Osteogenesis imperfecta (OI) is an inherited disorder characterized by bone fragility with extraskeletal manifestations mostly due to COL1A1and COL1A2 variants. Currently, 23 genes have been implicated in the pathogenesis of OI; however, literature on genotype-phenotype correlation and incidence of non-skeletal clinical features are limited. This study aims to identify genotype-phenotype correlations in patients with OI, allowing clinicians to better inform families of prognosis, optimize patient care, and facilitate evidence-based clinical decision-making. We retrospectively reviewed 294 patients with OI to collect demographic data, clinical characteristics, and genotypic information. Patients were stratified by COL1A1/1A2 vs non- COL1A1/1A2 variants to evaluate differences in phenotype. The majority of OI was due to variants in COL1A1/1A2 (91%), with the remaining 9% due to non- COL1A1/1A2 variants. Most patients in the COL1A1/2 group were White compared to the non- COL1A1/2 group (78% vs 50%; p = 0.004). COL1A/1A2 patients had higher incidence of blue sclerae (83% vs 58%, p = 0.002), dentinogenesis imperfecta (49% vs 15%, p < 0.001), and family history of OI(34% vs 12%, p = 0.03). Those in the non- COL1A1/1A2 group have higher rates of scoliosis compared to those in the COL1A1/1A2 group (62% vs 40%, p = 0.04), as well as higher rates of expressive language disorder/delay (15% vs 0.4% in non- COL1A1/1A2 and COL1A1/1A2 patients, respectively; p < 0.001). Identifying the underlying molecular etiology early is imperative for optimal clinical care, allowing for appropriate risk counseling, identification of affected relatives, and improved anticipatory care and management. These data support that rare subtypes of OI occur more frequently in non-White individuals and demonstrated genetic associations with incidence of blue sclera, dentinogenesis imperfecta, scoliosis, and expressive language disorders.

Normal pregnancy relies on inflammation for implantation, placentation, and parturition, but uncontrolled inflammation can lead to poor maternal and infant outcomes. Maternal diet is one modifiable factor that can impact inflammation. Omega-3 and -6 fatty acids obtained through the diet are metabolized into bioactive compounds that effect inflammation. Recent evidence has shown that the downstream products of omega-3 and -6 fatty acids may influence physiology during pregnancy. In this review, the current knowledge relating to omega-3 and omega-6 metabolites during pregnancy will be summarized.

The prenatal period is critical for auditory development; thus, prenatal influences on auditory development may significantly impact long-term hearing ability. While previous studies identified a protective effect of carotenoids on adult hearing, the impact of these nutrients on hearing outcomes in neonates is not well understood. The purpose of this study is to investigate the relationship between maternal and umbilical cord plasma retinol and carotenoid concentrations and abnormal newborn hearing screen (NHS) results. Mother–infant dyads (n = 546) were enrolled at delivery. Plasma samples were analyzed using HPLC and LC–MS/MS. NHS results were obtained from medical records. Statistical analysis utilized Mann–Whitney U tests and logistic regression models, with p ≤ 0.05 considered statistically significant. Abnormal NHS results were observed in 8.5% of infants. Higher median cord retinol (187.4 vs. 162.2 μg/L, p = 0.01), maternal trans-β-carotene (206.1 vs. 149.4 μg/L, p = 0.02), maternal cis-β-carotene (15.9 vs. 11.2 μg/L, p = 0.02), and cord trans-β-carotene (15.5 vs. 8.0 μg/L, p = 0.04) were associated with abnormal NHS. Significant associations between natural log-transformed retinol and β-carotene concentrations and abnormal NHS results remained after adjustment for smoking status, maternal age, and corrected gestational age. Further studies should investigate if congenital metabolic deficiencies, pesticide contamination of carotenoid-rich foods, maternal hypothyroidism, or other variables mediate this relationship.

