Infant Plasma Research Articles

Plasma and Breast Milk Pharmacokinetics of Tenofovir Disoproxil Fumarate in Nursing Mother with Chronic Hepatitis B-Infant Pairs.

Tenofovir use is associated with lower risk of mother-to-infant transmission of the virus, and discontinuation of the treatment is not safe. However, the safety of the drug during pregnancy and breastfeeding is not clear. In this study, we aimed to determine the tenofovir concentration in plasma of mother-infant pairs along with breast milk in chronic hepatitis B patients during the lactation period. A total of 11 mother-infant pairs were enrolled in the study. All the mothers received tenofovir disoproxil fumarate (TDF) 245 mg/day for at least 1 month because of chronic hepatitis B infection. Maternal blood, breast milk, and infant blood samples were obtained concomitantly. Tenofovir concentrations were determined by liquid chromatography-tandem mass spectrometry. The median concentrations of tenofovir in maternal plasma and breast milk samples were 88.44 (interquartile range [IQR], 62.47 to 116.17) ng/ml and 6.69 (IQR, 4.88 to 7.03) ng/ml, respectively. Tenofovir concentrations were undetectable (<4 ng/ml) in all of the infant plasma samples. The ratio of tenofovir concentration in breast milk to that in maternal plasma was 0.07. Tenofovir disoproxil fumarate passes through the breast milk in a small amount. Infants had no detectable tenofovir level in their plasma. Our study suggests that tenofovir disoproxil fumarate treatment is safe during the breastfeeding period in chronic hepatitis B patients.

Pre-Existing Infant Antibody-Dependent Cellular Cytotoxicity Associates with Reduced HIV-1 Acquisition and Lower Morbidity

SummaryIn humans, pre-existing anti-HIV-1 neutralizing antibodies (nAbs) have not been associated with decreased HIV-1 acquisition. We evaluated antibody-dependent cellular cytotoxicity (ADCC) present in pre-transmission infant and maternal plasma and breast milk (BM) against the contemporaneous maternal HIV-1 variants. HIV-1 exposed uninfected as compared to HIV-1 exposed infected infants had higher ADCC and a combination of ADCC and nAb responses against their corresponding mother’s strains. ADCC did not correlate with nAbs suggesting they are independent activities. The infected infants with high as compared to low ADCC, but not those with higher ADCC plus nAbs, had lower morbidity and mortality up to 1 year after birth. ADCC was lower in BM supernatants as compared to BM isolated IgG, but was not significantly different in the transmitting versus non-transmitting mothers’ BM or plasma. A high IgA to IgG ratio, as in BM supernatants, was also more prevalent in the infected infants, and it was also associated with lower infant ADCC. Overall, ADCC, more so than nAbs, against the exposure strains associates with lower mother-to-child-transmission (MTCT) and decreased post-infection infant morbidity. Future strategies should aim to elicit robust ADCC activity to prevent MTCT and to improve infant outcomes.

Pilot Feasibility, Reliability, and Validity Assessment of Infant Skin Carotenoids Measured by Reflection Spectroscopy as a Non-invasive Biomarker of Carotenoid Intake

Abstract Objectives Skin carotenoid measurement by reflection spectroscopy offers a rapid, non-invasive assessment of carotenoid intake and status. However, feasibility, reliability, and validity have not been established in infants. We hypothesize that skin carotenoid measurement of infants’ heels and fingers will be feasible, reliable, and valid. Methods Skin carotenoid score (SCS) was measured by a modified, portable reflection spectroscopy device (Veggie Meter) at the index finger and heel of the foot in infants at 4 (n = 21), 6 (n = 12), and 8 (n = 9) months of age. Infant plasma, milk formula, and mother's breast milk carotenoid concentrations were measured by HPLC, while infant carotenoid intake was estimated from 7-day food diaries and 3 × 24-hour parent recalls. Feasibility was assessed by time to acquire triplicate reads and reliability was assessed by the coefficient of variation (CV) of triplicates and the Pearson's correlation between mean heel and finger SCS. Validity was established in 4-month-olds if skin carotenoid scores were moderately correlated (r &amp;gt; 0.5) with breast milk carotenoid concentrations during exclusive milk-feeding (n = 16) and with infant plasma carotenoid concentrations (n = 11). Results Twenty-one infants (52% female) were enrolled (47% non-Hispanic white, 29% Hispanic white, 14% African American, and 10% Asian). Triplicate heel and finger SCSs were feasibly acquired in 56 ± 11 to 87 ± 32 seconds, respectively. Heel and finger SCS reliability was similar (mean CV range 18 ± 13 to 32 ± 22%), and mean within-subject heel and finger SCSs were highly correlated (r = 0.81, P = 1 × 10−5) in 4-month-olds. Finger and heel SCSs were valid correlates of total infant plasma carotenoid concentrations (r = 0.77, P = 0.006 and r = 0.66, P = 0.026, respectively). Finger SCS significantly correlated with breast milk carotenoids (r = 0.66, P = 0.006), while heel SCS non-significantly correlated (r = 0.40, P = 0.13). Conclusions This pilot suggests that infant skin carotenoids can be feasibly measured by reflection spectroscopy and that finger SCSs are correlated with both infant plasma carotenoid concentrations and maternal breast milk carotenoid concentrations. Skin carotenoid measurement should be further investigated to facilitate the assessment of infant dietary intake and health outcomes. Funding Sources Texas Children's Hospital, USDA-ARS.

