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Study of the fetal and maternal microbiota in pregnant women with intrauterine growth restriction and its relationship with inflammatory biomarkers: A case-control study protocol (SPIRIT compliant).

ABSTRACT: In general terms, fetal growth restriction (FGR) is considered the impossibility of achieving the genetically determined potential size. In the vast majority of cases, it is related to uteroplacental insufficiency. Although its origin remains unknown and causes are only known in 30% of cases, it is believed to be related to an interaction of environmental and genetic factors with either a fetal or maternal origin. One hypothesis is that alterations in the gastrointestinal microbiota composition, and thus alteration in the immune response, could play a role in FGR development. We performed an observational, prospective study in a subpopulation affected with FGR to elucidate the implications of this microbiota on the FGR condition.A total of 63 fetuses with FGR diagnosed in the third trimester as defined by the Delphi consensus, and 63 fetuses with fetal growth appropriate for gestational age will be recruited. Obstetric and nutritional information will be registered by means of specific questionnaires. We will collect maternal fecal samples between 30 to 36 weeks, intrapartum samples (maternal feces, maternal and cord blood) and postpartum samples (meconium and new-born feces at 6 weeks of life). Samples will be analyzed in the Department of Biochemistry and Molecular Biology II, Nutrition and Food Technology Institute of the University of Granada (UGR), for the determination of the gastrointestinal microbiota composition and its relationship with inflammatory biomarkers.This study will contribute to a better understanding of the influence of gastrointestinal microbiota and related inflammatory biomarkers in the development of FGR.Trial registration: NCT04047966. Registered August 7, 2019, during the recruitment stage. Retrospectively registered. Ongoing research.

SUBMITTER: Fernandez-Gonzalez S

PROVIDER: S-EPMC7668451 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Study of the fetal and maternal microbiota in pregnant women with intrauterine growth restriction and its relationship with inflammatory biomarkers: A case-control study protocol (SPIRIT compliant).

Fernandez-Gonzalez Sergi S Ortiz-Arrabal Olimpia O Torrecillas Ariadna A Pérez-Cruz Miriam M Chueca Natalia N Gómez-Roig María D MD Gómez-Llorente Carolina C

Medicine 20201101 46

In general terms, fetal growth restriction (FGR) is considered the impossibility of achieving the genetically determined potential size. In the vast majority of cases, it is related to uteroplacental insufficiency. Although its origin remains unknown and causes are only known in 30% of cases, it is believed to be related to an interaction of environmental and genetic factors with either a fetal or maternal origin. One hypothesis is that alterations in the gastrointestinal microbiota composition, ...[more]

PMID: 33181648

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Project description:IntroductionPre-eclampsia (PE) and intrauterine growth restriction (IUGR) are two major pregnancy complications, related to chronic uteroplacental hypoperfusion. Nowadays, there is no screening or diagnostic test for uteroplacental vascularisation deficiency in pregnant women. Since 2004, 3 three-imensional power Doppler (3DPD) angiography has been used for the evaluation of uteroplacental vascularisation and three vascular indices are usually calculated: Vascularisation Index (VI), Flow Index (FI) and vascularisation-FI (VFI). A high intraobserver and interobserver reproducibility and a potential interest for placental function study were reported by our team and others.The main objective of our study is to determine differences in 3DPD indices at first trimester between pregnancies defined at their outcome as uncomplicated pregnancy, PE (mild and severe) and IUGR in nulliparous women.Methods and analysisThis is a national multicentre prospective cohort study conducted in four French maternity units. We expect to include 2200 women in a period of 36 months. The nulliparous pregnant women will be recruited during their first trimester consultation (11-13+6 gestation week (GW)).The 3DPD and uterine artery Doppler acquisition will be included in the current routine 11-13+6 GW ultrasound. Also, additional blood samples will be taken for biomarker analysis (PAPP-A and P1GF) and biological collection. Uteroplacental VIs (FI and VFI) will be measured. For each subgroup (uncomplicated pregnancy, PE and IUGR), mean values in 3DPD indices will be computed and compared using a pairwise t test with a Bonferroni correction p value adjustment.Ethics and disseminationThe study was approved by the French Ethics Committee, the Comité de Protection des Personnes SUD MEDITERRANEE IV on 13 February 2018 with reference number 17 12 03. The results of this study will be published in a peer-reviewed journal and will be presented at relevant conferences.Trial registration numberNCT03342014; Pre-results. PHRCN-16-0567.

