A harmonized analysis of five Canadian pregnancy cohort studies: exploring the characteristics and pregnancy outcomes associated with prenatal alcohol exposure.

BACKGROUND: As a teratogen, alcohol exposure during pregnancy can impact fetal development and result in adverse birth outcomes. Despite the clinical and social importance of prenatal alcohol use, limited routinely collected information or epidemiological data exists in Canada. The aim of this study was to pool data from multiple Canadian cohort studies to identify sociodemographic characteristics before and during pregnancy that were associated with alcohol consumption during pregnancy and to assess the impact of different patterns of alcohol use on birth outcomes. METHODS: We harmonized information collected (e.g., pregnant women's alcohol intake, infants' gestational age and birth weight) from five Canadian pregnancy cohort studies to consolidate a large sample (n = 11,448). Risk factors for any alcohol use during pregnancy, including any alcohol use prior to pregnancy recognition, and binge drinking, were estimated using binomial regressions including fixed effects of pregnancy cohort membership and multiple maternal risk factors. Impacts of alcohol use during pregnancy on birth outcomes (preterm birth and low birth weight for gestational) were also estimated using binomial regression models. RESULTS: In analyses adjusting for multiple risk factors, women's alcohol use during pregnancy, both any use and any binge drinking, was associated with drinking prior to pregnancy, smoking during pregnancy, and white ethnicity. Higher income level was associated with any drinking during pregnancy. Neither drinking during pregnancy nor binge drinking during pregnancy was significantly associated with preterm delivery or low birth weight for gestational age in our sample. CONCLUSIONS: Pooling data across pregnancy cohort studies allowed us to create a large sample of Canadian women and investigate the risk factors for alcohol consumption during pregnancy. We suggest that future pregnancy and birth cohorts should always include questions related to the frequency and amount of alcohol consumed before and during pregnancy that are prospectively harmonized to support data reusability and collaborative research.

Low-intensity physical activity may protect pregnant women against spontaneous preterm labour: a prospective case-control study.

The innate immune system plays a significant role in onset of parturition. Maternal antenatal physical activity can influence immune function and timing of labour. We examined physical activity patterns and concentration of 19 cytokines at 16 and 27 weeks gestational age (GA), in peripheral plasma of 28 asymptomatic women who later had spontaneous preterm labour (SPTL, <37 weeks GA) and 52 women who later delivered at term (TL; ≥37 weeks GA). This nested case-control study used data from the Ontario Birth Study cohort. Exercise was assessed using the International Physical Activity Questionnaire, and cytokines were analyzed using Luminex assays. There was no significant difference in exercise patterns between SPTL and TL subjects. Plasma concentration of interleukin (IL)-10 was significantly higher in SPTL women at 16 and 27 weeks, while tumour necrosis factor alpha (TNF-α), IL-8, and monocyte chemoattractant protein (MCP)-1 concentrations were increased at 27 weeks GA (p < 0.05). Concentration of IL-10 was negatively correlated with the amount of reported walking (ρ = -0.264, p = 0.03). Women should be encouraged to partake in low-intensity exercise throughout pregnancy, as it may confer a protective effect against SPTL through IL-10-mediated pathways. Additionally, plasma cytokine analysis at 27 weeks GA may be useful for predicting SPTL in asymptomatic women. Novelty: In women that delivered preterm, plasma levels of anti-inflammatory cytokine IL-10 were significantly elevated at 16 and 27 weeks of gestation. Plasma levels of IL-10 were negatively correlated with the amount of reported walking. Concentration of IL-8, MCP-1 and TNF-α were increased in plasma of asymptomatic women that subsequently deliver preterm.

Using Precision Medicine with a Neurodevelopmental Perspective to Study Inflammation and Depression.

PURPOSE OF REVIEW: To consider various precision medicine approaches to further elucidate the relationship between inflammation and depression and to illustrate how a neurodevelopmental perspective can help in this regard. RECENT FINDINGS: Inflammation associates most strongly with phenotypes of depression that reflect illness behavior and/or metabolic dysfunction and obesity. A separate body of research has shown that maternal inflammation during pregnancy can alter brain circuitry important for mood regulation and/or reward in the developing fetus. Our research group is finding that maternal CRP levels differentially predict positive and negative affect in children assessed at age 4 years, depending on the timing of plasma sampling during pregnancy and the sex of the child. Recent authors have stressed the need to use a variety of precision medicine approaches to refine our understanding of inflammation-depression links. Adding a neurodevelopmental perspective may help to address some of the methodological challenges in this active area of study.

