Maternal Antibiotics Research Articles

Autism Spectrum and gastrointestinal health: Screening on the influence of environmental factors on gastrointestinal problems

AbstractAutism spectrum disorder (ASD) is a complex neurodevelopmental condition that combines genetic and environmental factors. The human microbiota is colonized by permanent or transitory microorganisms, depending on the host and the external factors controlling their permanence. The composition of the gut microbiota (GM) in ASD individuals is notably different from that in controls, which may contribute to the clinical conditions observed in these individuals. This study aimed to indirectly investigate the influence of GM on the gut‐brain axis in individuals with ASD and controls by analyzing environmental factors that contribute to the microbiota composition. Two questionnaires were designed to collect data, one for the ASD Group (ASDG) and the other one for the Control Group (CG). The raw data from both questionnaires were collected from 2772 respondents. After triage, answers from 1687 ASD individuals, along with 466 respondents from the CG, were analyzed, resulting in a total of 2237 respondents. Our results showed that gastrointestinal problems (GP) escalate as individuals age and become more prominent in ASD individuals. In contrast, feeding problems (FP) did not appear to escalate in either group as individuals aged, even though the FP decreased in the CG. ANOVA revealed significant differences in breastfeeding status compared to GPs among preterm control individuals born via cesarean section (p‐value = 0.027). The mean values of GP for breastfed and nonbreastfed individuals, for ASDG (0.257; 0.268) and CG (0.105; 0.248), highlighted the differences in breastfeeding effects on GP for the study groups. The use of antibiotics during pregnancy seemed to be significant for GPs in the ASDG only for breastfed individuals (p‐value <0.001), but not in the CG group. In conclusion, variables such as mode of delivery, FPs, type of birth, and length of breastfeeding do not seem to be determining factors for GP in the ASDG but are relevant for the CG. However, for ASDG individuals whose mothers took antibiotics during pregnancy, breastfeeding may act as a protective factor, as maternal antibiotic administration during pregnancy seems to aggravate GP‐values across the ages of the participants. Considering GP as a proxy for GM and recognizing the importance of GM composition for central nervous system (CNS) function, it appears that in individuals with ASD, GM seems to be more dependent on other factors, which might be linked to the genetic background of each one. These findings suggest that future studies of the gut‐brain axis in individuals with ASD might consider the individual's genetic background, environmental factors, and GM.

Intrapartum antibiotic exposure and infectious diseases in childhood – a population-based cohort study

Intrapartum antibiotics are used to prevent group B streptococcus disease in newborn infants. We hypothesised that intrapartum antibiotic exposure is associated with the occurrence of childhood infectious diseases because it influences the development of the gut microbiome. The cohort for this population-based study comprised vaginally delivered children born in Northern Finland in 2007-2018. We used structured electronic medical records linked to comprehensive national registers. Primary outcome was the number of infectious disease episodes leading to an emergency room visit, outpatient hospital visit, or hospitalisation from birth until five years of age. Analyses were performed on 9733 children (48.8% girls) exposed to intrapartum antibiotics and on 35,842 unexposed children (49.9% girls). Exposure to intrapartum antibiotics was associated with increased risk of any infectious disease episode at the ages 7-28 days (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.10-1.54) and 1-2 years (aIRR 1.10, 95% CI 1.02-1.18). The occurrence of urinary tract infections was associated with the exposure to intrapartum antibiotics whereas the occurrence of severe infections caused by pathogens susceptible to penicillin was reversely associated with the exposure to intrapartum antibiotics. Maternal intrapartum antibiotics were associated with the occurrence of infectious diseases in the offspring. The observed associations appeared to depend on bacterial pathogens and their antimicrobial susceptibility to penicillin. Pediatric Research Foundation, Alma och K.A. Snellman Foundation, Orion Research Foundation, Päivikki and Sakari Sohlberg Foundation, Finnish Medical Foundation, Academy of Finland, Finland.

