Pleiotropic modifiers of age-related diabetes and neonatal intestinal obstruction in cystic fibrosis.

Individuals with cystic fibrosis (CF) develop complications of the gastrointestinal tract influenced by genetic variants outside of CFTR. Cystic fibrosis-related diabetes (CFRD) is a distinct form of diabetes with a variable age of onset that occurs frequently in individuals with CF, while meconium ileus (MI) is a severe neonatal intestinal obstruction affecting ∼20% of newborns with CF. CFRD and MI are slightly correlated traits with previous evidence of overlap in their genetic architectures. To better understand the genetic commonality between CFRD and MI, we used whole-genome-sequencing data from the CF Genome Project to perform genome-wide association. These analyses revealed variants at 11 loci (6 not previously identified) that associated with MI and at 12 loci (5 not previously identified) that associated with CFRD. Of these, variants at SLC26A9, CEBPB, and PRSS1 associated with both traits; variants at SLC26A9 and CEBPB increased risk for both traits, while variants at PRSS1, the higher-risk alleles for CFRD, conferred lower risk for MI. Furthermore, common and rare variants within the SLC26A9 locus associated with MI only or CFRD only. As expected, different loci modify risk of CFRD and MI; however, a subset exhibit pleiotropic effects indicating etiologic and mechanistic overlap between these two otherwise distinct complications of CF.

First Insight into Fetal Exposure to Legacy and Emerging Plasticizers Revealed by Infant Hair and Meconium: Occurrence, Biotransformation, and Accumulation.

Epidemiological studies have demonstrated the embryonic and developmental toxicity of plasticizers. Thus, understanding the in utero biotransformation and accumulation of plasticizers is essential to assessing their fate and potential toxicity in early life. In the present study, 311 infant hair samples and 271 paired meconium samples were collected at birth in Guangzhou, China, to characterize fetal exposure to legacy and emerging plasticizers and their metabolites. Results showed that most of the target plasticizers were detected in infant hair, with medians of 9.30, 27.6, and 0.145 ng/g for phthalate esters (PAEs), organic phosphate ester (OPEs), and alternative plasticizers (APs), and 1.44, 0.313, and 0.066 ng/g for the metabolites of PAEs, OPEs, and APs, respectively. Positive correlations between plasticizers and their corresponding primary metabolites, as well as correlations among the oxidative metabolites of bis(2-ethylhexyl) phthalate (DEHP) and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH), were observed, indicating that infant hair retained the major phase-I metabolism of the target plasticizers. While no positive correlations were found in parent compounds or their primary metabolites between paired infant hair and meconium, significant positive correlations were observed among secondary oxidative metabolites of DEHP and DINCH in hair and meconium, suggesting that the primary metabolites in meconium come from hydrolysis of plasticizers in the fetus but most of the oxidative metabolites come from maternal-fetal transmission. The parent compound/metabolite ratios in infant hair showed a decreasing trend across pregnancy, suggesting in utero accumulation and deposition of plasticizers. To the best of our knowledge, this study is the first to report in utero exposure to both parent compounds and metabolites of plasticizers by using paired infant hair and meconium as noninvasive biomonitoring matrices and provides novel insights into the fetal biotransformation and accumulation of plasticizers across pregnancy.

Gestational Exposure to PM2.5 and Specific Constituents, Meconium Metabolites, and Neonatal Neurobehavioral Development: A Cohort Study.

Exposure to fine particulate matter (PM2.5) during pregnancy has been inversely associated with neonatal neurological development. However, the associations of exposure to specific PM2.5 constituents with neonatal neurological development remain unclear. We investigated these associations and examined the mediating role of meconium metabolites in a Chinese birth cohort consisting of 294 mother-infant pairs. Our results revealed that exposure to PM2.5 and its specific constituents (i.e., organic matter, black carbon, sulfate, nitrate, and ammonium) in the second trimester, but not in the first or third trimester, was inversely associated with the total neonatal behavioral neurological assessment (NBNA) scores. The PM2.5 constituent mixture in the second trimester was also inversely associated with NBNA scores, and sulfate was identified as the largest contributor. Furthermore, meconium metabolome analysis identified four metabolites, namely, threonine, lysine, leucine, and saccharopine, that were associated with both PM2.5 constituents and NBNA scores. Threonine was identified as an important mediator, accounting for a considerable proportion (14.53-15.33%) of the observed inverse associations. Our findings suggest that maternal exposure to PM2.5 and specific constituents may adversely affect neonatal behavioral development, in which meconium metabolites may play a mediating role.