Project description:ImportanceBile acids play essential roles in metabolic modulation. Excessive serum total bile acid (sTBA) levels during pregnancy are associated with adverse perinatal outcomes; however, their association with the risk of intrauterine growth restriction (IUGR) remains unclear.ObjectiveTo investigate the association between maternal sTBA concentration during pregnancy and the risk of IUGR.Design, setting, and participantsThis retrospective cohort study included pregnant individuals who delivered live singleton neonates and had regular antenatal examination records available at a hospital-based center in Shanghai, China, from 2014 to 2018. Data were analyzed from July to November 2020.ExposuresMaternal sTBA concentration during pregnancy.Main outcomes and measuresFetal birth weight and probability of low birth weight (LBW) and IUGR.ResultsThis study included 68 245 singleton pregnancies with live births for analysis. The mean (SD) age of the pregnant individuals was 30.5 (3.8) years, 67 168 patients (98.4%) were Han, and 50 155 (73.5%) were nulliparous. Nonlinear regression models suggested that there was an inverted J-shaped association between maternal sTBA level during pregnancy and fetal birth weight, with a steep decrease in birth weight at high sTBA levels (estimated mean [SE] birth weight for sTBA of 40.8 ug/mL, 2879 [39.9] g) and greater birth weights at lower sTBA levels (estimated mean [SE] birth weight for sTBA 0.4 μg/mL, 3290 [3.9] g; and for 4.1 μg/mL, 3334 [1.6] g). Lower birth weight and a higher incidence of IUGR were observed in patients with gestational hypercholanemia (sTBA ≥4.08 μg/mL) compared with those without gestational hypercholanemia (birth weight: estimated adjusted mean [SE], 3309 [3.32] vs 3338 [0.80] g; P = .005; incidence of IUGR: 62 of 4467 [1.4%] vs 312 of 63 778 [0.5%]; P < .001). Moreover, compared with patients with sTBA concentrations of less than 4.08 μg/mL, those with gestational hypercholanemia had an increased risk of LBW (adjusted odds ratio [aOR], 1.29; 95% CI, 1.09-1.53) and IUGR (aOR, 2.18; 95% CI, 1.62-2.91). In addition, there was an additive interaction between hypertensive disorders in pregnancy (HDP) and hypercholanemia on LBW and IUGR risk. The highest risks of LBW and IUGR were found in pregnant individuals with both HDP and hypercholanemia compared with those with normotensive pregnancies with sTBA concentrations less than 4.08 μg/mL (LBW: aOR, 9.13; 95% CI, 6.88-12.12; IUGR: aOR, 19.14; 95% CI, 12.09-30.28).Conclusions and relevanceThis study found that gestational hypercholanemia was associated with an increased risk of LBW and IUGR, especially in pregnant individuals with HDP. Therefore, it would be meaningful to monitor sTBA concentration during the follow-up of pregnancies with potential IUGR.

Project description:ImportanceSevere early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes.ObjectiveTo determine whether sildenafil reduces perinatal mortality or major morbidity.Design, setting, and participantsThis placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants.InterventionsParticipants were randomized to sildenafil, 25 mg, 3 times a day vs placebo.Main outcomes and measuresThe primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge.ResultsOut of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008).Conclusions and relevanceThese findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension.Trial registrationClinicalTrials.gov Identifier: NCT02277132.

Project description:BackgroundBisphenol A (BPA) is an environmental contaminant with endocrine-disrupting properties that induce fetal growth restriction (FGR). Previous studies on pregnant ewes revealed that BPA exposure causes placental apoptosis and oxidative stress (OS) and decreases placental efficiency, consequently leading to FGR. Nonetheless, the response of gut microbiota to BPA exposure and its role in aggravating BPA-mediated apoptosis, autophagy, mitochondrial dysfunction, endoplasmic reticulum stress (ERS), and OS of the maternal placenta and intestine are unclear in an ovine model of gestation.ResultsTwo pregnant ewe groups (n = 8/group) were given either a subcutaneous (sc) injection of corn oil (CON group) or BPA (5 mg/kg/day) dissolved in corn oil (BPA group) once daily, from day 40 to day 110 of gestation. The maternal colonic digesta and the ileum and placental tissue samples were collected to measure the biomarkers of autophagy, apoptosis, mitochondrial dysfunction, ERS, and OS. To investigate the link between gut microbiota and the BPA-induced FGR in pregnant ewes, gut microbiota transplantation (GMT) was conducted in two pregnant mice groups (n = 10/group) from day 0 to day 18 of gestation after removing their intestinal microbiota by antibiotics. The results indicated that BPA aggravates apoptosis, ERS and autophagy, mitochondrial function injury of the placenta and ileum, and gut microbiota dysbiosis in pregnant ewes. GMT indicated that BPA-induced ERS, autophagy, and apoptosis in the ileum and placenta are attributed to gut microbiota dysbiosis resulting from BPA exposure.ConclusionsOur findings indicate the underlying role of gut microbiota dysbiosis and gut-placental axis behind the BPA-mediated maternal intestinal and placental apoptosis, OS, and FGR. The findings further provide novel insights into modulating the balance of gut microbiota through medication or probiotics, functioning via the gut-placental axis, to alleviate gut-derived placental impairment or FGR. Video Abstract.

Dataset Information

Study of the fetal and maternal microbiota in pregnant women with intrauterine growth restriction and its relationship with inflammatory biomarkers: A case-control study protocol (SPIRIT compliant).

Publications

Study of the fetal and maternal microbiota in pregnant women with intrauterine growth restriction and its relationship with inflammatory biomarkers: A case-control study protocol (SPIRIT compliant).

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