Omega-3 and omega-6 fatty acids are important for neonatal development and health. One mechanism by which omega-3 and omega-6 fatty acids exert their effects is through their metabolism into oxylipins and specialized pro-resolving mediators. However, the influence of oxylipins on fetal growth is not well understood. Therefore, the objective of this study was to identify oxylipins present in maternal and umbilical cord plasma and investigate their relationship with infant growth. Liquid chromatography–tandem mass spectrometry was used to quantify oxylipin levels in plasma collected at the time of delivery. Spearman’s correlations highlighted significant correlations between metabolite levels and infant growth. They were then adjusted for maternal obesity (normal body mass index (BMI: ≤30 kg/m2) vs. obese BMI (>30 kg/m2) and smoking status (never vs. current/former smoker) using linear regression modeling. A p-value < 0.05 was considered statistically significant. Our study demonstrated a diverse panel of oxylipins from the lipoxygenase pathway present at the time of delivery. In addition, both omega-3 and omega-6 oxylipins demonstrated potential influences on the birth length and weight percentiles. The oxylipins present during pregnancy may influence fetal growth and development, suggesting potential metabolites to be used as biomarkers for infant outcomes.

Polyunsaturated fatty acids (PUFAs) are essential for fetal development, and intrauterine transfer is the only supply of PUFAs to the fetus. The prevailing theory of gestational nutrient transfer is that certain nutrients (including PUFAs) may have prioritized transport across the placenta. Numerous studies have identified correlations between maternal and infant fatty acid concentrations; however, little is known about what role maternal PUFA status may play in differential intrauterine nutrient transfer. Twenty mother–infant dyads were enrolled at delivery for collection of maternal and umbilical cord blood, and placental tissue samples. Plasma concentrations of PUFAs were assessed using gas chromatography (GC-FID). Intrauterine transfer percentages for each fatty acid were calculated as follows: ((cord blood fatty acid level/maternal blood fatty acid level) × 100). Kruskal–Wallis tests were used to compare transfer percentages between maternal fatty acid tertile groups. A p-value < 0.05 was considered significant. There were statistically significant differences in intrauterine transfer percentages of arachidonic acid (AA) (64% vs. 65% vs. 45%, p = 0.02), eicosapentaenoic acid (EPA) (41% vs. 19% vs. 17%, p = 0.03), and total fatty acids (TFA) (27% vs. 26% vs. 20%, p = 0.05) between maternal plasma fatty acid tertiles. Intrauterine transfer percentages of AA, EPA, and TFA were highest in the lowest tertile of respective maternal fatty acid concentration. These findings may indicate that fatty acid transfer to the fetus is prioritized during gestation even during periods of maternal nutritional inadequacy.

Background and Aims: Inadequate nutrient provision causes neonatal growth failure and malnutrition. Therefore, this study aimed to 1) quantify infant growth velocity from birth to hospital discharge, 2) determine the incidence of neonatal malnutrition at the time of discharge from a government hospital newborn unit in Nakuru, Kenya. Methods: After ethical approval, data was collected for infants (n=104) hospitalized >14 days (June 2016 - December 2018) including: birth gestational age (GA), birth and discharge weight (grams, g) with z-scores (2013 Fenton Preterm or 2006 World Health Organization 0-2 Year growth chart), hospital length of stay (LOS) days. Growth during hospitalization was calculated in g/day [(discharge weight – birth weight)/LOS] and g/kilogram(kg)/day [1000xln(birth weight/discharge weight)/LOS). Malnutrition was diagnosed by birth to discharge weight z-score change (decline): mild = 0.8-1.2 standard deviations (SD), moderate = >1.2-2.0 SD, severe = >2.0 SD. P-value <0.05 was significant. Results: 94/104 (90.4%) infants were preterm with median birth GA 32 weeks, weight 1500 g (z-score -0.33), LOS 21 days and discharge weight 1735 g (z-score -1.95). Median weight gain was 8.2 g/day or 5.2 g/kg/day with weight z-score change -1.34 SD. Linear regression predicted each hospital day decreased z-score by -0.031 (p<0.001). At discharge, 81.7% of infants met malnutrition criteria—27.1% mild, 49.4% moderate, 23.5% severe. Conclusions: Infants with LOS >14 days in a government hospital newborn unit in Nakuru, Kenya, experience growth rates below recommended velocities by the World Health Organization (23-34 grams/day from 0-4 months). Nutrition intervention is necessary to support appropriate growth.