Seasonality of plasma tryptophan and kynurenine in pregnant mothers with a history of seasonal affective disorder: Vulnerability or adaptation?

Objectives: Maternal-foetal tryptophan metabolism plays multiple roles in neurodevelopment and immunomodulation across pregnancy. Tryptophan and the immune system are both influenced by the seasons of the year. We thus compared tryptophan and kynurenine levels in subgroups of pregnant women defined by maternal seasonality and season-of-conception (SoC).Methods: Maternal plasma samples taken at 9-15 and 23-29 weeks of pregnancy were analysed in 47 women with historical full or sub-syndromal Seasonal Affective Disorder (SAD) and 144 pregnant controls. Repeated measure ANCOVAs compared tryptophan and kynurenine levels in the two study groups over the two pregnancy sampling times, using SoC as a moderator.Results: Significant differences in both plasma tryptophan and kynurenine were found across the eight subgroups defined by maternal seasonality and SoC. These results were independent of the state of depression.Conclusions: Pregnant women with a history of full or sub-syndromal SAD exhibited a different pattern of plasma tryptophan and kynurenine across the seasons compared to control mothers, independent of current mood state. Follow-up of the children will determine the implications of these findings for neurodevelopment and psychiatric risk. Maternal seasonality and SoC may be important considerations when studying tryptophan and its metabolites in human pregnancy and foetal brain development.

Effect of Oral Probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 on the Vaginal Microbiota, Cytokines and Chemokines in Pregnant Women.

Spontaneous preterm birth is associated with vaginal microbial dysbiosis. As certain strains of lactobacilli help restore homeostasis in non-pregnant women, the goal was to determine the effect of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 administered orally, twice daily for 12 weeks on the vaginal microbiota, cytokines and chemokines of low-risk pregnant women. A double-blind, placebo-controlled, randomized trial comparing probiotic lactobacilli to placebo daily was performed in 86 asymptomatic pregnant women who had an Intermediate or Bacterial Vaginosis Nugent score at 13 weeks. After drop outs, 32 women receiving probiotics and 34 receiving placebo completed the study. The Nugent score returned to normal in 30% of the women in both groups at 28 weeks and was maintained until 35 weeks. The majority of subjects had normal pregnancy outcomes. Ninety-three bacterial species were detected at 13 weeks, with Lactobacillus iners, Lactobacillus crispatus, Gardnerella vaginalis and Atopobium vaginae being the most abundant across pregnancy. There was no difference in the Shannon diversity index between the probiotic and placebo groups at 13, 28 or 35 weeks. Almost all subjects consumed fermented foods and many of the organisms in the vagina are also known to be present in fermented foods. Interleukin-4 in the placebo group and Interleukin-10 in both probiotic and placebo groups increased slightly at 28 weeks but were not different at 35 weeks when compared to 13 weeks. In conclusion, this study showed no adverse issues resulting from 12 week use of probiotic Lactobacillus strains GR-1 and RC-14 during pregnancy in women at low risk for premature birth. The vaginal microbiota demonstrated flux irrespective of this oral probiotic administration.

Association between maternal acetaminophen use and adverse birth outcomes in a pregnancy and birth cohort.

INTRODUCTION: Acetaminophen is the only analgesic recommended for use during pregnancy. This use has recently been linked to childhood developmental disorders, a finding that requires further investigation. Adverse birth outcomes-preterm birth, low birthweight, and small for gestational age-are associated with increased risk of developmental disorders and can serve as intermediate outcomes when examining the impact of maternal acetaminophen use. METHODS: Clinical and lifestyle-factor data were gathered from 1200 women within the Ontario Birth Study who delivered between January 2013 and June 2017. Poisson regression with robust error variance was used to estimate the relationship between acetaminophen use before and during pregnancy and low birthweight, preterm birth, and small for gestational age. RESULTS: Offspring of mothers who used acetaminophen before pregnancy had a higher risk of low birthweight and small for gestational age. Acetaminophen use

Maternal Mental Health in Assisted and Natural Conception: A Prospective Cohort Study.