Assessment of Fetal Exposure and Elimination of Perfluoroalkyl and Polyfluoroalkyl Substances: New Evidence from Paired Serum, Placenta, and Meconium Samples.

Multiple pieces of evidence have shown that prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) is closely related to adverse birth outcomes for infants. However, difficult access to human samples limits our understanding of PFASs transport and metabolism across the human placental barrier, as well as the accurate assessment of fetal PFASs exposure. Herein, we assess fetal exposure to 28 PFASs based on paired serum, placenta, and meconium samples. Overall, 21 PFASs were identified first to be exposed to the fetus prenatally and to be metabolized and excreted by the fetus. In meconium samples, 25 PFASs were detected, with perfluorooctane sulfonate and perfluorohexane sulfonic acid being the dominant congeners, suggesting the metabolism and excretion of PFASs through meconium. Perfluoroalkyl sulfonic acids might be more easily eliminated through the meconium than perfluorinated carboxylic acids. Importantly, based on molecular docking, MRP1, OATP2B1, ASCT1, and P-gp were identified as crucial transporters in the dynamic placental transfer of PFASs between the mother and the fetus. ATSC5p and PubchemFP679 were recognized as critical structural features that affect the metabolism and secretion of PFASs through meconium. With increasing carbon chain length, both the transplacental transfer efficiency and meconium excretion efficiency of PFASs showed a structure-dependent manner. This study reports, for the first time, that meconium, which is a noninvasive and stable biological matrix, can be strong evidence of prenatal PFASs exposure.

Impact of highly effective modulator therapy on gastrointestinal symptoms and features in people with cystic fibrosis.

Highly effective modulator therapy (HEMT), particularly the triple combination elexacaftor-tezacaftor-ivacaftor (ETI), significantly improved clinical outcomes and quality of life in people with Cystic Fibrosis (pwCF). This review analyzes current knowledge on the impact of HEMTs on gastrointestinal (GI) symptoms and features in pwCF. A descriptive review of English literature until February 29, 2024, was conducted using medical databases. Observational studies and clinical trials addressing GI reflux disease (GERD), lower GI symptoms and pancreatic disease were considered. Studies report positive effects of HEMTs on pH levels and bicarbonate secretion as well as improvement on intestinal inflammation. HEMTs also demonstrated positive effects on GERD and lower GI symptoms or conditions CF related such as dysbiosis. Taking ETI during pregnancy could also allow resolution of meconium ileus in fetuses with CF. The best benefits were observed in pancreatic function, potentially delaying CF-related diabetes and recovering pancreatic function in some children on ETI. Larger trials, particularly in pediatric populations, need to confirm these findings and explore long-term effects.

An evaluation of in utero polycyclic aromatic hydrocarbon exposure on the neonatal meconium microbiome.

INTRODUCTION: In utero exposure to environmental polycyclic aromatic hydrocarbon (PAH) is associated with neurodevelopmental impairments[1-8], prematurity[9-12] and low birthweight[9,13-15]. The gut microbiome serves as an intermediary between self and external environment; therefore, exploring the impact of PAH on microbiota may elucidate their role in disease. Here, we evaluated the effect of in utero PAH exposure on meconium microbiome. METHODS: We evaluated 49 mother-child dyads within Fair Start Birth Cohort with full term delivery and adequate meconium sampling. Prenatal PAH was measured using personal active samplers worn for 48 h during third trimester. Post-processing, 35 samples with adequate biomass were evaluated for association between tertile of PAH exposure (high (H) vs low/medium (L/M)) and microbiome diversity. RESULTS: No significant differences were observed in alpha diversity metrics, Chao1 and Shannon index, between exposure groups for total PAH. However, alpha diversity metrics were negatively associated with log benzo[a]anthracene (BaA) and log chrysene (Chry) with high exposure, but positively associated with log benzo[a]pyrene (BaP) with low/medium exposure. After adjustment for birthweight and sex, alpha diversity metrics were negatively associated with log BaA, BaP, Chry, Indeno (Zhang et al., 2021; Perera et al., 2018)pyrene (IcdP) and total PAH with high exposure. Conversely, with low/medium exposure, alpha diversity metrics positively correlated with log BaP and benzo[b]fluoranthane (BbF). No significant difference in beta diversity was observed across groups using UniFrac, weighted UniFrac, or Bray-Curtis methods. Differential expression analysis showed differentially abundant taxa between exposure groups. CONCLUSION: Bacterial taxa were detectable in 35/49 (71%) meconium samples. Altered alpha diversity metrics and differentially abundant taxa between groups suggest in utero PAH exposure may impede early colonization. Sample size is limited, but these findings provide supporting evidence for wider scale research. Research on long-term impact of prenatal PAH exposure on childhood health outcomes is ongoing. Differential effects of specific PAHs need further evaluation.