Background: QuPath is an open-source digital image analyzer notable for its user-friendly design, cross-platform compatibility, and customizable functionality. Since it was first released in 2016, at least 624 publications have reported its use, and it has been applied in a wide spectrum of settings. However, there are currently limited reports of its use in placental tissue. Here, we present the use of QuPath to quantify staining of G-protein coupled receptor 18 (GPR18), the receptor for the pro-resolving lipid mediator Resolvin D2, in placental tissue. Methods: Whole slide images of vascular smooth muscle (VSM) and extravillous trophoblast (EVT) cells stained for GPR18 were annotated for areas of interest. Visual scoring was performed on these images by trained and in-training pathologists, while QuPath scoring was performed with the methodology described herein. Results: Bland-Altman analyses showed that, for the VSM category, the two methods were comparable across all staining levels. For EVT cells, the high-intensity staining level was comparable across methods, but the medium and low staining levels were not comparable. Conclusions: Digital image analysis programs offer great potential to revolutionize pathology practice and research by increasing accuracy and decreasing the time and cost of analysis. Careful study is needed to optimize this methodology further.

Carotenoids are antioxidant nutrients with the potential to provide protection against oxidative stress. Plasma carotenoid concentrations are lower in newborn infants compared to their mothers; however, limited information is available regarding how concentrations differ by gestational age. The objective of this research is to assess maternal and umbilical cord plasma carotenoid concentrations and maternal-umbilical cord plasma ratios across five groups of birth gestational age. Mother-infant dyads were enrolled at delivery for collection of maternal and umbilical cord blood. Plasma carotenoids were analyzed by HPLC and LC-MS/MS. Birth gestational age was categorized into five groups, and the Kruskal–Wallis test compared carotenoid concentrations and maternal-umbilical cord plasma ratios between these groups. A p-value of < 0.05 was considered statistically significant. 370 mother-infant dyads were included, with most infants delivered at early term (20.3%) or term (64.6%). Though maternal plasma concentrations increased with birth gestational age, we observed less variability in umbilical cord plasma concentrations, thus the maternal-umbilical cord plasma ratio also increased with birth CGA groups for lutein + zeaxanthin (p = 0.008), β-cryptoxanthin (p = 0.027), α-carotene (p = 0.030); β-carotene approached significance (p = 0.056). Additional research is needed to determine if carotenoid concentrations were physiologic to varying gestational ages or if they were impacted by factors associated with preterm birth.

Retinol (vitamin A) is essential, so the objective of this Institutional Review Board approved study is to evaluate retinol placental concentration, intrauterine transfer, and neonatal status at time of term delivery between cases of maternal retinol adequacy, insufficiency, and deficiency in a United States population. Birth information and biological samples were collected for mother–infant dyads (n = 260). Maternal and umbilical cord blood retinol concentrations (n = 260) were analyzed by HPLC and categorized: deficient (≤0.7 umol/L), insufficient (>0.7–1.05 umol/L), adequate (>1.05 umol/L). Intrauterine transfer rate was calculated: (umbilical cord blood retinol concentration/maternal retinol concentration) × 100. Non-parametric statistics used include Spearman’s correlations, Mann–Whitney U, and Kruskal–Wallis tests. p-values <0.05 were statistically significant. Only 51.2% of mothers were retinol adequate, with 38.4% insufficient, 10.4% deficient. Only 1.5% of infants were retinol adequate. Placental concentrations (n = 73) differed between adequate vs. deficient mothers (median 0.13 vs. 0.10 μg/g; p = 0.003). Umbilical cord blood concentrations were similar between deficient, insufficient, and adequate mothers (0.61 vs. 0.55 vs. 0.57 μmol/L; p = 0.35). Intrauterine transfer increased with maternal deficiency (103.4%) and insufficiency (61.2%) compared to adequacy (43.1%), p < 0.0001. Results indicate that intrauterine transfer rate is augmented in cases of maternal retinol inadequacy, leading to similar concentrations in umbilical cord blood at term delivery.