OBJECTIVE: This study sought to compare the pregnancy and postpartum self-reported mood and mental health status of women who conceived with assisted reproductive technology (ART) with those of women who conceived spontaneously. METHODS: In this prospective cohort study, 1176 pregnant women from prenatal clinics in the Ontario Birth Study were enrolled. In the pregnancy and the postpartum period, women who conceived with ART, including in vitro fertilization and intrauterine insemination, were compared with women who conceived spontaneously regarding depression and anxiety at 12-16 weeks and 24-28 weeks gestation and 6-10 weeks postpartum. The following main outcome measures were used: Edinburgh Postnatal Depression Scale, two-item Patient Health Questionnaire, State Trait Anxiety Inventory six-item scale, and two-item Generalized Anxiety Disorder scale (Canadian Task Force Classification II-2). RESULTS: Women who conceived with ART demonstrated a decreased likelihood of depression compared with women who spontaneously conceived (SC) at 24-28 weeks gestation (Edinburgh Postnatal Depression Scale: ART 3.6% vs. SC 15%; P < 0.01; two-item Patient Health Questionnaire: ART 0.0% vs. SC 4.0%; P = 0.027), as well as decreased perceived stress (mean score: ART 3.25 vs. SC 4.02; P < 0.01). Women in the ART group also had a lower percentage of positive two-item Generalized Anxiety Disorder scores (ART 2.7% vs. SC 7.5%; P = 0.049). There was no difference in self-reported depression, anxiety, or perceived stress between groups at 12-16 weeks gestation or at 6-10 weeks postpartum. CONCLUSION: Women who conceived using ART reported decreased rates of depressive symptoms, perceived stress, and generalized anxiety during the second trimester of pregnancy compared with women who had SC pregnancies, and both groups experienced similar mental health status earlier in gestation and in the postpartum period.

The Potential for Fetal Alcohol Spectrum Disorder Prevention of a Harmonized Approach to Data Collection about Alcohol Use in Pregnancy Cohort Studies.

Prenatal alcohol exposure is a leading cause of disability, and a major public health concern in Canada. There are well-documented barriers for women and for service providers related to asking about alcohol use in pregnancy. Confidential research is important for learning about alcohol use before, during and after pregnancy, in order to inform fetal alcohol spectrum disorder (FASD) prevention strategies. The Research Advancement through Cohort Cataloguing and Harmonization (ReACH) initiative provides a unique opportunity to leverage the integration of the Canadian pregnancy and birth cohort information regarding women's drinking during pregnancy. In this paper, we identify: The data that can be collected using formal validated alcohol screening tools; the data currently collected through Canadian provincial/territorial perinatal surveillance efforts; and the data currently collected in the research context from 12 pregnancy cohorts in the ReACH Catalogue. We use these findings to make recommendations for data collection about women's alcohol use by future pregnancy cohorts, related to the frequency and quantity of alcohol consumed, the number of drinks consumed on an occasion, any alcohol consumption before pregnancy, changes in use since pregnancy recognition, and the quit date. Leveraging the development of a Canadian standard to measure alcohol consumption is essential to facilitate harmonization and co-analysis of data across cohorts, to obtain more accurate data on women's alcohol use and also to inform FASD prevention strategies.

Increased richness and diversity of the vaginal microbiota and spontaneous preterm birth.

BACKGROUND: The bacterial community present in the female lower genital tract plays an important role in maternal and neonatal health. Imbalances in this microbiota have been associated with negative reproductive outcomes, such as spontaneous preterm birth (sPTB), but the mechanisms underlying the association between a disturbed microbiota and sPTB remain poorly understood. An intrauterine infection ascending from the vagina is thought to be an important contributor to the onset of preterm labour. Our objective was to characterize the vaginal microbiota of pregnant women who had sPTB (n = 46) and compare to those of pregnant women who delivered at term (n = 170). Vaginal swabs were collected from women at 11-16 weeks of gestational age. Microbiota profiles were created by PCR amplification and pyrosequencing of the cpn60 universal target region. RESULTS: Profiles clustered into seven community state types: I (Lactobacillus crispatus dominated), II (Lactobacillus gasseri dominated), III (Lactobacillus iners dominated), IVA (Gardnerella vaginalis subgroup B or mix of species), IVC (G. vaginalis subgroup A dominated), IVD (G. vaginalis subgroup C dominated) and V (Lactobacillus jensenii dominated). The microbiota of women who experienced preterm birth (< 37 weeks gestation) had higher richness and diversity and higher Mollicutes prevalence when compared to those of women who delivered at term. The two groups did not cluster according to CST, likely because CST assignment is driven in most cases by the dominance of one particular species, overwhelming the contributions of more rare taxa. In conclusion, we did not identify a specific microbial community structure that predicts sPTB, but differences in microbiota richness, diversity and Mollicutes prevalence were observed between groups. CONCLUSIONS: Although a causal relationship remains to be determined, our results confirm previous reports of an association between Mollicutes and sPTB and further suggest that a more diverse microbiome may be important in the pathogenesis of some cases.