Associating prenatal antibiotics exposure with attention deficit hyperactivity disorder symptoms in preschool children: The role of maternal vitamin D

BackgroundThe associations between prenatal antibiotics exposure and attention-deficit/hyperactivity disorder (ADHD) in preschoolers, and the role of maternal vitamin D in these associations, remain to be explored. ObjectivesTo evaluate the relationships between multiple maternal urinary antibiotics levels and preschoolers’ ADHD symptoms, and to identify the potential modifying effects of maternal vitamin D. MethodsBased on a prospective birth cohort, the present study included 2033 motherchild pairs. Maternal urine and serum samples were collected during all three trimesters to measure the urinary concentrations of 43 antibiotics (including two metabolites) and the serum vitamin D levels. The ADHD symptoms of preschoolers were assessed using the Diagnostic and Statistical Manual–oriented ADHD problems scale in the Achenbach Child Behavior Checklist. Multiple informant models in the form of logistic regression were conducted to investigate the associations between prenatal antibiotics exposure and preschooler ADHD symptoms, and these associations were stratified by child sex and maternal vitamin D status. ResultsCompared with the lowest tertile concentrations, maternal exposure to the middle tertile concentrations of doxycycline and human antibiotics/preferred as human antibiotics (HAs/PHAs), and the highest tertile concentrations of doxycycline during the first trimester were associated with an increased risk of ADHD symptoms in children. An increased risk of ADHD symptoms was observed in girls exposed to the highest tertile levels of sulfamethazine during the second trimester. Furthermore, pregnant women with vitamin D deficiency have a greater risk of ADHD symptoms in their offspring after exposure to doxycycline in the first trimester. ConclusionsMaternal exposure to doxycycline and HAs/PHAs during the first trimester increases the risk of ADHD symptoms in preschoolers. Mid-pregnancy sulfamethazine exposure increases the risk of ADHD symptoms in girls. Maternal vitamin D deficiency during pregnancy may exacerbate the adverse effects of doxycycline exposure on ADHD symptoms.

Association between maternal antibiotic exposure and emotional and behavioural problems in children at four years of age: A biomonitoring-based prospective study

BackgroundMaternal exposure to multiple antibiotics exposure during pregnancy has attracted extensive attention, but biomonitoring studies linking prenatal antibiotic exposure to emotional and behavioural problems in children are limited. MethodsA total of 2475 pregnant women from the Ma’anshan Birth Cohort were included, and the Strengths and Difficulties Questionnaire was completed when their children turned four years of age. The levels of 41 maternal urinary antibiotics and two metabolites were measured during the first, second and third trimesters. Generalized estimating equations and binary logistic regression models were applied to analyse the associations between maternal antibiotic exposure and emotional and behavioural problems in children and to determine the sensitive period, respectively. A quantile-based g-computation (QGC) approach was employed to examine the combined effects of multiple antibiotics on emotional and behavioural problems in children. ResultsOverall, florfenicol and preferred-as-veterinary antibiotic (PVA) exposure during pregnancy increased the risk of emotional problems in children, and ofloxacin exposure increased the risk of hyperactivity-inattention. Maternal exposure to trimethoprime, ciprofloxacin, florfenicol, other antibiotics and PVA exposure during the first trimester was positively associated with emotional problems in children. Second-trimester trimethoprime concentrations and third-trimester ciprofloxacin concentrations were positively associated with hyperactivity-inattention. Third-trimester veterinary antibiotic (VA) exposure was negatively associated with hyperactivity-inattention, and second-trimester VA and PVA exposure was negatively associated with peer problems. The QGC model revealed that mixed antibiotic exposure in the first trimester exacerbated the risk of childhood emotional problems (the contribution of ciprofloxacin is prominent), and mixed antibiotic exposure in the second trimester increased the risk of hyperactivity-inattention (the contribution of trimethoprime is prominent). ConclusionMaternal mixed antibiotic exposure during the first and second trimesters increases the risk of emotional problems and hyperactivity-inattention in children at four years of age.

Delivery mode is a larger determinant of infant gut microbiome composition at 6 weeks than exposure to peripartum antibiotics.

