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.

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

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.

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 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.

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.

The All Our Babies pregnancy cohort: design, methods, and participant characteristics.

BACKGROUND: The prospective cohort study design is ideal for examining diseases of public health importance, as its inherent temporal nature renders it advantageous for studying early life influences on health outcomes and research questions of aetiological significance. This paper will describe the development and characteristics of the All Our Babies (AOB) study, a prospective pregnancy cohort in Calgary, Alberta, Canada designed to examine determinants of maternal, infant, and child outcomes and identify barriers and facilitators in health care utilization. METHODS: Women were recruited from health care offices, communities, and through Calgary Laboratory Services before 25 weeks gestation from May 2008 to December 2010. Participants completed two questionnaires during pregnancy, a third at 4 months postpartum, and are currently being followed-up with questionnaires at 12, 24, and 36 months. Data was collected on pregnancy history, demographics, lifestyle, health care utilization, physical and mental health, parenting, and child developmental outcomes and milestones. In addition, biological/serological and genetic markers can be extracted from collected maternal and cord blood samples. RESULTS: A total of 4011 pregnant women were eligible for recruitment into the AOB study. Of this, 3388 women completed at least one survey. The majority of participants were less than 35 years of age, Caucasian, Canadian born, married or in a common-law relationship, well-educated, and reported household incomes above the Calgary median. Women who discontinued after the first survey (n=123) were typically younger, non-Caucasian, foreign-born, had lower education and household income levels, were less likely to be married or in a common-law relationship, and had poor psychosocial health in early pregnancy. In general, AOB participants reflect the pregnant and parenting population at local and provincial levels, and perinatal indicators from the study are comparable to perinatal surveillance data. CONCLUSIONS: The extensive and rich data collected in the AOB cohort provides the opportunity to answer complex questions about the relationships between biology, early experiences, and developmental outcomes. This cohort will contribute to the understanding of the biologic mechanisms and social/environmental pathways underlying associations between early and later life outcomes, gene-environment interactions, and developmental trajectories among children.

An inventory of Canadian pregnancy and birth cohort studies: research in progress.

BACKGROUND: A web-based inventory was developed as a voluntary registry of Canadian pregnancy and birth cohort studies, with the objective to foster collaboration and sharing of research tools among cohort study groups as a means to enrich research in maternal and child health across Canada. DESCRIPTION: Information on existing birth cohort studies conducted in Canada exclusively or as part of broader international initiatives was accessed by searching the literature in PubMed and PsychInfo databases. Additional studies were identified by enquiring about the research activities of researchers at Canadian universities or working in affiliated hospitals or research centres or institutes. Of the fifty-eight birth cohort studies initially identified, forty-six were incorporated into the inventory if they were of a retrospective and/or prospective longitudinal design and with a minimum of two phases of data collection, with the first period having occurred before, during, or shortly after pregnancy and had an initial study sample size of a minimum of 200 participants.Information collected from each study was organized into four main categories: basic information, data source and period of collection, exposures, and outcome measures and was coded and entered into an Excel spreadsheet. The information incorporated into the Excel spreadsheet was double checked, completed when necessary, and verified for completeness and accuracy by contacting the principal investigator or research coordinator. All data collected were then uploaded onto the website of the Institute of Human Development Child and Youth Health of the Canadian Institutes of Health Research. Subsequently, the database was updated and developed as an online searchable inventory on the website of the Maternal, Infant, Child and Youth Research Network. CONCLUSIONS: This inventory is unique, as it represents detailed information assembled for the first time on a large number of Canadian birth cohort studies. Such information provides a valuable resource for investigators in the planning stages of cohort studies and identifying current research gaps.

Birth weight curves tailored to maternal world region.

BACKGROUND: Newborns of certain immigrant mothers are smaller at birth than those of domestically born mothers. Contemporary, population-derived percentile curves for these newborns are lacking, as are estimates of their risk of being misclassified as too small or too large using conventional rather than tailored birth weight curves. METHODS: We completed a population-based study of 766 688 singleton live births in Ontario from 2002 to 2007. Smoothed birth weight percentile curves were generated for males and females, categorized by maternal world region of birth: Canada (63.5%), Europe/Western nations (7.6%), Africa/Caribbean (4.9%), Middle East/North Africa (3.4%), Latin America (3.4%), East Asia/Pacific (8.1%), and South Asia (9.2%). We determined the likelihood of misclassifying an infant as small for gestational age (≤ 10th percentile for weight) or as large for gestational age (≥ 90th percentile for weight) on a Canadian-born maternal curve versus one specific to maternal world region of origin. RESULTS: Significantly lower birth weights were seen at gestation-specific 10th, 50th, and 90th percentiles among term infants born to mothers from each world region, with the exception of Europe/Western nations, compared with those for infants of Canadian-born mothers. For example, for South Asian babies born at 40 weeks' gestation, the absolute difference at the 10th percentile was 198 g (95% CI 183 to 212) for males and 170 g (95% CI 161 to 179) for females. Controlling for maternal age and parity, South Asian males had an odds ratio of 2.60 (95% CI 2.53 to 2.68) of being misclassified as small for gestational age, equivalent to approximately 116 in 1000 newborns; for South Asian females the OR was 2.41 (95% CI 2.34 to 2.48), equivalent to approximately 106 per 1000 newborns. Large for gestational age would be missed in approximately 61 per 1000 male and 57 per 1000 female South Asian newborns if conventional rather than ethnicity-specific birth weight curves were used. CONCLUSIONS: Birth weight curves need to be modified for newborns of immigrant mothers originating from non-European/Western nations.