Meconium microbiota in naturally delivered canine puppies.

BACKGROUND: Microbial colonization during early life has a pivotal impact on the host health, shaping immune and metabolic functions, but little is known about timing and features of this process in dogs. The objectives of this study were to characterize the first step of intestinal microbiota development in naturally delivered canine puppies and to investigate its relationship with the maternal bacterial flora, using traditional culture and molecular analyses. Sixty puppies of two breeds, Appenzeller Cattle Dog (n = 3 dams) and Lagotto Romagnolo (n = 6), housed in the same breeding kennel, were included in the study. Swabs were collected in duplicate (for culture and for molecular analysis) from the dams' vagina and rectum at the end of parturition, from puppies' rectum, before maternal care, and from the environment (floor of the nursery and parturition box). RESULTS: 93.3% meconium samples showed bacterial growth, limited to a few colonies in 57.0% of cases. High growth was detected for Enterococcus faecalis, which was the most frequently isolated bacterium. The genus Enterococcus was one of the most represented in the dams' rectum and vagina (88.9% and 55.6%, respectively). The genera Staphylococcus, Enterococcus, Escherichia and Proteus were also often isolated in meconium but were usually present in maternal samples as well, together with ubiquitous bacteria (Acinetobacter, Psychrobacter). In the environmental samples, just a few bacterial species were found, all with low microbial load. Additionally, bacteria of the phyla Proteobacteria, Firmicutes, and Actinobacteria were identified in meconium through molecular analysis, confirming the culture results and the early colonization of the newborn gut. Maternal, meconium and environmental samples had similar alpha diversity, while beta-diversity showed differences among families (i.e. a dam and her litter), and association indexes revealed a significant correlation between family members and between sample origin, suggesting a strong contribution of the maternal flora to the initial seeding of the canine neonatal gut and a strong individual dam imprint. CONCLUSION: This study showed that the meconium of vaginally delivered puppies has its own microbiota immediately after birth, and that it is shaped by the dam, which gives a specific imprint to her litter.

Correlation analysis between the amniotic fluid contamination and clinical grading of neonatal hypoxic-ischemic encephalopathy and biomarkers of brain damage.

BACKGROUND: Amniotic fluid contamination (AFC) is a risk factor for neonatal hypoxic ischemic encephalopathy (HIE); however, the correlation between AFC level and the incidence and clinical grading of HIE, in addition to relevant biomarkers of brain damage, have not been assessed. METHODS: This single-center observational study included 75 neonates with moderate-to-severe HIE. The neonates with HIE were divided into four subgroups according to the AFC level: normal amniotic fluid with HIE group (NAF-HIE), I°AFC with HIE group (I°AFC-HIE), II°AFC with HIE group (II°AFC-HIE), and III°AFC with HIE group (III°AFC-HIE). The control groups consisted of 35 healthy neonates. The clinical grading of neonatal HIE was performed according to the criteria of Sarnat and Sarnat. Serum tau protein and S100B were detected by enzyme-linked immunosorbent assay kits. Correlations of serum tau protein and S100B were evaluated using the Pearson correlation analysis. RESULTS: (1) The incidence of neonatal HIE in the NAF-HIE group was 20 cases (26. 7%), I°AFC-HIE was 13 cases (17.3%), II°AFC-HIE was 10 cases (13.3%), and III°AFC-HIE was 32 cases (42. 7%). The incidence of moderate-to-severe HIE in the I°-III°AFC-HIE groups was 73.3% (55/75). (2) In 44 cases with severe HIE, 26 cases (59.1%) occurred in the III°AFC-HIE group, which had a significantly higher incidence of severe HIE than moderate HIE (p < 0.05). In NAF-HIE and I°AFC-HIE groups, the incidence of moderate HIE was 45.2% and 29.0%, respectively, which was higher than that of severe HIE (X2 = 9.2425, p < 0.05; X2 = 5.0472, p < 0.05, respectively). (3) Serum tau protein and S100B levels in the HIE groups were significantly higher than in the control group (all p < 0.05), and were significantly higher in the III°AFC-HIE group than in the NAF-HIE and I°AFC-HIE groups (all p < 0.05). (4) Serum tau protein and S100B levels in the severe HIE group were significantly higher in the moderate HIE group (all p < 0.05). (5) Serum tau protein and S100B levels were significantly positively correlated (r = 0.7703, p < 0.0001). CONCLUSION: Among children with severe HIE, the incidence of III°AFC was higher, and the levels of serum tau protein and S100B were increased. AFC level might be associated with HIE grading.