Background. Previous research has shown that delivery mode can shape infant gut microbiome composition. However, mothers delivering by caesarean section routinely receive prophylactic antibiotics prior to delivery, resulting in antibiotic exposure to the infant via the placenta. Previously, only a small number of studies have examined the effect of delivery mode versus antibiotic exposure on the infant gut microbiome with mixed findings.Objective. We aimed to determine the effect of delivery mode compared to antibiotic use during labour and delivery on the infant and maternal gut microbiome at 6 weeks post-partum.Methodology. Twenty-five mother-infant dyads were selected from the longitudinal Queensland Family Cohort Study. The selected dyads comprised nine vaginally delivered infants without antibiotics, seven vaginally delivered infants exposed to antibiotics and nine infants born by caesarean section with routine maternal prophylactic antibiotics. Shotgun-metagenomic sequencing of DNA from stool samples collected at 6 weeks post-partum from mother and infant was used to assess microbiome composition.Results. Caesarean section infants exhibited decreases in Bacteroidetes (ANCOM-BC q<0.0001, MaAsLin 2 q=0.041), changes to several functional pathways and altered beta diversity (R 2=0.056, P=0.029), while minimal differences due to antibiotic exposure were detected. For mothers, caesarean delivery (P=0.0007) and antibiotic use (P=0.016) decreased the evenness of the gut microbiome at 6 weeks post-partum without changing beta diversity. Several taxa in the maternal microbiome were altered in association with antibiotic use, with few differentially abundant taxa associated with delivery mode.Conclusion. For infants, delivery mode appears to have a larger effect on gut microbiome composition at 6 weeks post-partum than intrapartum antibiotic exposure. For mothers, both delivery mode and intrapartum antibiotic use have a small effect on gut microbiome composition at 6 weeks post-partum.

State of the Art: Intrapartum Antibiotics in Cesarean Section—The Infant Microbiota and Allergic Diseases

(Acta Obstet Gynecol Scand. 2023;102:811–820) Recent changes in guidelines for administering maternal antibiotics for cesarean deliveries (CD) have increased neonatal exposure to antibiotics. Potential long-term effects of this exposure are relatively unknown; recent evidence in other fields has indicated a long-lasting impact of antibiotic exposure on gut microbiota composition, which raises concerns about the effects of antibiotics on the fragile and new gut microbiota of neonates around the time of birth. This review assessed the current guidelines and applications for CD antibiotics, as well as discussed the importance of neonatal intestinal microbiota and the potential consequences of antibiotic prophylaxis in the development of the neonatal immune system and allergic disease.

Early life factors and oral microbial signatures define the risk of caries in a Swedish cohort of preschool children

The oral cavity harbors complex communities comprising bacteria, archaea, fungi, protozoa, and viruses. The oral microbiota is establish at birth and develops further during childhood, with early life factors such as birth mode, feeding practices, and oral hygiene, reported to influence this development and the susceptibility to caries. We here analyzed the oral bacterial composition in saliva of 260 Swedish children at two, three and five years of age using 16S rRNA gene profiling to examine its relation to environmental factors and caries development at five years of age. We were able to assign the salivary bacterial community in each child at each time point to one of seven distinct clusters. We observed an individual dynamic in the development of the oral microbiota related to early life factors, such as being first born, born by C-section, maternal perinatal antibiotics use, with a distinct transition between three and five years of age. Different bacterial signatures depending on age were related to increased caries risk, while Peptococcus consistently linked to reduced risk of caries development.

Inadvertent antibiotic exposure during pregnancy may increase the risk for neural tube defects in offspring

BackgroundAs emerging environmental contaminants, antibiotics pose potential threats to human health, in particular to pregnant women and infants. However, the potential harm of inadvertent antibiotic exposure (IAE) is often disregarded in light of the focus on intentional antibiotic use during pregnancy. Currently, little is known about the effects of IAE during pregnancy on fetal neural tube development. MethodsIn this case-control study, we used questionnaire data from 855 subjects to investigate the effects of intentional antibiotic use in early pregnancy on neural tube defects (NTDs). Then we tested for placental antibiotics in mothers who had not intentionally used antibiotics, and the compounds were detected in 379 subjects; these were considered IAE cases. We assessed the association between IAE during pregnancy and fetal NTDs using both multivariable logistic and multi-pollutant exposure models. We also analyzed the correlation between maternal dietary habits and placental antibiotics to explore possible sources of IAE. ResultsOnly 50 of 855 participants (5.8%) intentionally used antibiotics and such use showed no significant association with NTD risk (odds ratio [OR] = 1.92, confidence interval [95%CI] = [0.66, 5.59]). However, 14 of 15 placental antibiotics were detected in 378 of 379 subjects (99.7%) and multivariable logistic analysis indicated that high levels of placental macrolides were significantly associated with increased NTD risk (4.42 [2.01–10.45]). Multi-pollutant exposure analysis suggested an increase in NTD risk with an increase in exposure to a mixture of placental antibiotics, among which macrolides were the most important contributor. In addition, the level of placental macrolides was positively correlated with the intake frequency of milk. Finally, mothers who drank river, well, or pond water had higher levels of placental macrolides than those who drank only tap water. ConclusionsIntentional antibiotic use during early pregnancy may not be associated with NTDs, while IAE during pregnancy is associated with higher NTD risk in offspring. Macrolides are crucial risk factors. Milk, and river, well, or pond water may be important sources of IAE.