The Ontario Birth Study: A prospective pregnancy cohort study integrating perinatal research into clinical care.

BACKGROUND: Pregnancy and early childhood represent critical periods that impact health throughout the life-course. The Ontario Birth Study (OBS) is a pregnancy cohort study designed as a platform for research on pregnancy complications, maternal and infant health, and the developmental origins of health and disease. METHODS: Pregnant women <17 weeks gestational age were recruited between 2013 and 2015 from antenatal clinics at Mount Sinai Hospital, Toronto, Canada. Life style and diet questionnaires, biospecimens, and clinical data were collected throughout the pregnancy and postpartum period at the time of clinical care. The OBS was integrated into clinical care to reduce participant burden, improve efficiency, and increase research potential. RESULTS: There were 3181 eligible women approached for recruitment and 1374 (43%) participated in the study. Among the 1374 participants, 1272 (93%) delivered a liveborn infant and were followed to 6-10 weeks postpartum. Of the 1272 women who completed the study, 98% had at least one pregnancy blood sample collected, 97% had vaginal swabs collected, 90% completed the prenatal life style questionnaires, and 78% completed the Diet History Questionnaire. Most women (88%) were ≥30 years of age, 55% had no previous children, 24% were overweight or obese pre-pregnancy and 78% of parents had postsecondary education. Most pregnancies were singleton (3% twins), 34% delivered by caesarean section, and 6% preterm (<37 weeks gestation). CONCLUSIONS: The OBS is a contemporary cohort with detailed data including banked biospecimens for studies of pregnancy health and the gene-environment interactions that establish developmental trajectories to health, learning, and social functioning.

Effect of Lactobacillus rhamnosus GR-1 Supernatant on Cytokine and Chemokine Output From Human Amnion Cells Treated With Lipoteichoic Acid and Lipopolysaccharide.

Preterm birth occurs in 9% to 13% of all human pregnancies and accounts for 80% of all neonatal morbidities and mortalities. Approximately 40% of all preterm births are idiopathic and about half are associated with infection and/or an activated inflammatory process. Further to studies showing anti-inflammatory effects of supernatant from the probiotic Lactobacillus rhamnosus GR-1 (GR-1), we tested its ability to modulate cytokine and chemokine production from amnion cells in response to stimulation by bacterial wall components, lipopolysaccharide (LPS), and lipoteichoic acid (LTA). Placentae were collected from women undergoing elective cesarean section at term. Amnion cells were cultured for 48 hours to confluence, serum starved for 12 hours, and then treated with GR-1 supernatant (1:20 dilution), followed after 12 hours by LPS (100 ng/mL) or LTA (10 ng/mL) for an additional 12 hours. Both LTA and LPS caused significant increases in the concentration of the pro-inflammatory cytokine, tumor necrosis factor α (TNF-α; 103.9 ± 67.5 pg/mL and 368.3 ± 65.7 pg/mL, respectively) in medium from cultured amnion cells compared to control (<4 pg/mL). There was no significant effect of GR-1 supernatant alone on TNF-α output, but there was significant reduction after LPS treatment. The basal output of the immunomodulatory cytokine, interleukin 6, was 613 ± 170 pg/mL and increased significantly after addition of GR-1 supernatant, LTA, LPS, and combinations of LTA/LPS with GR-1 supernatant. In conclusion, probiotic L rhamnosus GR-1 attenuates the effect of both LPS and LTA in stimulating the output of the pro-inflammatory cytokine TNF-α from mixed cultures of human amnion cells in keeping with previous findings in human trophoblast cells.

The vaginal microbiome of pregnant women is less rich and diverse, with lower prevalence of Mollicutes, compared to non-pregnant women.