Effects of prenatal ethanol exposure on the lungs of postnatal lambs.

Prenatal ethanol exposure increases collagen deposition and alters surfactant protein (SP) expression and immune status in lungs of near-term fetal sheep. Our objectives were to determine 1) whether these prenatal effects of repeated gestational ethanol exposure persist after birth and 2) whether surfactant phospholipid composition is altered following prenatal ethanol exposure. Pregnant ewes were chronically catheterized at 90 days of gestational age (DGA) and given a 1-h daily infusion of ethanol (0.75 g/kg, n = 9) or saline (n = 7) from 95 to 135 DGA; ethanol administration ceased after 135 DGA. Lambs were born naturally at full term (146 ± 0.5 DGA). Lung tissue was examined at 9 wk postnatal age for alterations in structure, SP expression, and inflammation; bronchoalveolar lavage fluid was examined for alterations in surfactant phospholipid composition. At 134 DGA, surfactant phospholipid concentration in amniotic fluid was significantly reduced (P < 0.05) by ethanol exposure, and the composition was altered. In postnatal lambs, there were no significant differences between treatment groups in birth weight, postnatal growth, blood gas parameters, and lung weight, volume, tissue fraction, mean linear intercept, collagen content, proinflammatory cytokine gene expression, and bronchoalveolar lavage fluid surfactant phospholipid composition. Although SP-A, SP-B, and SP-C mRNA levels were not significantly different between treatment groups, SP-D mRNA levels were significantly greater (P < 0.05) in ethanol-treated animals; as SP-D has immunomodulatory roles, innate immunity may be altered. The adverse effects of daily ethanol exposure during late gestation on the fetal lung do not persist to 2 mo after birth, indicating that the developing lung is capable of repair.

Alcohol exposure during late gestation adversely affects myocardial development with implications for postnatal cardiac function.

Prenatal exposure to high levels of ethanol is associated with cardiac malformations, but the effects of lower levels of exposure on the heart are unclear. Our aim was to investigate the effects of daily exposure to ethanol during late gestation, when cardiomyocytes are undergoing maturation, on the developing myocardium. Pregnant ewes were infused with either ethanol (0.75 g/kg) or saline for 1 h each day from gestational days 95 to 133 (term ∼145 days); tissues were collected at 134 days. In sheep, cardiomyocytes mature during late gestation as in humans. Within the left ventricle (LV), cardiomyocyte number was determined using unbiased stereology and cardiomyocyte size and nuclearity determined using confocal microscopy. Collagen deposition was quantified using image analysis. Genes relating to cardiomyocyte proliferation and apoptosis were examined using quantitative real-time PCR. Fetal plasma ethanol concentration reached 0.11 g/dL after EtOH infusions. Ethanol exposure induced significant increases in relative heart weight, relative LV wall volume, and cardiomyocyte cross-sectional area. Ethanol exposure advanced LV maturation in that the proportion of binucleated cardiomyocytes increased by 12%, and the number of mononucleated cardiomyocytes was decreased by a similar amount. Apoptotic gene expression increased in the ethanol-exposed hearts, although there were no significant differences between groups in total cardiomyocyte number or interstitial collagen. Daily exposure to a moderate dose of ethanol in late gestation accelerates the maturation of cardiomyocytes and increases cardiomyocyte and LV tissue volume in the fetal heart. These effects on cardiomyocyte growth may program for long-term cardiac vulnerability.

Lactobacillus rhamnosus GR-1 stimulates colony-stimulating factor 3 (granulocyte) (CSF3) output in placental trophoblast cells in a fetal sex-dependent manner.

