with PHIV and NPHIV, respectively). Mean scores for each of the Bayley-III domains were not significantly different between infants born to women with PHIV vs. NPHIV in unadjusted models. After adjustment, infants of women with PHIV had lower language (91.9 vs. 94.8, P = 0.05) and motor (93.7 vs. 96.8, P = 0.03) composite scores, but no differences in cognitive composite scores. CONCLUSIONS: Cognitive domain outcomes of infants born to women with PHIV vs. NPHIV are reassuring. Differences in early language and motor functioning, while of modest clinical significance, highlight the importance of long-term monitoring of neurodevelopment in children of women with PHIV.

Maternal Perinatal HIV Infection Is Associated With Increased Infectious Morbidity in HIV-exposed Uninfected Infants.

BACKGROUND: The aging population of females with perinatally-acquired HIV (PHIV) are having their own children. HIV-exposed uninfected infants (HEU-N) born to women living with non-perinatally-acquired HIV (NPHIV) experience higher infectious morbidity compared with HIV-unexposed infants (HUU). Little is known about the infectious morbidity risk of HIV-exposed uninfected infants (HEU-P) born to PHIV women. METHODS: We evaluated prevalence of infectious cause hospitalizations (ICH) during the first year of life among HEU-P, HEU-N and HUU infants in a United States (U.S) tertiary care center. Maternal HIV status was categorized as PHIV vs. NPHIV vs. HIV-uninfected. Generalized Estimating Equation models were fit to evaluate the association between maternal HIV status and infant ICH. RESULTS: ICH was evaluated among 205 infants, 28 HEU-P infants, 112 HEU-N infants, and 65 HUU infants. PHIV women were younger compared with NPHIV and HIV-uninfected women (median age 22 years vs. 29 and 23 respectively, p<0.01). Overall, 21% of HEU-P, 4% of HEU-N and 12% of HUU infants experienced at least one ICH event (p<0.01) in the first year of life. After adjusting for confounders, HEU-P infants were at increased ICH risk compared with HEU-N infants [adjusted odds ratio (aOR)=7.45, 95% Confidence Interval (CI):1.58-35.04]. In sub-group analysis of HEU infants, excluding HUU infants, this relationship persisted after adjustment for maternal CD4 and HIV RNA level (aOR=10.24, 95% CI:1.66-63.31) CONCLUSIONS:: In a small U.S. cohort, HEU-P infants experienced increased ICH risk. Differences in intrauterine environments, social factors, or access to care may be important factors to assess in future larger studies.

Influenza Vaccination, Pregnancy Safety, and Risk of Early Pregnancy Loss.

Since 2004, the Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists have recommended routine influenza vaccination for all pregnant women in any trimester. Maternal influenza vaccination has been shown to decrease the risk of influenza and its complications among pregnant women and their infants in the first 6 months of life. In a recent article published in Vaccine, Donahue and colleagues reported a possible association between influenza vaccination when given very early in the first trimester and spontaneous abortion. There are limited conclusions that should be drawn from this study given the case-control design as well as the small number of patients included in the subanalysis that is the basis for the report. A prior first-trimester safety study from this group, using a similar study design, had not observed any association with spontaneous abortion, and other reports of first-trimester vaccine safety have not observed an association. The lack of a biologically plausible mechanism for the suggested association between previous influenza vaccination and early pregnancy loss is of concern. The study's reported observation is not definitive and needs be replicated in appropriately designed studies before changing clinical practice. Pregnant women are at high risk for severe influenza-related complications, including death, and health care providers have an obligation to their patients to continue to recommend and provide influenza vaccinations.

Lower mitochondrial DNA and altered mitochondrial fuel metabolism in HIV-exposed uninfected infants in Cameroon.