Determinants of Plasma Ferritin at 3 Months of Age Among Rural Bangladeshi Infants From the JiVitA-3 Trial

ObjectivesFerritin, a biomarker of iron stores, is rarely reported in infants despite a known role for iron in growth and development. Iron stores accumulated in utero decline in infancy, although breastmilk iron supports infant status. In rural northwest Bangladesh, an iron-replete area, infants are small and prone to common illnesses despite prevalent breastfeeding. We explored determinants of ferritin in 3 mo old infants in this setting. MethodsIn a double-blind, cluster-randomized trial (JiVitA-3) of multiple micronutrient or iron-folic acid supplementation from pregnancy ascertainment to 3 mo postpartum, maternal and infant hemoglobin (Hb), anthropometry, and plasma were obtained 3 mo after birth. Growth was assessed as weight gain since birth. In a preliminary analysis (n = 378), infant plasma ferritin, maternal ferritin, and infant α1-acid glycoprotein (AGP), a biomarker of inflammation, were assessed. Distributions are shown as mean ± SD or median (IQR) if skewed; associations of infant ferritin with biomarkers and anthropometry were assessed with Spearman correlation (rs) or linear regression with log10-transformed variables, if skewed. ResultsAmong infants, plasma ferritin was 118 (70,182) μg/L, Hb 111 ± 11 g/L; and AGP 0.91 (0.68, 1.17) g/L, with 40.5% of infants inflamed (AGP > 1.00 g/L). Among mothers, ferritin was 60 (38, 88) μg/L and Hb 121 ± 10 g/L. Ferritin was lower in boys (n = 200) than girls (n = 178) [102 (58,159) vs 142 (87,212) μg/L], but weight (5.4 ± 0.6 vs 4.9 ± 0.8 kg) and weight gain since birth (2.8 ± 0.5 vs 2.4 ± 0.7) were higher (all p < 0.0001). When adjusted for sex, infant ferritin was positively associated with AGP (p = 0.025). Adjusted for AGP and low birth weight status, each 1 kg gain in weight from birth to 3 months was associated with 32.0% lower ferritin (95%CI: –45.7, –14.9; p = 0.001) in boys, but not girls [8.4% lower ferritin (95%CI: –21.6, 7.1; p = 0.269)]. Ferritin was not associated with infant Hb (rs = 0.02), or maternal ferritin (rs = –0.003) or Hb (rs = –0.001) (all p > 0.05). ConclusionsInfant ferritin was unassociated with aspects of maternal or infant iron status. It was associated positively with AGP, which was commonly elevated, and negatively with growth in boys, whose size and rate of growth exceeded that of girls. Funding SourcesBill and Melinda Gates Foundation.

Assessment of internal exposure to methylsiloxanes in children and associated non-dietary exposure risk