Vitamin E plays different roles in health based on its three isoforms: alpha (α)-tocopherol is anti-inflammatory, gamma (γ)-tocopherol is pro-inflammatory, delta (δ)-tocopherol remains unknown. As inflammation may promote hypertension, the objective of this study is to examine relationships between maternal serum tocopherol levels at time of delivery and pregnancy-related blood pressure (BP) changes. Hypothesis is that increased level of α-tocopherol has favorable effects and γ-tocopherol has adverse effects on maternal BP. An IRB-approved cross-sectional study enrolled mother-infant dyads (n = 342) at time of delivery (Omaha, NE, USA) for collection of electronic health data and maternal blood. High-performance liquid chromatography analyzed serum tocopherol levels. Maternal BP values were collected from 1st and 3rd trimester clinic/hospital visits with changes calculated in systolic BP and mean arterial pressure (MAP = diastolic BP + 1/3(systolic BP – diastolic BP). Mothers were classified as hypertensive if: systolic BP ≥140, diastolic BP ≥ 90, or diagnosis of preeclampsia. Two-sample t-test and Pearson correlation coefficients compared relationships between serum tocopherol levels and BP data. P-value < 0.05 was significant. Mean maternal age was 28.5 years, majority (61.4%) Caucasian, 10.4% (n = 29) with hypertension. Mean serum levels: α-tocopherol 15,229 + 5849 mcg/L, γ-tocopherol 1642 + 868 mcg/L, δ-tocopherol 226 + 164 mcg/L, with α: γ ratio 11.5 + 8.7. Mean serum α-tocopherol level was higher in normotensive vs. hypertensive mothers (15,751 vs. 13,819 mcg/L; P = 0.06). Ratio of α: γ demonstrated an inverse correlation with change in maternal systolic BP (r = −0.128; P = 0.03). No other relationships were significant. Increasing maternal α-tocopherol and α: γ ratio has favorable association with maintaining normal BP during pregnancy. More research is needed to specifically identify serum thresholds and tocopherol isoform ratios for favorably reducing risk of pregnancy-related hypertension. Department of Pediatrics and the Child Health Research Institute at the University of Nebraska Medical Center and Children's Hospital & Medical Center (Omaha, NE).

Preterm birth is a leading cause of child morbidity and mortality, so strategies to reduce early birth must remain a priority. One key approach to enhancing birth outcomes is improving maternal dietary intake. Therefore, the purpose of this review is to discuss mechanisms on perinatal status of fat-soluble nutrients (carotenoids, retinol, tocopherols) and omega-3 fatty acids and how they impact risk for preterm birth. Literature review demonstrates that maternal dietary intake and biological (blood and placental tissue) levels of fat-soluble nutrients during pregnancy may provide antioxidative, anti-inflammatory, and immunomodulatory health benefits. Omega-3 fatty acids also promote increased production of specialized pro-resolving mediators, subsequently mediating inflammation resolution. Combined effects of these nutrients support appropriate placental organogenesis and function. Consequently, fat-soluble nutrients and omega-3 fatty acids serve as strong influencers for preterm birth risk. As dietary intake remains a modifiable factor, future intervention would benefit from a focus on optimizing perinatal status of these specific nutrients.