OBJECTIVE: Evaluate blood mitochondrial DNA (mtDNA) content in HIV/antiretroviral-exposed uninfected (HEU) vs. HIV-unexposed uninfected (HUU) infants and investigate differences in mitochondrial-related metabolites by exposure group. DESIGN: We enrolled a prospective cohort of HIV-infected and HIV-uninfected pregnant woman/infant pairs in Cameroon. METHODS: Dried blood spot mtDNA : nuclear DNA ratio was measured by monochrome multiplex quantitative polymerase chain reaction in HEU infants exposed to in-utero antiretrovirals and postnatal zidovudine (HEU-Z) or nevirapine (HEU-N), and in HUU infants at 6 weeks of life. Acylcarnitines and branch-chain amino acids (BCAAs) were measured via tandem mass spectrometry and consolidated into seven uncorrelated components using principal component analysis. Linear regression models were fit to assess the association between in-utero/postnatal HIV/antiretroviral exposure and infant mtDNA, adjusting for confounders and principal component analysis-derived acylcarnitine/BCAA component scores. RESULTS: Of 364 singleton infants, 38 were HEU-Z, 117 HEU-N, and 209 HUU. Mean mtDNA content was lowest in HEU-Z infants (140 vs. 160 in HEU-N vs. 174 in HUU, P = 0.004). After adjusting for confounders, HEU-Z infants remained at increased risk for lower mtDNA content compared with HUU infants (ß: -4.46, P = 0.045), whereas HEU-N infants did not, compared with HUU infants (ß: -1.68, P = 0.269. Furthermore, long-chain acylcarnitines were associated with lower (ß: -2.35, P = 0.002) and short-chain and BCAA-related acylcarnitines were associated with higher (ß: 2.96, P = 0.001) mtDNA content. CONCLUSION: Compared with HUU infants, HEU infants receiving postnatal zidovudine appear to be at increased risk for decreased blood mtDNA content which may be associated with altered mitochondrial fuel utilization in HEU-Z infants.

Growth patterns in the first year of life differ in infants born to perinatally vs. nonperinatally HIV-infected women.

OBJECTIVE: To compare the growth patterns in the first year of life between children born to perinatally HIV-infected (PHIV) vs. nonperinatally HIV-infected (NPHIV) women in the United States. DESIGN: Retrospective cohort study of HIV-infected pregnant women who received care and delivered a live-born at two urban tertiary centers from January 2004 to March 2012. METHODS: We collected data via chart review on demographics, behavioral risk factors, HIV clinical markers, combination antiretroviral therapy (cART), mode of HIV acquisition, pregnancy outcomes, and infant anthropometrics on study participants. Mixed-effects models were used to assess the association between maternal mode of HIV acquisition and weight-for-age z-score (WAZ), length-for-age z-score (LAZ), and weight-for-length z-score (WLZ). RESULTS: Of the 152 pregnancies evaluated, 32 and 120 infants were born to 25 PHIV and 99 NPHIV women, respectively. Infants of PHIV women exhibited lower mean WAZ and LAZ throughout the first year of life in unadjusted analyses. After adjusting for potential confounders, the relationship between PHIV women and LAZ persisted (ß = -0.54, P = 0.026). Small-for-gestational age for each birth anthropometric parameter (birth length, birth weight, and both birth length and weight) was associated with decreased LAZ (ß = -0.48, P = 0.007), WAZ (ß = -0.99, P < 0.001), and WLZ (ß = -0.36, P = 0.027), respectively. A delivery HIV RNA level below 400 copies/ml was associated with increased WAZ and WLZ (ß = 0.43, P = 0.015 and ß = 0.38, P = 0.021, respectively). CONCLUSIONS: Infants of PHIV women may remain at persistently decreased lengths throughout the first year of life. Further studies aimed at understanding intrauterine and environmental factors in PHIV women are warranted.

Low vitamin D status among pregnant Latin American and Caribbean women with HIV Infection.

OBJECTIVE: To evaluate the prevalence and predictors of low vitamin D status among pregnant women with HIV infection. METHODS: The present cross-sectional study analyzed repository specimens collected at 12-34 weeks of pregnancy among women enrolled across 17 sites in Latin America and the Caribbean between 2002 and 2009. Logistic regression modeling was used to identify factors associated with low vitamin D status (25-hydroxyvitamin D <30 ng/mL). RESULTS: Among 715 women, 218 (30.5%) were vitamin D deficient (<20 ng/mL) and 252 (35.2%) were insufficient (21- /mL). Factors associated with low vitamin D status included residence in subtropical latitudes (adjusted odds ratio [aOR] 1.97, 95% confidence interval [CI] 1.35-2.88), assessment during non-summer seasons (autumn: aOR 1.85, 95% CI 1.20-2.86; spring: 4.3, 2.65-6.95; winter: 10.82, 5.74-20.41), employment (aOR 1.56, 95% CI 1.06-2.38), and assessment before 20 weeks of pregnancy (aOR 1.89, 95% CI 1.18-3.06). Factors protective against low vitamin D status were CD4 count below 200 cells per mm(3) (aOR 0.45, 95% CI 0.26-0.77) and protease inhibitors (aOR 0.62, 95% CI 0.40-0.95). CONCLUSION: Low vitamin D status was prevalent among pregnant women with HIV infection. Further studies are warranted to identify the impact of low maternal vitamin D status.