Methylsiloxanes (MSs) are a significant source of indoor environmental pollution due to their high production level and widespread application, and pose a potential health risk. Given the special vulnerability of children to environmental contaminants, assessment of indoor MSs exposure in children is quite essential. In this study, we assessed internal exposure doses and external exposure levels of MSs in children from industrial and residential areas in southwestern China. Indoor air, indoor dust, and personal care product (PCP) samples were collected to evaluate indoor non-dietary MSs exposure in children through various pathways. The concentrations of MSs in indoor environments of industrial areas were approximately one to four orders of magnitude higher than those of residential areas. Sun protection products contained the highest concentrations of MSs. Relatively high levels of cyclic methylsiloxanes (CMSs) were found in plasma of children from industrial areas, which were one to two orders of magnitude higher than those in children from residential areas. The highest MSs levels in plasma were detected in infants (0–1 year), with values of 1.4 × 102 ng/mL and 1.3 × 102 ng/mL for CMSs (D4–D6) and linear methylsiloxanes (LMSs) (L5–L16), respectively. The internal exposure dose of infants in residential areas is driven by major unknown sources of MSs. The average daily doses via inhalation and dust ingestion in children from industrial areas were one to three orders of magnitude higher than in those from residential areas, indicating that these children should be considered a highly exposed population. Inhalation and dust ingestion were both major exposure pathways to MSs for children of all age groups in industrial areas, whereas dermal absorption from PCPs was the predominant exposure pathway for children of all age groups in residential areas (except for infants). Although the exposure risk to D4 and D5 was at an acceptable level for all children studied, the total daily exposure doses of these two cyclic compounds via inhalation for infants in the industrial areas was near the chronic reference dose. Meanwhile, MSs may accumulate in infant plasma within a short period of time (<6 months). Therefore, infants should be the focus of greater attention in future research. As indoor environments may pose high risks for infants in industrial areas, they should be the focus of future research.

Incorporating Breastfeeding-Related Variability with Physiologically Based Pharmacokinetic Modeling to Predict Infant Exposure to Maternal Medication Through Breast Milk: a Workflow Applied to Lamotrigine.

Current methods to assess risk in infants exposed to maternal medication through breast milk do not specifically account for infants most vulnerable to high drug exposure. A workflow applied to lamotrigine incorporated variability in infant anatomy and physiology, milk intake volume, and milk concentration to predict infant exposure. An adult physiologically based pharmacokinetic model of lamotrigine was developed and evaluated. The model was scaled to account for growth and maturation of a virtual infant population (n=100). Daily infant doses were simulated using milk intake volume and concentration models described by a nonlinear equation of weight-normalized intake across infant age and a linear function on the relationship of observed milk concentrations and maternal doses, respectively. Average infant plasma concentration at steady state was obtained through simulation. Models were evaluated by comparing observed to simulated infant plasma concentrations from breastfeeding infants based on a 90% prediction interval (PI). Upper AUC ratio (UAR) was defined as a novel risk metric. Twenty-five paired (milk concentrations measured) and 18 unpaired (milk concentrations unknown) infant plasma samples were retrieved from the literature. Forty-four percent and 11% of the paired and unpaired infant plasma concentrations were outside of the 90% PI, respectively. Over all ages (0-7 months), unpaired predictions captured more observed infant plasma concentrations within 90% PI than paired. UAR was 0.18-0.44 when mothers received 200 mg lamotrigine, suggesting that infants can receive 18-44% of the exposure per dose as compared to adults. UARs determined for further medications could reveal trends to better classify at-risk mother-infant pairs.

One-Carbon Metabolism in Nepalese Infant–Mother Pairs and Child Cognition at 5 Years Old

One-carbon metabolism (OCM) refers to the transfer of methyl groups central to DNA methylation and histone modification. Insufficient access to methyl donors and B-vitamin cofactors affects epigenetic maintenance and stability, and when occurring in early life may impact future health and neurodevelopment. The objective of this study was to examine the relative associations between one-carbon metabolites in Nepalese mother-infant pairs and child cognition measured at 5 y of age. This is a cross-sectional study from Bhaktapur, Nepal, in a population at high risk of subclinical B-vitamin deficiencies and cumulative infection burden. Venous blood samples from 500 mother-infant pairs were collected when the infants were 2 to 12 mo old, and metabolite concentrations measured by microbiological assays and GC-tandem MS. We re-enrolled 321 of these children at 5 y and assessed cognition by the Ages and Stages Questionnaire, 3rd edition, and subtests from the Developmental Neuropsychological Assessment, 2nd edition (NEPSY-II). The associations of the independent metabolites or unobserved metabolic phenotypes (identified by latent class analysis) with the cognitive outcomes were estimated by seemingly unrelated regression. We explored direct and indirect relations between the OCM pathway and the cognitive outcomes using path analysis. Infant cystathionine concentration was inversely associated with 4 cognitive outcomes (standardized βs ranging from -0.22 to -0.11, P values from <0.001 to 0.034). Infants with a metabolic phenotype indicating impaired OCM and low vitamin B-12 status had poorer cognitive outcomes compared with infants with normal OCM activity and adequate vitamin B-12 status (standardized βs ranging from -0.80 to -0.40, P <0.001 and 0.05). In the path analysis, we found several OCM biomarkers were associated with affect recognition through infant plasma cystathionine. Elevated plasma cystathionine during infancy reflects a metabolic phenotype of impaired OCM and low vitamin B-12 status and is associated with poorer cognitive function when the children are 5 y old.