A common trajectory of gut microbiome development during the first month in healthy neonates with limited inter-individual environmental variations

The early development of the gut microbiome is governed by multiple factors and has significantly long-term effects on later-in-life health. To minimize inter-individual variations in the environment, we determined developmental trajectories of the gut microbiome in 28 healthy neonates during their stay at a postpartum center. Stool samples were collected at three time points: the first-pass meconium within 24 h of life, and at 7 and 28 days of age. Illumina sequencing of the V3–V4 region of 16S rRNA was used to investigate microbiota profiles. We found that there was a distinct microbiota structure at each time point, with a significant shift during the first week. Proteobacteria was most abundant in the first-pass meconium; Firmicutes and Actinobacteria increased with age and were substituted as the major components. Except for a short-term influence of different delivery modes on the microbiota composition, early microbiome development was not remarkably affected by gravidity, maternal intrapartum antibiotic treatment, premature rupture of membranes, or postnatal phototherapy. Hence, our data showed a similar developmental trajectory of the gut microbiome during the first month in healthy neonates when limited in environmental variations. Environmental factors external to the host were crucial in the early microbiome development.

Maternal or Paternal Antibiotics? Intergenerational Transmission and Reproductive Toxicity in Zebrafish.

Despite the known direct toxicity of various antibiotics to aquatic organisms, the potential chronic impact through intergenerational transmission on reproduction remains elusive. Here, we exposed zebrafish to a mixture of 15 commonly consumed antibiotics at environmentally relevant concentrations (1 and 100 μg L-1) with a cross-mating design. A high accumulation of antibiotics was detected in the ovary (up to 904.58 ng g-1) and testis (up to 1704.49 ng g-1) of F0 fish. The transmission of antibiotics from the F0 generation to the subsequent generation (F1 offspring) was confirmed with a transmission rate (ki) ranging from 0.11 to 2.32. The maternal transfer of antibiotics was significantly higher, relative to paternal transfer, due to a greater role of transmission through ovarian enrichment and oviposition compared to testis enrichment. There were similar impairments in reproductive and developmental indexes on F1 eggs found following both female and male parental exposure. Almost all antibiotics were eliminated in F2 eggs in comparison to F1 eggs. However, there were still reproductive and developmental toxic responses observed in F2 fish, suggesting that antibiotic concentration levels were not the only criterion for evaluating the toxic effects for each generation. These findings unveil the intergenerational transmission mechanism of antibiotics in fish models and underscore their potential and lasting impact in aquatic environments.

Maternal and Infant Antibiotic and Acid Suppressant Use and Risk of Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE), a chronic disease with significant patient and health care burden, has increased rapidly in incidence across many countries. Elucidating risk factors for disease development is a priority for health care practitioners and patients. To evaluate the association of maternal and infant use of antibiotics and acid suppressants with the development of EoE. This was a population-based, case-control study of pediatric EoE (1996-2019) in Denmark using pathology, prescription, birth, inpatient, and outpatient health registry data and with complete ascertainment of all EoE cases among Danish residents born between 1997 and 2018. Study data were analyzed from September 2020 to August 2023. Maternal and infant use of antibiotics and acid suppressants, examining medication class, timing, and frequency of use. Development of EoE. Included in the study was a total of 392 cases and 3637 sex- and year of birth-matched controls with a median (IQR) age of 11.0 (6.0-15.0) years, 2772 male individuals (68.8%), and 1257 female individuals (31.2%). Compared with children with no antibiotic prescriptions filled during infancy, those with any use of an antibiotic had an associated 40% increase in risk of EoE (adjusted odds ratio [aOR], 1.4; 95% CI, 1.1-1.7). Those with 3 or more prescriptions had an associated 80% increase in risk of EoE (aOR, 1.8; 95% CI, 1.3-2.5). Frequency of maternal antibiotic use was associated with an increased risk (1 prescription: aOR, 1.4; 95% CI, 1.0-1.8; 3≤ prescriptions: aOR, 2.1; 95% CI, 1.4-3.2). Risk was highest for use in the third trimester and in the first 6 months from birth. Any acid suppressant use in infancy was associated with increased risk of EoE (aOR, 15.9; 95% CI, 9.1-27.7). Restriction of cases to those diagnosed at 5 years or older yielded similar results (aOR, 11.6; 95% CI, 5.5-24.8). For maternal use, 3 or more prescriptions were associated with an increased risk of EoE for her offspring (aOR, 5.1; 95% CI, 1.8-14.8). Maternal and infant antibiotic use were associated with increased risk of developing EoE, in a dose-response manner, and the magnitude of association was highest for exposure near the time of delivery. Increased risk was also observed with maternal and infant acid suppressant use. Exposure during early life, a period of known developmental susceptibility, may confer the greatest risk and opportunity for risk mitigation.