Diuresis-led volume replacement strategy in extremely low birth weight infants.

AIM: In extremely low birth weight infants, fluid overload has been associated with bronchopulmonary dysplasia and death. Excessive weight loss may increase the risk of meconium obstruction and intestinal perforation. As these infants display oliguria followed by polyuria, we embarked on a diuresis-led volume replacement strategy as of January 2020. METHODS: This single-centre analysis presents data of infants <1000 g birth weight surviving for more than 3 days admitted 2017-2019 (n = 217, daily volume increase) versus 2020-2022 (n = 2022, diuresis-led volume replacement). RESULTS: The second cohort had lower gestational age (median [interquartile range]: 253/7 [243/7-264/7] vs. 263/7 [251/7-282/7] weeks), less antenatal steroids (58% vs. 69%), more indomethacin (66% vs. 47%) and higher initial diuresis (5.6 [4.9-6.8] vs. 4.8 [4.2-5.5] mL/kg/h) but did not differ by relative weight loss at Day 7 of life. Employing binary logistic regression with gestational age, antenatal steroids and indomethacin as covariates, the cohorts did not differ by rates of patent ductus arteriosus, abdominal surgery or severe retinopathy of prematurity, while there were significant declines in sepsis (from 32% to 19%), bronchopulmonary dysplasia (from 26% to 23%) and mortality (from 13% to 7%). CONCLUSION: Diuresis-led volume replacement appears to be safe and maybe beneficial.

Transitional Hemodynamics in Neonates Born Through Meconium-Stained Amniotic Fluid: A Prospective Observational Study.

Neonates born through meconium-stained amniotic fluid (MSAF) are at increased risk of altered cardiopulmonary transition at birth. There is a paucity of literature evaluating the transitional hemodynamics in these neonates. We aimed to evaluate transitional hemodynamics via echocardiography in neonates born through MSAF, compared to healthy neonates. The primary objective was to assess pulmonary vascular resistance using left pulmonary artery-velocity time integral (LPA-VTI). The secondary objectives were to assess other pulmonary vascular parameters and myocardial function. We enrolled 35 MSAF-born and 35 healthy neonates. Echocardiography was performed at 24 and 48 h of life by a pediatric cardiologist. Echocardiographic parameters were compared between MSAF-born and healthy neonates, and between MSAF-born neonates who developed meconium aspiration syndrome (MAS) and who did not (non-MAS). Among 35 MSAF-born neonates, 14 (40%) were non-vigorous, 18 (51%) required admission to neonatal intensive care unit, 8 (23%) developed MAS, 3 (9%) pulmonary hypertension and 1 (3%) air leak. On echocardiography, LPA-VTI (cm; mean ± SD) was significantly decreased at 24 and 48 h in MSAF-born neonates (14.38 ± 2.48; 15.55 ± 2.48), compared to healthy neonates (16.60 ± 2.14; 17.66 ± 2.71), respectively. Further, LPA-VTI was significantly reduced at 24 and 48 h among MAS (11.81 ± 3.0; 12.43 ± 2.5), compared to non-MAS neonates (15.15 ± 1.72; 16.48 ± 1.55), respectively. Other pulmonary vascular and myocardial function parameters were comparable between the two groups. Pulmonary adaptation was significantly delayed in neonates with MSAF, which was more pronounced in MAS neonates. Further studies should explore the utility of these parameters for early prediction of cardiorespiratory morbidities in this population.

Adverse obstetric outcomes in cases of meconium-stained amniotic fluid complicated with intrapartum fever.

PURPOSE: Meconium-stained amniotic fluid (MSAF) often signifies colonization of the amniotic sac by microorganisms. This study investigated additional adverse obstetric outcomes associated with MSAF in deliveries complicated by maternal intrapartum fever (IF). METHODS: This retrospective study included all singleton pregnancies from 2014 to 2020, with intrapartum maternal fever ≥ 38 °C during a trial of labor. In accordance with departmental protocol, all patients received intravenous antibiotic therapy consisting of ampicillin and gentamicin in the absence of allergies to these medications. Subsequent antibiotic therapy was adjusted based on the culture results. Antibiotic treatment was discontinued postpartum after 48 h without fever. Swab cultures were obtained immediately postpartum from both the maternal and fetal sides of the placenta. Maternal and fetal outcomes, along with positive placental cultures, were compared between participants with MSAF&IF and those with clear amniotic fluid &IF (control group). RESULTS: In comparison to the control group (n = 1089), the MSAF&IF group (n = 264) exhibited significantly higher rates of cesarean delivery (CD) (p = 0.001), CD due to non-reassuring fetal heart rate (p = 0.001), and cord pH ≤ 7.1 (p = 0.004). Positive swab cultures from the placental maternal and fetal sides were more prevalent among the MSAF&IF group (23.1% vs. 17.6%, p = 0.041 and 29.2% vs. 22.9%, p = 0.032, respectively). Placental cultures yielding gastrointestinal pathogens and extended spectrum beta-lactamase were notably more common in the MSAF&IF group compared to controls (p = 0.023). However, there was no significant difference between groups regarding the rate of group B streptococcus positive placental cultures. CONCLUSIONS: Women experiencing IF and MSAF during labor face an elevated risk of CD compared to those with IF alone. The presence of MSAF heightens the risk of positive placental cultures, particularly with gastrointestinal and extended spectrum beta-lactamase pathogens.