Sertraline concentrations in pregnant women are steady and the drug transfer to their infants is low

PurposeSertraline, a selective serotonin reuptake inhibitor (SSRI), is one of the most commonly used antidepressant during pregnancy. Plasma sertraline concentrations vary markedly between individuals, partly explained by variability in hepatic drug metabolizing cytochrome P450-enzyme activity. Our purpose was to study the variability in the plasma concentrations in pregnant women and the passage to their infants.MethodPregnant women with moderate untreated depression were recruited in 2016–2019 in Stockholm Region and randomized to treatment with sertraline or placebo. All received Internet-based cognitive behavior therapy as non-medical treatment. Sertraline plasma concentrations were measured around pregnancy weeks 21 and 30, at delivery, 1-month postpartum, in cord blood and at 48 h of age in the infant. The clinical course of the infants was followed.ResultsNine mothers and 7 infants were included in the analysis. Median dose-adjusted sertraline concentration in second trimester was 0.15(ng/mL) /(mg/day), in third trimester and at delivery 0.19 and 1-month postpartum 0.25, with a 67% relative difference between second trimester and postpartum. The interindividual variation was 10-fold. Median concentrations in the infants were 33% and 25% of their mothers’, measured in cord blood, and infant plasma, respectively. Only mild and transient adverse effects were seen on the infants.ConclusionPlacental passage of sertraline to the infant is low. However, the interindividual variation in maternal concentrations during pregnancy is huge, why therapeutic drug monitoring might assist in finding the poor metabolizers at risk for adversity and increase the safety of the treatment.Trial registrationThe trial was registered at clinicaltrials.gov July 9, 2014 with TRN: NCT02185547.

Infant circulating MicroRNAs as biomarkers of effect in fetal alcohol spectrum disorders

Prenatal alcohol exposure (PAE) can result in cognitive and behavioral disabilities and growth deficits. Because alcohol-related neurobehavioral deficits may occur in the absence of overt dysmorphic features or growth deficits, there is a need to identify biomarkers of PAE that can predict neurobehavioral impairment. In this study, we assessed infant plasma extracellular, circulating miRNAs (exmiRNAs) obtained from a heavily exposed Cape Town cohort to determine whether these can be used to predict PAE-related growth restriction and cognitive impairment. PAE, controlling for smoking as a covariate, altered 27% of expressed exmiRNAs with clinically-relevant effect sizes (Cohen’s d ≥ 0.4). Moreover, at 2 weeks, PAE increased correlated expression of exmiRNAs across chromosomes, suggesting potential co-regulation. In confirmatory factor analysis, the variance in expression for PAE-altered exmiRNAs at 2 weeks and 6.5 months was best described by three-factor models. Pathway analysis found that factors at 2 weeks were associated with (F1) cell maturation, cell cycle inhibition, and somatic growth, (F2) cell survival, apoptosis, cardiac development, and metabolism, and (F3) cell proliferation, skeletal development, hematopoiesis, and inflammation, and at 6.5 months with (F1) neurodevelopment, neural crest/mesoderm-derivative development and growth, (F2) immune system and inflammation, and (F3) somatic growth and cardiovascular development. Factors F3 at 2 weeks and F2 at 6.5 months partially mediated PAE-induced growth deficits, and factor F3 at 2 weeks partially mediated effects of PAE on infant recognition memory at 6.5 months. These findings indicate that infant exmiRNAs can help identify infants who will exhibit PAE-related deficits in growth and cognition.

Exposure to pesticides in utero impacts the fetal immune system and response to vaccination in infancy

The use of pesticides to reduce mosquito vector populations is a cornerstone of global malaria control efforts, but the biological impact of most pesticides on human populations, including pregnant women and infants, is not known. Some pesticides, including carbamates, have been shown to perturb the human immune system. We measure the systemic absorption and immunologic effects of bendiocarb, a commonly used carbamate pesticide, following household spraying in a cohort of pregnant Ugandan women and their infants. We find that bendiocarb is present at high levels in maternal, umbilical cord, and infant plasma of individuals exposed during pregnancy, indicating that it is systemically absorbed and trans-placentally transferred to the fetus. Moreover, bendiocarb exposure is associated with numerous changes in fetal immune cell homeostasis and function, including a dose-dependent decrease in regulatory CD4 T cells, increased cytokine production, and inhibition of antigen-driven proliferation. Additionally, prenatal bendiocarb exposure is associated with higher post-vaccination measles titers at one year of age, suggesting that its impact on functional immunity may persist for many months after birth. These data indicate that in utero bendiocarb exposure has multiple previously unrecognized biological effects on the fetal immune system.