Lower Preprandial Insulin and Altered Fuel Use in HIV/Antiretroviral-Exposed Infants in Cameroon.

CONTEXT: Intrauterine HIV/antiretroviral (ARV) and postnatal ARVs are known to perturb energy metabolism and could have permanent effects on future metabolic health. Such maladaptive effects could be mediated by changes in mitochondrial function and intermediary metabolism due to fetal and early-life ARV exposure in HIV/ARV-exposed uninfected (HEU) infants. OBJECTIVE: The objective of the study was to understand the relationship(s) between mitochondrial fuel use (assessed via acylcarnitines and branched chain amino acids) and preprandial insulin in infants exposed to in utero HIV/ARV plus postnatal zidovudine or nevirapine compared with HIV/ARV-unexposed uninfected (HUU) infants. DESIGN: This was a prospective cohort study with the following three groups: 1) intrauterine HIV/ARV/postnatal zidovudine-exposed (HEU-A), 2) intrauterine HIV/ARV/postnatal nevirapine-exposed (HEU-N), and 3) HUU infants. Principal component analysis and linear regression modeling were performed to assess the association between in utero HIV/ARV exposure and infant insulin. SETTING: The study was conducted at Cameroonian urban antenatal centers. PARTICIPANTS: HIV-infected and -uninfected pregnant woman/infant dyads participated in the study. MAIN OUTCOME: Preprandial insulin was the main outcome measured. RESULTS: Of 366 infants, 38 were HEU-A, 118 HEU-N. Forty intermediary metabolites were consolidated into seven principal components. In a multivariate analysis, both HEU-A (ß = -.116, P= .012) and HEU-N (ß = -.070, P= .022) demonstrated lower insulin compared with HUU infants. However, at high levels of plasma metabolites, HEU-A (ß = .027, P= .050) exhibited higher insulin levels than HEU-N or HUU infants. A unique array of short-chain acylcarnitines (ß = .044, P= .001) and branched-chain amino acids (ß = .033, P= .012) was associated with insulin. CONCLUSION: HEU-A and HEU-N infants have lower preprandial insulin levels at 6 weeks of age and appear to use metabolic fuel substrates differently than HUU infants. Future studies are warranted to determine whether observed differences have lasting metabolic implications, such as later insulin resistance.

Selective COX-2 inhibition and cardiovascular effects: a review of the rofecoxib development program.

See related Editorials on pages 561 and 563. Cyclo-oxygenase-2 (COX-2) inhibitors appear to alter the balance of vasoactive eicosanoids (prostacyclin and thromboxane) and to suppress the inflammatory mediators implicated in the progression of atherogenesis and ischemic myocardial injury. Neutral, harmful, and beneficial cardiovascular (CV) effects have all been postulated to result from these changes. Investigations conducted with rofecoxib, a selective COX-2 inhibitor, have substantially contributed to our understanding of this scientific area. Rofecoxib had little or no effect on platelet aggregation or platelet-derived thromboxane synthesis but reduced systemic prostacyclin synthesis by 50% to 60%. These findings prompted extensive analyses of CV thrombotic events within the rofecoxib development program. Among 5435 osteoarthritis trial participants, similar rates of CV thrombotic events were reported with rofecoxib, placebo, and comparator, nonselective NSAIDs (ibuprofen, diclofenac, and nabumetone). In the VIGOR gastrointestinal outcomes trial of >8000 patients, naproxen (an NSAID with aspirin-like sustained antiplatelet effects throughout its dosing interval) was associated with a significantly lower risk of CV events than was rofecoxib. A subsequent pooled analysis from 23 studies (including VIGOR) encompassing multiple disease states and including more than 14,000 patient-years at risk also demonstrated that rofecoxib was not associated with excess CV thrombotic events compared with either placebo or nonnaproxen NSAIDs. Again, naproxen appeared to be the outlier, suggesting a cardioprotective benefit of naproxen. Finally, among the predominantly elderly, male population participating in Alzheimer trials, both rofecoxib- and placebo-treated patients had similar rates of CV thrombotic events. The totality of data is not consistent with an increased CV risk among patients taking rofecoxib.

Comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs (ibuprofen, diclofenac, and nabumetone).

Aspirin, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), and specific cyclooxygenase-2 (COX-2) inhibitors each have distinctive effects on COX-1-mediated thromboxane biosynthesis, the major determinant of platelet aggregation. It is unclear whether these effects are associated with differences in thrombogenic risks. To compare the risk for thrombotic cardiovascular events among patients receiving rofecoxib, nonselective NSAIDs, and placebo, cardiovascular safety was assessed in 5,435 participants in 8 phase IIB/III osteoarthritis trials. The median treatment exposure was 31/2 months. The primary end point assessed was the risk of any arterial or venous thrombotic cardiovascular adverse event (AE). A second analysis assessed differences in the Anti-Platelet Trialists' Collaboration (APTC) events, a cluster end point that consists of the combined incidence of (1) cardiovascular, hemorrhagic, and unknown death; (2) myocardial infarction; and (3) cerebrovascular accident. Similar rates of thrombotic cardiovascular AEs were reported with rofecoxib, placebo, and comparator nonselective NSAIDs (ibuprofen, diclofenac, or nabumetone). In trials that compared rofecoxib with NSAIDs, the incidence of thrombotic cardiovascular AEs was 1.93/100 patient-years in the rofecoxib treatment group compared with 2.27/100 patient-years in the combined nonselective NSAID group. In trials that compared rofecoxib with placebo, the incidence of thrombotic cardiovascular AEs was 2.71/100 patient-years in the rofecoxib group compared with 2.57/100 patient-years in the placebo group. Consistent with the risks of cardiovascular AEs, similar rates of APTC events were reported with rofecoxib, placebo, and comparator nonselective NSAIDs. Thus, in the rofecoxib osteoarthritis development program, there was no difference between rofecoxib, comparator nonselective NSAIDs, and placebo in the risks of cardiovascular thrombotic events.

A comparison of adverse renovascular experiences among osteoarthritis patients treated with rofecoxib and comparator non-selective non-steroidal anti-inflammatory agents.

BACKGROUND: Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclo-oxygenase (COX) isoenzymes, i.e. COX-1 and COX-2. Rofecoxib, an agent that selectively inhibits COX-2, has been shown to provide equivalent anti-inflammatory and analgesic efficacy to comparator non-selective NSAIDs in osteoarthritis (OA) and other pain models with a significant improvement in gastrointestinal (GI) safety and tolerability. Based on renal physiology studies, it was predicted that rofecoxib would have renovascular effects similar to those observed with non-selective NSAIDs--specifically edema, blood pressure elevation, attenuation of the effects of ACE inhibitors, and (in rare circumstances), acute renal failure might be manifest in a small percentage of patients. OBJECTIVE: To assess the renovascular safety profile of rofecoxib in OA patients compared to that of non-selective NSAID comparators. METHODS: Renovascular adverse experiences (AEs) in over 5,000 participants in Phase IIb/III OA clinical trials were reviewed and compared between rofecoxib and non-selective NSAID comparators (ibuprofen 800mg tid, diclofenac 50 mg tid, nabumetone 1,500 mg qd). RESULTS: The incidence of lower extremity edema (LEE) AEs was generally similar between rofecoxib 12.5 mg/day, rofecoxib 25 mg/day, and non-selective comparator NSAIDs. Treatment discontinuations due to LEE AEs and clinically significant weight gain (> or = 2 kg) associated with LEE AEs were infrequent and generally similar in all active treatment groups. Congestive heart failure (CHF) was rare in all treatment groups. The incidence of hypertension AEs was low in all active treatment groups. Discontinuations due to hypertension AEs and hypertension AEs requiring a change or adjustment in blood pressure medications were similar and uncommon in all treatment groups. There was only a single report of acute renal failure (in the ibuprofen treatment group). CONCLUSIONS: In the rofecoxib phase IIb/III OA database, the renal safety profile for rofecoxib, a selective inhibitor of COX-2, was generally similar to that of the comparator, non-selective NSAIDs which were studied.