Does prenatal diagnosis of meconium peritonitis have the better recovery? A single-center over 10 years of experience.

OBJECTIVE: To evaluate whether infants with prenatal diagnosis of meconium peritonitis (MP) have a poorer prognosis. METHODS: A retrospective analysis of data from infants treated with surgery from January 2008 to December 2020 was conducted. The patients were divided into prenatal diagnosis group and postnatal diagnosis group based on the timing of diagnosis. The intraoperative and postoperative parameters of the two groups of patients were compared. RESULTS: A total of 71 cases of MP were included in the study, with 48 cases in the prenatal diagnosis group and 23 cases in the postnatal diagnosis group. The comparison of preoperative indicators between the two groups of patients showed no statistically significant differences in baseline (p > 0.05). Intraoperative indicators, including blood loss, anastomosis, retained intestinal tube length and excised intestinal tube length, showed no statistically significant differences between the two groups (p > 0.05). However, the postnatal diagnosis group had a significantly shorter operation time than the prenatal diagnosis group (p < 0.05). Postoperative indicators, including fasting time, albumin usage, complications, and abandonment or mortality rates, show no difference (p > 0.05). Nevertheless, the postnatal diagnosis group exhibited significantly shorter hospital stay and time to first bowel movement compared to the prenatal diagnosis group (p < 0.05). CONCLUSION: Prenatal diagnosis of meconium peritonitis is associated with increased surgical complexity, prolonged hospital stay, and delayed recovery of intestinal function. However, there is no evidence of higher mortality or more complications compared to infants diagnosed postnatally, and there is no significant difference in long-term prognosis.

Investigations, management and outcome of neonates presenting with distal intestinal obstruction: challenging the need for contrast enemas.

PURPOSE: To characterise the investigations, management and ultimate diagnosis of neonates with distal intestinal obstruction. METHODS: Retrospective review of term (> 37 weeks) neonates with admission diagnosis of distal intestinal obstruction over 10 years (2012-2022). Patient pathways were identified and associations between presentations, response to treatments and outcome investigated. RESULTS: A total of 124 neonates were identified and all included. Initial management was colonic irrigation in 108, contrast enema in 4, and laparotomy in 12. Of those responding to irrigations none underwent contrast enema. Ultimately, 22 neonates proceeded to laparotomy. Overall, 106 had a suction rectal biopsy and 41 had genetic testing for cystic fibrosis. Final diagnosis was Hirschsprung disease (HD) in 67, meconium ileus with cystic fibrosis (CF) in 9, meconium plug syndrome in 19 (including 3 with CF), intestinal atresia in 10 and no formal diagnosis in 17. Median length of neonatal unit stay was 11 days (7-19). CONCLUSIONS: Initial management of neonates with distal bowel obstruction should be colonic irrigation since this is therapeutic in the majority and significantly reduces the need for contrast enema. These infants should all have suction rectal biopsy to investigate for HD unless another diagnosis is evident. If a meconium plug is passed, testing for CF is recommended. Evaluation and therapy are multimodal and time consuming, placing burden on resources and families.

Meconium Proteins Involved in Iron Metabolism.