Infant Exposure to Dolutegravir Through Placental and Breast Milk Transfer: A Population Pharmacokinetic Analysis of DolPHIN-1.

BackgroundRapid reduction in human immunodeficiency virus (HIV) load is paramount to prevent peripartum transmission in women diagnosed late in pregnancy. We investigated dolutegravir population pharmacokinetics in maternal plasma, umbilical cord, breast milk, and infant plasma samples from DolPHIN-1 participants (NCT02245022) presenting with untreated HIV late in pregnancy (28–36 weeks gestation).MethodsPregnant women from Uganda and South Africa were randomized (1:1) to daily dolutegravir (50 mg/d) or efavirenz-based therapy. Dolutegravir pharmacokinetic sampling (0–24 hours) was undertaken 14 days after treatment initiation and within 1–3 weeks after delivery, with matched maternal and cord samples at delivery. Mothers were switched to efavirenz, and maternal and infant plasma and breast milk samples were obtained 24, 48, or 72 hours after the switch. Nonlinear mixed-effects modeling was used to describe dolutegravir in all matrices and to evaluate covariates.ResultsA total of 28 women and 22 infants were included. Maternal dolutegravir was described by a 2-compartment model linked to a fetal and breast milk compartment. Cord and breast milk to maternal plasma ratios were 1.279 (1.209–1.281) and 0.033 (0.021–0.050), respectively. Infant dolutegravir was described by breast milk–to–infant and infant elimination rate constants. No covariate effects were observed. The median predicted infant dolutegravir half-life and median time to protein-adjusted 90% inhibitory concentration (0.064 mg/L) for those above this threshold were 37.9 (range, 22.1–63.5) hours and 108.9 (18.6–129.6) hours (4.5 [0.8–5.4] days) (n = 13), respectively.ConclusionsBreastfeeding contributed relatively little to infant plasma exposure, but a median of 4.5 days of additional prophylaxis to some of the breastfed infants was observed after cessation of maternal dolutegravir (3–15 days postpartum), which waned with time postpartum as transplacental dolutegravir cleared.

Composition and origin of lung fluid proteome in premature infants and relationship to respiratory outcome.

BackgroundInfants born at extremely low gestational age are at high risk for bronchopulmonary dysplasia and continuing lung disease. There are no early clinical biomarkers for pulmonary outcome and limited therapeutic interventions.ObjectivesWe performed global proteomics of premature infant tracheal aspirate (TA) and plasma to determine the composition and source of lung fluid proteins and to identify potential biomarkers of respiratory outcome.MethodsTA samples were collected from intubated infants in the TOLSURF cohort before and after nitric oxide treatment, and plasma was collected from NO CLD infants. Protein abundance was assayed by HPLC/tandem mass spectrometry and Protein Prospector software. mRNA abundance in mid-gestation fetal lung was assessed by RNA sequencing. Pulmonary morbidity was defined as a need for ventilatory support at term and during the first year.ResultsAbundant TA proteins included albumin, hemoglobin, and actin-related proteins. 96 of 137 detected plasma proteins were present in TA (r = 0.69, p<0.00001). Based on lung RNAseq data, ~88% of detected TA proteins in injured infant lung are derived at least in part from lung epithelium with overrepresentation in categories of cell membrane/secretion and stress/inflammation. Comparing 37 infants at study enrollment (7–14 days) who did or did not develop persistent pulmonary morbidity, candidate biomarkers of both lung (eg., annexin A5) and plasma (eg., vitamin D-binding protein) origin were identified. Notably, levels of free hemoglobin were 2.9-fold (p = 0.03) higher in infants with pulmonary morbidity. In time course studies, hemoglobin decreased markedly in most infants after enrollment coincident with initiation of inhaled nitric oxide treatment.ConclusionsWe conclude that both lung epithelium and plasma contribute to the lung fluid proteome in premature infants with lung injury. Early postnatal elevation of free hemoglobin and heme, which are both pro-oxidants, may contribute to persistent lung disease by depleting nitric oxide and increasing oxidative/nitrative stress.