The vaginal microbiome plays an important role in maternal and neonatal health. Imbalances in this microbiota (dysbiosis) during pregnancy are associated with negative reproductive outcomes, such as pregnancy loss and preterm birth, but the underlying mechanisms remain poorly understood. Consequently a comprehensive understanding of the baseline microbiome in healthy pregnancy is needed. We characterized the vaginal microbiomes of healthy pregnant women at 11-16 weeks of gestational age (n = 182) and compared them to those of non-pregnant women (n = 310). Profiles were created by pyrosequencing of the cpn60 universal target region. Microbiome profiles of pregnant women clustered into six Community State Types: I, II, III, IVC, IVD and V. Overall microbiome profiles could not be distinguished based on pregnancy status. However, the vaginal microbiomes of women with healthy ongoing pregnancies had lower richness and diversity, lower prevalence of Mycoplasma and Ureaplasma and higher bacterial load when compared to non-pregnant women. Lactobacillus abundance was also greater in the microbiomes of pregnant women with Lactobacillus-dominated CSTs in comparison with non-pregnant women. This study provides further information regarding characteristics of the vaginal microbiome of low-risk pregnant women, providing a baseline for forthcoming studies investigating the diagnostic potential of the microbiome for prediction of adverse pregnancy outcomes.

Maternal Whole Blood Gene Expression at 18 and 28 Weeks of Gestation Associated with Spontaneous Preterm Birth in Asymptomatic Women.

The heterogeneity of spontaneous preterm birth (SPTB) requires an interdisciplinary approach to determine potential predictive risk factors of early delivery. The aim of this study was to investigate maternal whole blood gene expression profiles associated with spontaneous preterm birth (SPTB, <37 weeks) in asymptomatic pregnant women. The study population was a matched subgroup of women (51 SPTBs, 114 term delivery controls) who participated in the All Our Babies community based cohort in Calgary (n = 1878). Maternal blood at 17-23 (sampling time point 1, T1) and 27-33 weeks of gestation (T2) were collected. Total RNA was extracted and microarray was performed on 326 samples (165 women). Univariate analyses determined significant clinical factors and differential gene expression associated with SPTB. Thirteen genes were validated using qRT-PCR. Three multivariate logistic models were constructed to identify gene expression at T1 (Model A), T2 (Model B), and gene expression fold change from T1 to T2 (Model C) associated with SPTB. All models were adjusted for clinical factors. Model C can predict SPTB with 65% sensitivity and 88% specificity in asymptomatic women after adjusting for history of abortion and anaemia (occurring before T2). Clinical data enhanced the sensitivity of the Models to predict SPTB. In conclusion, clinical factors and whole blood gene expression are associated with SPTB in asymptomatic women. An effective screening tool for SPTB during pregnancy would enable targeted preventive approaches and personalised antenatal care.

Is there a role for probiotics in the prevention of preterm birth?

Preterm birth (PTB) continues to be a global health challenge. An over-production of inflammatory cytokines and chemokines, as well as an altered maternal vaginal microbiome has been implicated in the pathogenesis of inflammation/infection-associated PTB. Lactobacillus represents the dominant species in the vagina of most healthy pregnant women. The depletion of Lactobacillus in women with bacterial vaginosis (BV) has been associated with an increased risk of PTB. It remains unknown at what point an aberrant vaginal microbiome composition specifically induces the cascade leading to PTB. The ability of oral or vaginal lactobacilli probiotics to reduce BV occurrence and/or dampen inflammation is being considered as a means to prevent PTB. Certain anti-inflammatory properties of lactobacilli suggest potential mechanisms. To date, clinical studies have not been powered with sufficiently high rates of PTB, but overall, there is merit in examining this promising area of clinical science.

One-year evaluation of the impact of an emergency obstetric and neonatal care training program in Western Kenya.