Background Perinatal inflammation adversely affects health. Therefore, aims of this IRB-approved study are: (1) compare inflammatory compounds within and between maternal and umbilical cord blood samples at the time of delivery, (2) assess relationships between inflammatory compounds in maternal and cord blood with birth characteristics/outcomes, and (3) assess relationships between blood and placental fat-soluble nutrients with blood levels of individual inflammatory compounds. Methods Mother−infant dyads were enrolled ( n = 152) for collection of birth data and biological samples of maternal blood, umbilical cord blood, and placental tissue. Nutrient levels included: lutein + zeaxanthin; lycopene; α-, β-carotene; β-cryptoxanthin; retinol; α-, γ-, δ-tocopherol. Inflammatory compounds included: tumor necrosis factor-α, superoxide dismutase, interleukins (IL) 1β, 2, 6, 8, 10. Results Median inflammatory compound levels were 1.2–2.3 times higher in cord vs. maternal blood, except IL2 (1.3 times lower). Multiple significant correlations existed between maternal vs. infant inflammatory compounds (range of r = 0.22–0.48). While relationships existed with blood nutrient levels, the most significant were identified in placenta where all nutrients (except δ-tocopherol) exhibited relationships with inflammatory compounds. Relationships between anti-inflammatory nutrients and proinflammatory compounds were primarily inverse. Conclusion Inflammation is strongly correlated between mother−infant dyads. Fat-soluble nutrients have relationships with inflammatory compounds, suggesting nutrition is a modifiable factor. Impact Mother and newborn inflammation status are strongly interrelated. Levels of fat-soluble nutrients in blood, but especially placenta, are associated with blood levels of proinflammatory and anti-inflammatory compounds in both mother and newborn infant. As fat-soluble nutrient levels are associated with blood inflammatory compounds, nutrition is a modifiable factor to modulate inflammation and improve perinatal outcomes.

Omega-3 fatty acids are important to pregnancy and neonatal development and health. One mechanism by which omega-3 fatty acids exert their protective effects is through serving as substrates for the generation of specialized pro-resolving lipid mediators (SPM) that potently limit and resolve inflammatory processes. We recently identified that SPM levels are increased in maternal blood at delivery as compared to umbilical cord blood, suggesting the placenta as a potential site of action for maternal SPM. To explore this hypothesis, we obtained human placental samples and stained for the SPM resolvin D2 (RvD2) receptor GPR18 via immunohistochemistry. In so doing, we identified GPR18 expression in placental vascular smooth muscle and extravillous trophoblasts of the placental tissues. Using in vitro culturing, we confirmed expression of GPR18 in these cell types and further identified that stimulation with RvD2 led to significantly altered responsiveness (cytoskeletal changes and pro-inflammatory cytokine production) to lipopolysaccharide inflammatory stimulation in human umbilical artery smooth muscle cells and placental trophoblasts. Taken together, these findings establish a role for SPM actions in human placental tissue.

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Omega (n)-3 fatty acids are vital to neonatal maturation, and recent investigations reveal n-3 fatty acids serve as substrates for the biosynthesis of specialized pro-resolving lipid mediators (SPM) that have anti-inflammatory and immune-stimulating effects. The role SPM play in the protection against negative maternal-fetal health outcomes is unclear, and there are no current biomarkers of n-3 fatty acid sufficiency. We sought to ascertain the relationships between n-3 fatty acid intake, SPM levels, and maternal-fetal health outcomes. We obtained n-3 fatty acid intake information from 136 mothers admitted for delivery using a food frequency questionnaire and measured docosahexaenoic acid (DHA)-derived SPMs resolvin D1 (RvD1) and RvD2 in maternal and cord plasma. We found significantly elevated SPM in maternal versus cord plasma, and increased SPM levels were associated with at-risk outcomes. We also identified that increased DHA intake was associated with elevated maternal plasma RvD1 (p = 0.03; R2 = 0.18) and RvD2 (p = 0.04; R2 = 0.20) in the setting of neonatal intensive care unit (NICU) admission. These findings indicate that increased n-3 fatty acid intake may provide increased substrate for the production of SPM during high-risk pregnancy/delivery conditions, and that increased maternal plasma SPM could serve as a biomarker for negative neonatal outcomes.