The lack of specific biological materials and biomarkers limits our knowledge of the mechanisms underlying intrauterine regulation of iron supply to the fetus. Determining the meconium content of proteins commonly used in the laboratory to assess the transport, storage, and distribution of iron in the body may elucidate their roles in fetal development. Ferritin, transferrin, haptoglobin, ceruloplasmin, lactoferrin, myeloperoxidase (MPO), neutrophil gelatinase-associated lipocalin (NGAL), and calprotectin were determined by ELISA in meconium samples obtained from 122 neonates. There were strong correlations between the meconium concentrations of haptoglobin, transferrin, and NGAL (p < 0.05). Meconium concentrations of ferritin were several-fold higher than the concentrations of the other proteins, with the exception of calprotectin whose concentration was approximately three-fold higher than that of ferritin. Meconium ceruloplasmin concentration significantly correlated with the concentrations of MPO, NGAL, lactoferrin, and calprotectin. Correlations between the meconium concentrations of haptoglobin, transferrin, and NGAL may reflect their collaborative involvement in the storage and transport of iron in the intrauterine environment in line with their recognized biological properties. High meconium concentrations of ferritin may provide information about the demand for iron and its utilization by the fetus. The associations between ceruloplasmin and neutrophil proteins may indicate the involvement of ceruloplasmin in the regulation of neutrophil activity in the intrauterine environment.

Links Between Vitamin D-Binding Protein, Alpha-1 Antitrypsin and Neutrophil Proteins in Meconium.

BACKGROUND/AIMS: Alpha-1 antitrypsin (AAT), vitamin-D binding protein (VDBP) and neutrophil granule proteins are specifically related to the neutrophil function and may be considered candidate biomarkers detected and measured in meconium (the first feces of newborn infants) as signals indicating abnormal processes in the fetal stage. Individual proteins found in meconium can be a source of information pertaining to the intrauterine metabolic processes. METHODS: Concentrations of AAT, VDBP, calprotectin, myeloperoxidase, lactoferrin and elastase were measured using ELISA tests in 80 meconium samples collected from 19 healthy, full-term neonates. RESULTS: The meconium concentrations of VDBP and AAT (mean±SD, [mg/g meconium]: 3.74±6.93, 3.72±1.79, respectively) were approximately 1000 times higher than those of the protein granule proteins calprotectin, myeloperoxidase, elastase and lactoferrin (mean ± SD, [µg/g meconium]: 285.7±215.8, 1.83±1.73, 1.72±2.70, 45.58±78.89, respectively). The correlation between VDBP and AAT was negative (r= - 0.40. p=0.000) and those between VDBP and calprotectin (r=0.38, p=0.000) and VDBP and myeloperoxidase (r=0.45, p=0.000) were positive. AAT was found to correlate positively with lactoferrin (r=0.38, p=0.000). CONCLUSION: The correlations between the concentrations of VDBP and AAT, and with neutrophil granule proteins observed in meconium indicate their functional relationship in the intrauterine environment of the developing fetus. Meconium can be seen as an apparently underutilized source of biomarkers for evaluation of metabolic processes specific to fetal development.

Vaginal and neonatal microbiota in pregnant women with preterm premature rupture of membranes and consecutive early onset neonatal sepsis.

BACKGROUND: Preterm premature rupture of membranes (PPROM), which is associated with vaginal dysbiosis, is responsible for up to one-third of all preterm births. Consecutive ascending colonization, infection, and inflammation may lead to relevant neonatal morbidity including early-onset neonatal sepsis (EONS). The present study aims to assess the vaginal microbial composition of PPROM patients and its development under standard antibiotic therapy and to evaluate the usefulness of the vaginal microbiota for the prediction of EONS. It moreover aims to decipher neonatal microbiota at birth as possible mirror of the in utero microbiota. METHODS: As part of the PEONS prospective multicenter cohort study, 78 women with PPROM and their 89 neonates were recruited. Maternal vaginal and neonatal pharyngeal, rectal, umbilical cord blood, and meconium microbiota were analyzed by 16S rRNA gene sequencing. Significant differences between the sample groups were evaluated using permutational multivariate analysis of variance and differently distributed taxa by the Mann-Whitney test. Potential biomarkers for the prediction of EONS were analyzed using the MetaboAnalyst platform. RESULTS: Vaginal microbiota at admission after PPROM were dominated by Lactobacillus spp. Standard antibiotic treatment triggers significant changes in microbial community (relative depletion of Lactobacillus spp. and relative enrichment of Ureaplasma parvum) accompanied by an increase in bacterial diversity, evenness and richness. The neonatal microbiota showed a heterogeneous microbial composition where meconium samples were characterized by specific taxa enriched in this niche. The vaginal microbiota at birth was shown to have the potential to predict EONS with Escherichia/Shigella and Facklamia as risk taxa and Anaerococcus obesiensis and Campylobacter ureolyticus as protective taxa. EONS cases could also be predicted at a reasonable rate from neonatal meconium communities with the protective taxa Bifidobacterium longum, Agathobacter rectale, and S. epidermidis as features. CONCLUSIONS: Vaginal and neonatal microbiota analysis by 16S rRNA gene sequencing after PPROM may form the basis of individualized risk assessment for consecutive EONS. Further studies on extended cohorts are necessary to evaluate how far this technique may in future close a diagnostic gap to optimize and personalize the clinical management of PPROM patients. TRIAL REGISTRATION: NCT03819192, ClinicalTrials.gov. Registered on January 28, 2019.