The University of Zimbabwe College of Health Sciences (UZ-CHS) BIRTH COHORT study: rationale, design and methods

BackgroundCommencing lifelong antiretroviral therapy (ART) immediately following HIV diagnosis (Option B+), has greatly improved maternal-infant health. Thus, large and increasing numbers of HIV-infected women are on ART during pregnancy, a situation concurrently increasing numbers of HIV-exposed-uninfected (HEU) infants. Compared to their HIV-unexposed-uninfected (HUU) counterparts, HEU infants show higher rates of adverse birth outcomes, mortality, infectious/non-communicable diseases including impaired growth and neurocognitive development. There is an urgent need to understand the impact of HIV and early life ART exposures, immune-metabolic dysregulation, comorbidities and environmental confounders on adverse paediatric outcomes.MethodsSix hundred (600) HIV-infected and 600 HIV-uninfected pregnant women ≥20 weeks of gestation will be enrolled from four primary health centres in high density residential areas of Harare. Participants will be followed up as mother-infant-pairs at delivery, week(s) 1, 6, 10, 14, 24, 36, 48, 72 and 96 after birth. Clinical, socio-economic, nutritional and environmental data will be assessed for adverse birth outcomes, impaired growth, immune/neurodevelopment, vertical transmission of HIV, hepatitis-B/C viruses, cytomegalovirus and syphilis. Maternal urine, stool, plasma, cord blood, amniotic fluid, placenta and milk including infant plasma, dried blood spot and stool will be collected at enrolment and follow-up visits. The composite primary endpoint is stillbirth and infant mortality within the first two years of life in HEU versus HUU infants. Maternal mortality in HIV-infected versus -uninfected women is another primary outcome. Secondary endpoints include a range of maternal and infant outcomes. Sub-studies will address maternal stress and malnutrition, maternal-infant latent tuberculosis, Helicobacter pylori infections, immune-metabolomic dysregulation including gut, breast milk and amniotic fluid dysbiosis.DiscussionThe University of Zimbabwe-College of Health-Sciences-Birth-Cohort study will provide a comprehensive assessment of risk factors and biomarkers for HEU infants’ adverse outcomes. This will ultimately help developing strategies to mitigate effects of maternal HIV, early-life ART exposures and comorbidities on infants’ mortality and morbidity.Trial registrationClinicalTrial.gov Identifier: NCT04087239. Registered 12 September 2019.

Validation and Determination of 25(OH) Vitamin D and 3-Epi25(OH)D3 in Breastmilk and Maternal- and Infant Plasma during Breastfeeding.

Vitamin D deficiency in pregnant women and their offspring may result in unfavorable health outcomes for both mother and infant. A 25hydroxyvitamin D (25(OH)D) level of at least 75 nmol/L is recommended by the Endocrine Society. Validated, automated sample preparation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were used to determine the vitamin D metabolites status in mother-infant pairs. Detection of 3-Epi25(OH)D3 prevented overestimation of 25(OH)D3 and misclassification of vitamin D status. Sixty-three percent of maternal 25(OH)D plasma levels were less than the recommended level of 25(OH)D at 3 months. Additionally, breastmilk levels of 25(OH)D decreased from 60.1 nmol/L to 50.0 nmol/L between six weeks and three months (p < 0.01). Furthermore, there was a positive correlation between mother and infant plasma levels (p < 0.01, r = 0.56) at 3 months. Accordingly, 31% of the infants were categorized as vitamin D deficient (25(OH)D < 50 nmol/L) compared to 25% if 3-Epi25(OH)D3 was not distinguished from 25(OH)D3. This study highlights the importance of accurate quantification of 25(OH)D. Monitoring vitamin D metabolites in infant, maternal plasma, and breastmilk may be needed to ensure adequate levels in both mother and infant in the first 6 months of infant life.

Evaluation of HIV-1 neutralizing and binding antibodies in maternal-infant transmission in Thailand

Despite anti-retroviral therapy (ART) interventions for HIV+ pregnant mothers, over 43,000 perinatal infections occur yearly. Understanding risk factors that lead to mother-to-child transmission (MTCT) of HIV are critical. We evaluated maternal and infant plasma binding and neutralizing antibody responses in a drug-naïve, CRF01_AE infected MTCT cohort from Thailand to determine associations with transmission risk. Env V3-specific IgG and neutralizing antibody responses were significantly higher in HIV- infants, as compared to HIV+ infants. In fact, infant plasma neutralizing antibodies significantly associated with non-transmission. Conversely, increased maternal Env V3-specific IgG and neutralizing antibody responses were significantly associated with increased transmission risk, after controlling for maternal viral load. Our results highlight the importance of evaluating both maternal and infant humoral immune responses to better understand mechanisms of protection, as selective placental antibody transport may have a role in MTCT. This study further emphasizes the complex role of Env-specific antibodies in MTCT of CRF01_AE HIV.

Validity and Reproducibility of a Semi-Quantitative Food-Frequency Questionnaire Designed to Measure the Nutrient Intakes of Canadian South Asian Infants at 12 Months of Age.