Incidence of group B streptococcus early-onset sepsis in term neonates with second-line prophylaxis maternal intrapartum antibiotics: a multicenter retrospective study

BackgroundThe difference in incidence of early onset sepsis (EOS) caused by Group B Streptococcus (GBS) among term neonates whose mothers receive first versus second-line intrapartum prophylaxis is poorly described. ObjectiveTo compare the incidence of GBS EOS in term neonates born to mothers who receive first, second-line or no intrapartum antibiotics, and describe the short term and survival outcomes of neonates who developed GBS EOS stratified by maternal antepartum prophylaxis. Study DesignThis was a retrospective review of electronic medical records. We queried the Pediatrix Medical Group Clinical Data Warehouse to evaluate the outcomes of term neonates born to GBS positive mothers between 2003 – 2020, and compared the incidence and outcomes of neonates with GBS EOS whose mothers received first versus second-line/no intrapartum prophylaxis. ResultsAmong 496,180 neonates, 104,196 (21%) were born to GBS positive mothers. Out of 97,983 GBS positive mothers with adequate prenatal antibiotic documentation, 49,234 (50%), 12,679 (13%) and 36,070 (37%) received first-line, second-line and no intrapartum prophylaxis, respectively. Incidence of GBS EOS among all neonates with maternal GBS carriage was 0.22% (231/104,196). Neonates whose mothers received second-line intrapartum antibiotics and no antibiotics had higher risk of GBS EOS infection compared to first-line intrapartum antibiotics [adjusted odds ratio (aOR) 4.12, 95% confidence interval (CI): 2.66 – 6.38 and aOR 3.80, 95% CI: 2.66 – 5.44, respectively]. No statistically significant difference in the risk of GBS EOS in neonates born to mothers who received second-line versus no antibiotics (aOR 0.92, 95% CI: 0.64 – 1.33). ConclusionNeonates exposed to second-line maternal GBS prophylaxis had increased risk of GBS EOS compared to those exposed to first-line maternal GBS prophylaxis. There was no statistically significant difference in GBS EOS incidence between second-line versus no antibiotics in mothers with GBS carriage.

Early Gut Microbiota Profile in Healthy Neonates: Microbiome Analysis of the First-Pass Meconium Using Next-Generation Sequencing Technology.

Gut microbiome development during early life has significant long-term effects on health later in life. The first-pass meconium is not sterile, and it is important to know the initial founder of the subsequent gut microbiome. However, there is limited data on the microbiota profile of the first-pass meconium in healthy neonates. To determine the early gut microbiota profile, we analyzed 39 samples of the first-pass meconium from healthy neonates using 16S rRNA sequencing. Our results showed a similar profile of the microbiota composition in the first-pass meconium samples. Pseudomonas was the most abundant genus in most samples. The evenness of the microbial communities in the first-pass meconium was extremely poor, and the average Shannon diversity index was 1.31. An analysis of the relationship between perinatal characteristics and the meconium microbiome revealed that primigravidae babies had a significantly higher Shannon diversity index (p = 0.041), and the Bacteroidales order was a biomarker for the first-pass meconium of these neonates. The Shannon diversity index was not affected by the mode of delivery, maternal intrapartum antibiotic treatment, prolonged rupture of membranes, or birth weight. Our study extends previous research with further characterization of the gut microbiome in very early life.