Intrapartum amnioinfusion reduces meconium aspiration syndrome and improves neonatal outcomes in patients with meconium-stained fluid: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to reassess the effect of prophylactic transcervical amnioinfusion for intrapartum meconium-stained amniotic fluid on meconium aspiration syndrome and other adverse neonatal and maternal outcomes. DATA SOURCES: From inception to November 2021, a systematic search of the literature was performed in PubMed, Embase, Web of Science, and Scopus databases and gray literature sources. STUDY ELIGIBILITY CRITERIA: We identified randomized controlled trials of patients with intrapartum moderate to thick meconium-stained amniotic fluid that evaluated the effect of amnioinfusion on adverse neonatal and maternal outcomes. METHODS: Of note, 2 reviewers independently abstracted data and gauged study quality by assigning a modified Jadad score. Meconium aspiration syndrome constituted the primary outcome. The secondary outcomes were meconium below the cords, Apgar scores of <7 at 5 minutes, neonatal acidosis, cesarean delivery, cesarean delivery for fetal heart rate abnormalities, neonatal intensive care unit admission, and postpartum endometritis. This study calculated the odds ratios with 95% confidence intervals for categorical outcomes and weighted mean differences with 95% confidence intervals for continuous outcomes. RESULTS: A total of 24 randomized studies with 5994 participants met the inclusion criteria. The overall odds of meconium aspiration syndrome was reduced by 67% in the amnioinfusion group (pooled odds ratio, 0.33; 95% confidence interval, 0.21-0.51). Except for postpartum endometritis, amnioinfusion was associated with a significant reduction in all secondary outcomes. CONCLUSION: Our study found that the use of intrapartum amnioinfusion in the setting of meconium-stained amniotic fluid significantly reduces the odds of meconium aspiration syndrome and other adverse neonatal outcomes.

Meconium-stained amniotic fluid.

Green-stained amniotic fluid, often referred to as meconium-stained amniotic fluid, is present in 5% to 20% of patients in labor and is considered an obstetric hazard. The condition has been attributed to the passage of fetal colonic content (meconium), intraamniotic bleeding with the presence of heme catabolic products, or both. The frequency of green-stained amniotic fluid increases as a function of gestational age, reaching approximately 27% in post-term gestation. Green-stained amniotic fluid during labor has been associated with fetal acidemia (umbilical artery pH <7.00), neonatal respiratory distress, and seizures as well as cerebral palsy. Hypoxia is widely considered a mechanism responsible for fetal defecation and meconium-stained amniotic fluid; however, most fetuses with meconium-stained amniotic fluid do not have fetal acidemia. Intraamniotic infection/inflammation has emerged as an important factor in meconium-stained amniotic fluid in term and preterm gestations, as patients with these conditions have a higher rate of clinical chorioamnionitis and neonatal sepsis. The precise mechanisms linking intraamniotic inflammation to green-stained amniotic fluid have not been determined, but the effects of oxidative stress in heme catabolism have been implicated. Two randomized clinical trials suggest that antibiotic administration decreases the rate of clinical chorioamnionitis in patients with meconium-stained amniotic fluid. A serious complication of meconium-stained amniotic fluid is meconium aspiration syndrome. This condition develops in 5% of cases presenting with meconium-stained amniotic fluid and is a severe complication typical of term newborns. Meconium aspiration syndrome is attributed to the mechanical and chemical effects of aspirated meconium coupled with local and systemic fetal inflammation. Routine naso/oropharyngeal suctioning and tracheal intubation in cases of meconium-stained amniotic fluid have not been shown to be beneficial and are no longer recommended in obstetrical practice. A systematic review of randomized controlled trials suggested that amnioinfusion may decrease the rate of meconium aspiration syndrome. Histologic examination of the fetal membranes for meconium has been invoked in medical legal litigation to time the occurrence of fetal injury. However, inferences have been largely based on the results of in vitro experiments, and extrapolation of such findings to the clinical setting warrants caution. Fetal defecation throughout gestation appears to be a physiologic phenomenon based on ultrasound as well as in observations in animals.

Risk factors for a serious adverse outcome in neonates: a retrospective cohort study of vaginal births.