Purpose: Validated methods to assess diet of non-European infants are sparse. We assessed the validity and reliability of a semi-quantitative food-frequency questionnaire (FFQ) for South Asian infants in Canada.Methods: We developed an 80-item FFQ to assess infant nutrient intake in the South Asian Birth Cohort study (START). Caregivers completed the FFQ twice along with two 24-hour diet recalls. We measured infant plasma ferritin to cross-validate reported iron intake. We evaluated validity using Spearman's rho (ρ), and reliability using the intraclass correlation coefficient.Results: Seventy-six caregivers provided 2 FFQs and 2 24-hour diet recalls. Energy-adjusted, de-attenuated correlations between the FFQs and 24-hour diet recalls ranged from -0.29 (monounsaturated fat) through 1.00 (cholesterol). The FFQ overestimated energy intake by 128%. Iron intake by 24-hour diet recalls correlated with plasma ferritin (r = 0.41; P = 0.01; n = 37), but iron intake by FFQ did not. The average reproducibility coefficient of the FFQ ranged from 0.24 (macronutrients) to 0.65 (minerals).Conclusions: Among South Asian infants living in Canada, at least 2 days of diet recall completed with the primary caregiver yields more valid and reproducible estimates of nutrient intakes than a semi-quantitative FFQ, and it highlights that careful selection of FFQ portion sizes is important for assessing dietary intake with an FFQ.

Maternal Vitamin D Sufficiency Is Associated with Lower Circulating TNF-α in Breastfeeding Infants

Abstract Objectives Exclusively breastfeeding (BrF) infants are at risk for vitD deficiency if they or their mothers are not supplemented. However, it is unknown if maternal or direct infant vitD supplementation could have differential effects on the BrF child. We hypothesized that maternal vitD status may affect concentrations of pro-inflammatory cytokines in infants. Methods Exclusively BrF infants and mothers were enrolled in a clinical study in which infant vitD sufficiency was achieved by either direct supplementation with 400 IU/d vitD3 or mothers were supplemented with 6400 IU/d. Infant and maternal plasma 25-hydroxyvitamin D (25-D) values were determined by radioimmunoassay at enrollment (1-mo infant) and completion (5-mo). Concentrations of 10 pro-inflammatory cytokines in infant plasma were determined by electrochemiluminescence. ANOVA, t-tests and linear correlations were used to calculate relationships between vitD and circulating cytokines in 49 infant-mother pairs at study enrollment and 39 pairs at completion. Results Plasma concentrations of 10 pro-inflammatory cytokines measured were very low (pg/ml range). Neither infant nor maternal vitD status (sufficiency defined as plasma 25-D &amp;gt; 30 ng/ml) were associated with 9 measured cytokines in infant blood (IFN-γ, IL-1b, –2, –4, –6, –8, –10, –12, –13). In contrast, concentrations of tumor necrosis factor (TNF)-α in infant plasma were inversely correlated to maternal vitD status (r = −0.37; P = 0.02 at study completion). At study enrollment, BrF infants of vitD-sufficient mothers had mean 20% lower plasma TNF-α concentration than infants of vitD-insufficient mothers (P = 0.02), regardless of the infant's own vitD status. VitD sufficiency in infants per se was associated with mean 5% lower plasma TNF-α concentration, non-significantly different to that of vitD-deficient infants. Conclusions These results indicate that vitD-mediated changes in breastmilk composition can affect the immune system of BrF infants. Circulating concentrations of the major pro-inflammatory cytokine TNF-α were significantly lower in infants with vitD-sufficient mothers regardless of the infant's own vitD status. Studies are currently investigating vitD-associated effects on responses of BrF infants’ immune cells to antigenic challenge. Funding Sources NIH/NCATS, SC Translational Research Institute, MUSC Pediatrics.

Maternal-fetal disposition of domoic acid following repeated oral dosing during pregnancy in nonhuman primate