OBJECTIVE: To determine the impact of introducing an emergency obstetric and neonatal care training program on maternal and perinatal morbidity and mortality at Moi Teaching and Referral Hospital, Eldoret, Kenya. METHODS: A prospective chart review was conducted of all deliveries during the 3-month period (November 2009 to January 2010) before the introduction of the Advances in Labor and Risk Management International Program (AIP), and in the 3-month period (August-November 2011) 1 year after the introduction of the AIP. All women who were admitted and delivered after 28 weeks of pregnancy were included. The primary outcome was the direct obstetric case fatality rate. RESULTS: A total of 1741 deliveries occurred during the baseline period and 1812 in the postintervention period. Only one mother died in each period. However, postpartum hemorrhage rates decreased, affecting 59 (3.5%) of 1669 patients before implementation and 40 (2.3%) of 1751 afterwards (P=0.029). The number of patients who received oxytocin increased from 829 (47.6%) to 1669 (92.1%; P<0.001). Additionally, the number of neonates with 5-minute Apgar scores of less than 5 reduced from 133 (7.7%) of 1717 to 95 (5.4%) of 1745 (P=0.006). CONCLUSION: The introduction of the AIP improved maternal outcomes. There were significant differences related to use of oxytocin and postpartum hemorrhage.

Maternal alcohol consumption in pregnancy enhances arterial stiffness and alters vasodilator function that varies between vascular beds in fetal sheep.

While the impact of alcohol consumption by pregnant women on fetal neurodevelopment has received much attention, the effects on the cardiovascular system are not well understood. We hypothesised that repeated exposure to alcohol (ethanol) in utero would alter fetal arterial reactivity and wall stiffness, key mechanisms leading to cardiovascular disease in adulthood. Ethanol (0.75 g (kg body weight)(-1)) was infused intravenously into ewes over 1 h daily for 39 days in late pregnancy (days 95-133 of pregnancy, term ∼147 days). Maternal and fetal plasma ethanol concentrations at the end of the hour were ∼115 mg dl(-1), and then declined to apparent zero over 8 h. At necropsy (day 134), fetal body weight and fetal brain-body weight ratio were not affected by alcohol infusion. Small arteries (250-300 µm outside diameter) from coronary, renal, mesenteric, femoral (psoas) and cerebral beds were isolated. Endothelium-dependent vasodilatation sensitivity was reduced 10-fold in coronary resistance arteries, associated with a reduction in endothelial nitric oxide synthase mRNA (P = 0.008). Conversely, vasodilatation sensitivity was enhanced 10-fold in mesenteric and renal resistance arteries. Arterial stiffness was markedly increased (P = 0.0001) in all five vascular beds associated with an increase in elastic modulus and, in cerebral vessels, with an increase in collagen Iα mRNA. Thus, we show for the first time that fetal arteries undergo marked and regionally variable adaptations as a consequence of repeated alcohol exposure. These alcohol-induced vascular effects occurred in the apparent absence of fetal physical abnormalities or fetal growth restriction.

Probiotic Lactobacillus rhamnosus GR-1 supernatant prevents lipopolysaccharide-induced preterm birth and reduces inflammation in pregnant CD-1 mice.

OBJECTIVE: The objective of this study was to determine the effect of probiotic Lactobacillus rhamnosus GR-1 supernatant (GR-1 SN) on lipopolysaccharide-induced preterm birth (PTB) and outputs of cytokines, chemokines, and progesterone in pregnant CD-1 mice. STUDY DESIGN: We compared PTB rates after intrauterine injection of lipopolysaccharide with and without previous GR-1 SN treatment. Cytokines and chemokines in the maternal plasma, myometrium, placenta, and amniotic fluid were examined with multiplex assay, and circulating maternal progesterone was measured with enzyme-linked immunoassay. Statistical significance was assessed with 2-tailed 1-way analysis of variance or analysis of variance on ranks. Fetal sex ratios in mice that delivered preterm were compared with those that delivered at term after lipopolysaccharide and GR-1 SN treatments. RESULTS: GR-1 SN reduced lipopolysaccharide-induced PTB by 43%. GR-1 SN significantly decreased the lipopolysaccharide-induced production of interleukin (IL)-1ß, -6, and -12p40, tumor necrosis factor-α, CCL4, and CCL5 in maternal plasma; IL-6, -12p70, -17, and -13 and tumor necrosis factor-α in myometrium; IL-6, -12p70, and -17 in placenta; and IL-6, tumor necrosis factor-α, CCL3, and CCL4 in amniotic fluid. Maternal plasma progesterone was reduced significantly after lipopolysaccharide injection with and without GR-1 SN pretreatment. There was no difference in fetal sex ratios between mice that delivered preterm and those that did not after lipopolysaccharide and GR-1 SN treatments. CONCLUSION: The supernatant of probiotic L rhamnosus GR-1 attenuated lipopolysaccharide-induced inflammation and PTB in vivo. GR-1 SN may confer therapeutic benefits in the prevention of infection-associated PTB by controlling systemic and intrauterine inflammation.