Lutein + zeaxanthin (L + Z) are carotenoids recognized in eye health, but less is known about their status during pregnancy. While quantified in maternal and umbilical cord blood, they have never been analyzed in placenta. The purpose of this study is to quantify combined L + Z concentrations in human placenta and correlate with levels in maternal dietary intake, maternal serum, and umbilical cord blood. The proportions of combined L + Z were compared within diet, placenta, maternal serum, and umbilical cord blood among additional carotenoids (lycopene, β-cryptoxanthin, α-carotene, and β-carotene). This Institutional Review Boardapproved cross-sectional study enrolled 82 mother-infant pairs. Placenta, maternal serum, and umbilical cord blood samples were analyzed for carotenoids concentrations. Mothers completed a food frequency questionnaire and demographic/birth outcome data were collected. L + Z were present in placenta, median 0.105 micrograms/gram (mcg/g) and were significantly correlated with maternal serum (r = 0.57; p < 0.001), umbilical cord blood levels (r = 0.49; p = 0.001), but not dietary intake (p = 0.110). L + Z were the most prevalent in placenta (49.1%) umbilical cord blood (37.0%), but not maternal serum (18.6%) or dietary intake (19.4%). Rate of transfer was 16.0%, the highest of all carotenoids. Conclusively, L + Z were identified as the two most prevalent in placenta. Results highlight unique roles L + Z may play during pregnancy.

The objective of the present study was to evaluate intakes and serum levels of vitamin A, vitamin E, and related compounds in a cohort of maternal–infant pairs in the Midwestern USA in relation to measures of health disparities. Concentrations of carotenoids and tocopherols in maternal serum were measured using HPLC and measures of socio-economic status, including food security and food desert residence, were obtained in 180 mothers upon admission to a Midwestern Academic Medical Center labour and delivery unit. The Kruskal–Wallis and independent-samples t tests were used to compare measures between groups; logistic regression models were used to adjust for relevant confounders. P < 0·05 was considered statistically significant. The odds of vitamin A insufficiency/deficiency were 2·17 times higher for non-whites when compared with whites (95 % CI 1·16, 4·05; P = 0·01) after adjustment for relevant confounders. Similarly, the odds of being vitamin E deficient were 3·52 times higher for non-whites (95 % CI 1·51, 8·10; P = 0·003). Those with public health insurance had lower serum lutein concentrations compared with those with private health insurance (P = 0·05), and living in a food desert was associated with lower serum concentrations of β-carotene (P = 0·02), after adjustment for confounders. Subjects with low/marginal food security had higher serum levels of lutein and β-cryptoxanthin compared with those with high food security (P = 0·004 and 0·02 for lutein and β-cryptoxanthin). Diet quality may be a public health concern in economically disadvantaged populations of industrialised societies leading to nutritional disadvantages as well.

Vitamin A is an essential nutrient in pregnancy, and other carotenoids have been independently associated with maternal-infant outcomes. The objective of this study was to quantify the status of vitamin A and carotenoids in Nigerian maternal-infant pairs at delivery, compare these to a cohort from a developed nation, and determine the impact on clinical outcomes. Maternal and cord blood samples were collected in 99 Nigerian mother-infant pairs. Concentrations of lutein + zeaxanthin, β-cryptoxanthin, lycopene, α- and β-carotenes, and retinol were measured using HPLC. Descriptive statistics were calculated and Spearman coefficients were used to assess correlations between maternal and cord measurements; Mann-Whitney tests were used to compare median plasma values between dichotomous variables. Linear regression models were used to adjust for relevant confounders. A p < 0.05 was considered statistically significant. Thirty-five percent of mothers had plasma retinol concentrations ≤0.70 µmol/L; 82% of infants had plasma retinol concentrations ≤0.70 µmol/L at delivery. Maternal and infant concentrations of vitamin A compounds were highly correlated and were associated with newborn growth and Apgar scores. Despite plasma concentrations of pro-vitamin A carotenoids higher than those reported in other populations, pregnant Nigerian women have a high prevalence of vitamin A deficiency. As vitamin A related compounds are modifiable by diet, future research determining the clinical impact of these compounds is warranted.