Domoic acid (DA) is a marine algal toxin that causes acute and chronic neurotoxicity in animals and humans. Prenatal exposure to DA has been associated with neuronal damage and cognitive and behavioral deficits in juvenile California sea lions, cynomolgus monkeys and rodents. Yet, the toxicokinetics (TK) of DA during pregnancy and the maternal-fetal disposition of DA have not been fully elucidated. In this study, we investigated the TK before, during, and after pregnancy and the maternal-fetal disposition of DA in 22 cynomolgus monkeys following daily oral doses of 0.075 or 0.15mg/kg/day of DA. The AUC0-τ of DA was not changed while the renal clearance of DA was increased by 30-90% during and after pregnancy when compared to the pre-pregnancy values. DA was detected in the infant plasma and in the amniotic fluid at delivery. The infant plasma concentrations correlated positively with both the maternal plasma and the amniotic fluid concentrations. The paired infant-to-maternal plasma DA concentration ratios ranged from 0.3 to 0.6 and increased as a function of time which suggests placental efflux and longer apparent fetal half-life than the maternal half-life. The paired amniotic fluid-to-infant plasma DA concentration ratios ranged from 4.5 to 7.5 which indicates significant accumulation of DA in the amniotic fluid. A maternal-fetal TK model was developed to explore the processes that give the observed maternal-fetal disposition of DA. The final model suggests that placental transport and recirculation of DA between the fetus and amniotic fluid are major determining factors of the maternal-fetal TK of DA.

Perindopril in Breast Milk and Determination of Breastfed Infant Exposure: A Prospective Observational Study.

ObjectiveThis study aimed to quantify the amount of perindopril and its active metabolite perindoprilat present in breast milk and corresponding maternal and infant plasma concentrations.DesignProspective, longitudinal, observational.SettingTertiary specialist paediatric and obstetric hospital in Adelaide, South Australia.PopulationBreastfeeding women actively treated with perindopril for hypertensive disorders postpartum.MethodsEight breast milk samples and a single plasma sample were collected from each participant over a 24 hrs period, and plasma samples were taken from eligible breastfed infants. Breast milk and plasma concentrations of perindopril and perindoprilat were analysed using a validated Liquid Chromatography tandem-Mass Spectrometry (LC-MS/MS) method.Main Outcome MeasuresMean breast milk concentrations of perindopril and perindoprilat, Relative Infant Dose (RID) <10%, and Theoretical Infant Dose (TID).ResultsTen women and three infants participated in the study. The mean concentration of perindopril in breast milk for each participant ranged from 0.003 to 1.2 ng/mL and perindoprilat 0.2–36 ng/mL. RID for perindopril was 0.0005–0.2% and perindoprilat 0.03–4.6%. TID for perindopril was 0.00045–0.18 µg/kg/day and perindoprilat 0.032–5.4 µg/kg/day. Infant plasma levels for perindopril ranged from 0.44 to 1.12 ng/mL and perindoprilat undetectable – 10.14 ng/mL. Maternal reports described normal infant growth and development.ConclusionInfant exposure to perindopril and perindoprilat through breast milk is low. However, some infants were found to have plasma perindoprilat concentrations consistent with pharmacodynamic effects. Perindopril may be used in mothers of healthy term infants, provided the infant is carefully monitored.

Early life temperamental anxiety is associated with excessive alcohol intake in adolescence: A rhesus monkey (Macaca mulatta) model.

Teenage alcohol abuse is a major health concern, particularly because the majority of alcohol consumed by teenagers is via binge drinking, a known risk factor for increasing the likelihood for the development of future alcohol use disorders (AUDs). Identifying individuals at risk for excessive alcohol intake in adolescence is a step toward developing effective preventative measures and intervention programs. As adults with AUDs tend to self-medicate their anxiety with alcohol, this longitudinal study assesses the role of infant anxiety-like temperament in the development of adolescent alcohol abuse using a nonhuman primate model. From birth until they were 5 months of age, behaviors of 64 rhesus monkeys (Macaca mulatta) were coded twice a week using an objective mother-infant scoring system that included behaviors traditionally used to assess anxiety and fearfulness in rhesus monkeys. When subjects were four months old, plasma cortisol was obtained. When subjects were adolescents (Mage = 44.88 months), another plasma cortisol sample was obtained about one month prior to allowing them unfettered access to an 8.4% (v/v) aspartame-sweetened alcohol solution for one hour a day over five-to-seven weeks. Results showed that behavioral indications of anxiety-like temperament in infancy, including high levels of mother-infant mutual ventral contact, low levels of environmental exploration, and low levels of interactions with peers were predictive of high adolescent alcohol intake (ie, drinking to intoxication). Plasma cortisol levels in infancy were positively correlated with plasma cortisol in adolescence, and both were positively correlated with high adolescent alcohol intake. Our findings indicate that high levels of traditional anxiety-like behaviors measured in the context of mother-infant interactions, coupled with high infant and adolescent plasma cortisol, are associated with binge-like high alcohol intake in adolescence, suggesting that individuals at risk for developing an AUD later in life may be determined, at least in part, by assessing their physiological and behavioral propensity for anxiety early in life.