Lipopolysaccharide-Induced Profiles of Cytokine, Chemokine, and Growth Factors Produced by Human Decidual Cells Are Altered by Lactobacillus rhamnosus GR-1 Supernatant.

The aim of this study was to assess the effects of bacterial lipopolysaccharide (LPS) and Lactobacillus rhamnosus GR-1 supernatant (GR-1SN) on secretion profiles of cytokines, chemokines, and growth factors from primary cultures of human decidual cells. Lipopolysaccharide significantly increased the output of proinflammatory cytokines (interleukin [IL]-1B, IL-2, IL-6, IL-12p70, IL-15, IL-17A, interferon gamma [IFN-γ], and tumor necrosis factor [TNF]); anti-inflammatory cytokines (IL-1RN, IL-4, IL-9, and IL-10); chemokines (IL-8, eotaxin, IFN-inducible protein 10 [IP-10], monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein-1α [MIP-1α], macrophage inflammatory protein-1ß [MIP-1ß], and regulated on activation normal T cell expressed and secreted [RANTES]); and growth factors (granulocyte colony-stimulating factor [CSF] 3, CSF-2, and vascular endothelial growth factor A [VEGFA]). Lactobacillus rhamnosus GR-1SN alone significantly increased CSF-3, MIP-1α MIP-1ß, and RANTES but decreased IL-15 and IP-10 output. The GR-1SN also significantly or partially reduced LPS-induced proinflammatory cytokines TNF, IFN-γ, IL-1ß, IL-2 IL-6, IL-12p70, IL-15, IL-17, and IP-10; partially reduced LPS-induced anti-inflammatory cytokines IL-1RN, IL-4 and IL-10, and LPS-induced VEGFA output but did not affect CSF-3, MIP-1α, MIP-1ß, MCP-1, IL-8, and IL-9. Our results demonstrate that GR-1SN attenuates the inflammatory responses to LPS by human decidual cells, suggesting its potential role in ameliorating intrauterine infection.

Meconium fatty acid ethyl esters as biomarkers of late gestational ethanol exposure and indicator of ethanol-induced multi-organ injury in fetal sheep.

BACKGROUND: Meconium fatty acid ethyl esters (FAEE) constitute a biomarker of heavy fetal ethanol exposure. Our objective was to measure meconium FAEE in fetal sheep following daily, relatively moderate-dose ethanol exposure in late gestation, and to evaluate their utility in identifying fetal organ-system injury. METHODS: Pregnant ewes received ethanol (0.75 g/kg; n = 14) or saline (n = 8) via 1-h i.v. infusion daily during the third trimester equivalent, while additional pregnant sheep served as untreated controls (n = 6). The daily ethanol regimen produced similar maximal maternal and fetal plasma ethanol concentrations of 0.11-0.12 g/dL. Ewes and fetuses were euthanized shortly before term, and meconium was collected and analyzed for FAEE (ethyl palmitate, stearate, linoleate, and oleate). RESULTS: Meconium total FAEE concentration was significantly higher in ethanol-exposed fetuses compared with controls, and a positive cut-off of 0.0285 nmol total FAEE/g meconium had 93.3% sensitivity and specificity for detecting fetal ethanol exposure. When the studied animals (ethanol-exposed and controls) were classified according to meconium FAEE concentration, FAEE-positive and FAEE-negative groups frequently differed with respect to previously examined pathological endpoints, including nephron endowment, lung collagen deposition, cardiomyocyte maturation, and tropoelastin gene expression in cerebral vessels. Furthermore, in all studied animals as a group (ethanol-exposed and controls combined), meconium FAEE concentration was correlated with many of these pathological endpoints in fetal organs. CONCLUSIONS: We conclude that, in fetal sheep, meconium FAEE could serve as a biomarker of daily ethanol exposure in late gestation and could identify fetuses with subtle ethanol-induced toxic effects in various organs. This study illustrates the potential for using meconium FAEE to identify neonates at risk for dysfunction of major organs following in-utero ethanol exposure that does not result in overt physical signs of ethanol teratogenicity.