Bacterial vaginosis is associated with a 1.4-fold increased risk of preterm birth. We have shown previously that Lactobacillus rhamnosus GR-1 supernatant up-regulates interleukin 10 and down-regulates tumor necrosis factor-alpha output in lipopolysaccharide (LPS)-treated human primary placenta cultures in a fetal sex-dependent manner. We hypothesize that lactobacilli also exert their anti-inflammatory effect by up-regulation of colony-stimulating factor 3 (granulocyte) (CSF3), which is secreted from both immune and placental trophoblast cells, and that this activity is dependent on the sex of the fetus. Placental trophoblast cells were isolated from term elective cesarean section placentae using a Percoll gradient and separated from CD45(+) cells using magnetic purification. Cells were treated with LPS in the presence or absence of pretreatments with L. rhamnosus GR-1 supernatant or chemical inhibitors of the intracellular signaling pathways. Phosphorylations of mitogen-activated protein kinase 14 (MAPK14, previously known as p38) and signal transducer and activator of transcription (STAT) 3 were measured by Western blot analysis, and levels of CSF3 were determined by ELISA. CSF3 output was increased only in the placental trophoblast cells of female fetuses treated with LPS, GR-1 supernatant, and a combination of both treatments. The GR-1 supernatant up-regulated the phosphorylation of STAT3 and MAPK14. CSF3 output was inhibited by both Janus kinases (JAK) and MAPK14 inhibitors. None of the treatments was able to increase CSF3 output in either the pure trophoblast or the CD45(+) cell preparations alone. These results suggest an underlying mechanism for the sex difference in incidence of preterm birth and provide potential evidence for a therapeutic benefit of lactobacilli in reducing the risk of preterm labor.

Daily ethanol exposure during late ovine pregnancy: physiological effects in the mother and fetus in the apparent absence of overt fetal cerebral dysmorphology.

High levels of ethanol (EtOH) consumption during pregnancy adversely affect fetal development; however, the effects of lower levels of exposure are less clear. Our objectives were to assess the effects of daily EtOH exposure (3.8 USA standard drinks) on fetal-maternal physiological variables and the fetal brain, particularly white matter. Pregnant ewes received daily intravenous infusions of EtOH (0.75 g/kg maternal body wt over 1 h, 8 fetuses) or saline (8 fetuses) from 95 to 133 days of gestational age (DGA; term ∼145 DGA). Maternal and fetal arterial blood was sampled at 131-133 DGA. At necropsy (134 DGA) fetal brains were collected for analysis. Maternal and fetal plasma EtOH concentrations reached similar maximal concentration (∼0.11 g/dl) and declined at the same rate. EtOH infusions produced mild reductions in fetal arterial oxygenation but there were no changes in maternal oxygenation, maternal and fetal Pa(CO(2)), or in fetal mean arterial pressure or heart rate. Following EtOH infusions, plasma lactate levels were elevated in ewes and fetuses, but arterial pH fell only in ewes. Fetal body and brain weights were similar between groups. In three of eight EtOH-exposed fetuses there were small subarachnoid hemorrhages in the cerebrum and cerebellum associated with focal cortical neuronal death and gliosis. Overall, there was no evidence of cystic lesions, inflammation, increased apoptosis, or white matter injury. We conclude that daily EtOH exposure during the third trimester-equivalent of ovine pregnancy has modest physiological effects on the fetus and no gross effects on fetal white matter development.

Retrospective review of predisposing factors and surgical outcomes in obstetric fistula patients at a single teaching hospital in Western Kenya.

OBJECTIVE: We examined success rates and complications of obstetric fistula (OF) surgical repairs in association with patient and fistula characteristics, including sociocultural and socioeconomic determinants of health. A better understanding of these associations will help guide surgical management and prevent predisposing factors. METHODS: We reviewed the medical records of 86 patients who underwent OF repair at Moi Teaching and Referral Hospital in Kenya between 1999 and 2007. RESULTS: Women with OF presented for repair with a variety of concurrent conditions. Seventy-eight percent had laboured for at least 24 hours; 29% had undergone previous unsuccessful surgery. Of the women who presented at postoperative follow-up, 54% still complained of incontinence. Persistent incontinence was associated with larger, more complicated fistulas and having had previous failed attempts at surgical repair. CONCLUSION: The association of factors such as duration of labour with OF reflects the limited availability of obstetrical care in Western Kenya. There is a significant difference in postoperative success of fistula repair between women with large fistulas or those who had previous failed surgery and other patients. This reflects the importance of primary and secondary prevention.

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.

Tumor necrosis factor stimulates matrix metalloproteinase 9 secretion from cultured human chorionic trophoblast cells through TNF receptor 1 signaling to IKBKB-NFKB and MAPK1/3 pathway.