OBJECTIVE: To investigate the hypothesis that risk factors in addition to an abnormal fetal heart rate pattern (aFHRp) are independently associated with adverse neonatal outcomes of labour. DESIGN: Observational prospective cohort study. SETTING: 17 UK maternity units. SAMPLE: 585 291 pregnancies between 1988 and 2000 inclusive. METHODS: Adjusted odds ratios (OR) with 95% confidence intervals (95% CI) were estimated from multivariable logistic regression. MAIN OUTCOME MEASURES: Adverse neonatal outcome at term (5-minute Apgar score <7, and a composite measure comprising 5-minute Apgar score <7, resuscitation by intubation and/or perinatal death). RESULTS: Analysis was based on 302 137 vaginal births at 37-42 weeks inclusive. We found a higher odds of Apgar score at 5 minutes <7 with suspected fetal growth restriction (OR 1.34, 95% CI 1.16-1.53), induction of labour (OR 1.41, 95% CI 1.25-1.58), nulliparity (OR 1.48, 95% CI 1.34-1.63), booking body mass index ≥30 (OR 1.18, 95% CI 1.02-1.37), maternal age <25 (OR 1.23, 95% CI 1.10-1.39), black ethnicity (OR 1.21, 95% CI 1.03-1.43), early-term birth at 37-38 weeks (OR 1.13, 95% CI 1.02-1.25), late-term birth at 41-42 weeks (OR 1.14, 95% CI 1.01-1.28), use of oxytocin (OR 1.27, 95% CI 1.14-1.41), maternal pyrexia (OR 1.87, 95% CI 1.46-2.40), aFHRp and presence of meconium (aFHRp without meconium: OR 2.40, 95% CI 2.15-2.69; meconium without aFHRp: OR 2.20, 195% CI.94-2.49; both aFHRp and meconium: OR 4.26, 95% CI 3.74-4.87). The results were similar when the composite adverse outcome was considered. CONCLUSIONS: A range of risk factors, including suspicion of fetal growth restriction, maternal pyrexia and presence of meconium, are implicated in poor birth outcomes in addition to aFHRp. Interpretation of the fetal heart rate pattern alone is insufficient as a basis for decisions about escalation and intervention.

Time to first passage of meconium and defecation frequency preceding necrotizing enterocolitis in preterm infants: a case-control study.

Necrotizing enterocolitis (NEC) is associated with significant morbidity and mortality in preterm infants. Early recognition and treatment of NEC are critical to improving outcomes. Enteric nervous system (ENS) immaturity has been proposed as a key factor in NEC pathophysiology. Gastrointestinal dysmotility is associated with ENS immaturity and may serve as a predictive factor for the development of NEC. In this case-control study, preterm infants (gestational age (GA) < 30 weeks) were included in two level-IV neonatal intensive care units. Infants with NEC in the first month of life were 1:3 matched to controls based on GA (± 3 days). Odds ratios for NEC development were analyzed by logistic regression for time to first passage of meconium (TFPM), duration of meconial stool, and mean daily defecation frequency over the 72 h preceding clinical NEC onset (DF < T0). A total of 39 NEC cases and 117 matched controls (median GA 27 + 4 weeks) were included. Median TFPM was comparable in cases and controls (36 h [IQR 13-65] vs. 30 h [IQR 9-66], p = 0.83). In 21% of both cases and controls, TFPM was ≥ 72 h (p = 0.87). Duration of meconial stool and DF < T0 were comparable in the NEC and control group (median 4 and 3, resp. in both groups). Odds of NEC were not significantly associated with TFPM, duration of meconial stools, and DF < T0 (adjusted odds ratio [95% confidence interval]: 1.00 [0.99-1.03], 1.16 [0.86-1.55] and 0.97 [0.72-1.31], resp.). CONCLUSION: In this cohort, no association was found between TFPM, duration of meconium stool, and DF < T0 and the development of NEC. WHAT IS KNOWN: • Necrotizing enterocolitis (NEC) is a life-threatening acute intestinal inflammatory disease of the young preterm infant. Early clinical risk factors for NEC have been investigated in order to facilitate early diagnosis and treatment. • Signs of disrupted gastrointestinal mobility, such as gastric retention and paralytic ileus, have been established to support the diagnosis of NEC. Nevertheless, defecation patterns have insufficiently been studied in relation to the disease. WHAT IS NEW: • Defecation patterns in the three days preceding NEC did not differ from gestational age-matched controls of corresponding postnatal age. Additionally, the first passage of meconium and the duration of meconium passage were comparable between cases and controls. Currently, defecation patterns are not useful as early warning signs for NEC. It remains to be elucidated whether these parameters are different based on the location of intestinal necrosis.