The identification of proinflammatory signal transduction pathways may suggest new therapeutic targets. In this study, we examine which signaling pathways are involved in tumor necrosis factor (TNF)-induced matrix metalloproteinase 9 (MMP9) secretion in human chorionic trophoblast (CT) cells. Purified CT cells were cultured in the presence of antibodies or chemical inhibitors that specifically block/inhibit distinct TNF receptors and kinase pathways. TNF-induced proMMP9 production, as measured by zymography, was significantly blocked/inhibited by TNF receptor 1 (TNFRSF1A) antibody, NFKB activation inhibitor (NFKBAI), and MAPK1/3 (ERK) inhibitor (U0126) (P < 0.01), but not by TNF receptor 2 (TNFRSF1B) antibody, MAPK14 (p38 MAPK) inhibitor (SB203580), and MAPK8/9/10 (JNK) inhibitor (SP600125). By Western blot analysis, we found that TNF rapidly and significantly increased phosphorylation of IKBKB, MAPK1/3, and MAPK8/9/10 and that the phosphorylation of these kinases by TNF was reduced significantly by TNFRSF1A neutralizing antibody, but not by TNFRSF1B neutralizing antibody. Moreover, we found that TNF increased TNF receptor-associated factor (TRAF) 1 and decreased TRAF2 protein expression through TNFRSF1A, but not TNFRSF1B. The CT cells that had increased TRAF1 and decreased TRAF2 after an initial TNF treatment demonstrated a dramatic deficiency in phosphorylation of the above protein kinases following a secondary TNF treatment. Localization of RELA subunit by immunocytochemistry was shifted to the nuclei after TNF treatment compared to cytosol in untreated controls. We also found cross-talk between the phosphoinositide 3-kinase pathway and ERK pathway. In summary, we have demonstrated that TNF stimulates proMMP9 production in CT cells through TNFRSF1A-TRAFs-IKBKB-NFKB and ERK signaling pathways, but not through TNFRSF1B and JNK/p38-AP-1 pathways.

Expression and regulation of prostaglandin receptors in the human placenta and fetal membranes at term and preterm.

Prostaglandins (PGs) play an important role in parturition in many species, including humans. The present study examined the distribution of PG receptor subtypes (EP1-4 and FP) in intrauterine tissues at term and preterm birth. Placentas and fetal membranes were collected from patients at term in labour (n = 12) or not in labour (n = 12). Preterm tissue was collected from three different groups of patients: (1) idiopathic preterm labour (PTL) without chorioamnionitis or betamethasone (BM) treatment (n = 9), (2) idiopathic PTL that received BM with no chorioamnionitis (PTL-BM; n = 9) and (3) pregnancies that were complicated with chorioamnionitis and had no BM (PTL-CHA; n = 6). EP1-4 and FP receptors were localised and levels of expression were determined by western blot analysis. All EP receptors and FP were localised to the amnion, placenta and choriodecidua. Moreover, isolated amnion mesenchymal, amnion epithelial, chorion trophoblast and syncytiotrophoblast cells in primary culture also expressed PG receptors. A significant increase was observed in EP1, EP3 and FP expression in placenta, chorion and amnion with labour. Maternal betamethasone treatment increased EP1, EP3 and FP receptor protein expression and chorioamnionitis decreased expression in all the receptor subtypes. These changes in PG receptors in the fetal membranes are consistent with the development of a feed-forwards cascade mediated through PG action that may contribute to the birth process.

All Our Babies Cohort Study: recruitment of a cohort to predict women at risk of preterm birth through the examination of gene expression profiles and the environment.

BACKGROUND: Preterm birth is the leading cause of perinatal morbidity and mortality. Risk factors for preterm birth include a personal or familial history of preterm delivery, ethnicity and low socioeconomic status yet the ability to predict preterm delivery before the onset of preterm labour evades clinical practice. Evidence suggests that genetics may play a role in the multi-factorial pathophysiology of preterm birth. The All Our Babies Study is an on-going community based longitudinal cohort study that was designed to establish a cohort of women to investigate how a women's genetics and environment contribute to the pathophysiology of preterm birth. Specifically this study will examine the predictive potential of maternal leukocytes for predicting preterm birth in non-labouring women through the examination of gene expression profiles and gene-environment interactions. METHODS/DESIGN: Collaborations have been established between clinical lab services, the provincial health service provider and researchers to create an interdisciplinary study design for the All Our Babies Study. A birth cohort of 2000 women has been established to address this research question. Women provide informed consent for blood sample collection, linkage to medical records and complete questionnaires related to prenatal health, service utilization, social support, emotional and physical health, demographics, and breast and infant feeding. Maternal blood samples are collected in PAXgene™ RNA tubes between 18-22 and 28-32 weeks gestation for transcriptomic analyses. DISCUSSION: The All Our Babies Study is an example of how investment in clinical-academic-community partnerships can improve research efficiency and accelerate the recruitment and data collection phases of a study. Establishing these partnerships during the study design phase and maintaining these relationships through the duration of the study provides the unique opportunity to investigate the multi-causal factors of preterm birth. The overall All Our Babies Study results can potentially lead to healthier pregnancies, mothers, infants and children.

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.