Antibiotic choice for Group B Streptococcus prophylaxis in mothers with reported penicillin allergy and associated newborn outcomes

ObjectiveTo evaluate the choice of antibiotic used for intrapartum Group B Streptococcus (GBS) prophylaxis in pregnant individuals with reported penicillin allergies compared to those without reported penicillin allergies and investigate whether there are associated differences in neonatal outcomes.Study DesignThis retrospective cohort study included mother-infant dyads of GBS positive pregnant individuals who labored and delivered newborns ≥ 35 weeks of gestation at a high-volume urban hospital (2005–2018). The type of antibiotic administered to the mothers for GBS prophylaxis (beta-lactam prophylaxis defined as penicillin-class drug or cefazolin; alternative prophylaxis defined as vancomycin or clindamycin) was compared between those with a penicillin allergy documented in their medical record versus those who did not. Neonatal outcomes included number of postnatal blood draws, antibiotic administration, neonatal intensive care unit (NICU) admission, bacteremia, and hospital length of stay and were compared between groups. Bivariable and multivariable analyses were performed.ResultsOf 11,334 mother-infant pairs, 1170 (10.3%) mothers had a penicillin allergy documented in their medical record. Of them, 49 (4.2%) received a penicillin, 259 (22.1%) received cefazolin, 449 (38.4%) received clindamycin, and 413 (35.3%) received vancomycin. Patients with a reported penicillin allergy were significantly more likely to receive alternative GBS prophylaxis compared to those without penicillin allergy (73.7% vs. 0.2%, p < 0.01). Neonates of patients who received alternative GBS prophylaxis were significantly more likely to undergo a postnatal lab draw compared to neonates of patients who received beta-lactam antibiotics (20.8% vs. 17.3%, OR 1.25 (95% CI 1.08–1.46)). This significant association persisted after adjusting for potential confounders (aOR 1.23, 95% CI 1.06–1.43). There were no other significant differences seen in other newborn outcomes.ConclusionPregnant individuals who report a penicillin allergy were more likely to receive alternative antibiotics for GBS prophylaxis compared to those without a penicillin allergy. This was associated with an increased frequency of postnatal blood draws among neonates of mothers with a reported penicillin allergy.Brief summaryAdministration of alternative intrapartum antibiotic prophylaxis with vancomycin or clindamycin is common in individuals with self-reported penicillin allergy, and maternal alternative antibiotic administration may impact neonatal care, particularly via increased lab draws.

Maternal antibiotic administration during gestation can affect the memory and brain structure in mouse offspring.

Maternal antibiotics administration (MAA) is among the widely used therapeutic approaches in pregnancy. Although published evidence demonstrates that infants exposed to antibiotics immediately after birth have altered recognition memory responses at one month of age, very little is known about in utero effects of antibiotics on the neuronal function and behavior of children after birth. Therefore, this study aimed to evaluate the impact of MAA at different periods of pregnancy on memory decline and brain structural alterations in young mouse offspring after their first month of life. To study the effects of MAA on 4-week-old offspring, pregnant C57BL/6J mouse dams (2-3-month-old; n = 4/group) were exposed to a cocktail of amoxicillin (205 mg/kg/day) and azithromycin (51 mg/kg/day) in sterile drinking water (daily/1 week) during either the 2nd or 3rd week of pregnancy and stopped after delivery. A control group of pregnant dams was exposed to sterile drinking water alone during all three weeks of pregnancy. Then, the 4-week-old offspring mice were first evaluated for behavioral changes. Using the Morris water maze assay, we revealed that exposure of pregnant mice to antibiotics at the 2nd and 3rd weeks of pregnancy significantly altered spatial reference memory and learning skills in their offspring compared to those delivered from the control group of dams. In contrast, no significant difference in long-term associative memory was detected between offspring groups using the novel object recognition test. Then, we histologically evaluated brain samples from the same offspring individuals using conventional immunofluorescence and electron microscopy assays. To our knowledge, we observed a reduction in the density of the hippocampal CA1 pyramidal neurons and hypomyelination in the corpus callosum in groups of mice in utero exposed to antibiotics at the 2nd and 3rd weeks of gestation. In addition, offspring exposed to antibiotics at the 2nd or 3rd week of gestation demonstrated a decreased astrocyte cell surface area and astrocyte territories or depletion of neurogenesis in the dentate gyrus and hippocampal synaptic loss, respectively. Altogether, this study shows that MAA at different times of pregnancy can pathologically alter cognitive behavior and brain development in offspring at an early age after weaning.

Maternal Antibiotic Treatment Dysregulates Goblet Cell Associated Antigen Passages in Neonatal Mice

Abstract Maternal antibiotic treatment (MAT) disrupts the development of the neonatal microbiome, intestinal immune development and increases susceptibility to sepsis in mouse models. Mechanisms by which MAT disrupts neonatal intestinal immune function will facilitate the development of novel strategies to reduce neonatal sepsis risk. Intestinal goblet cell associated antigen passages (GAPs) are portals for physiologic exposure of the immune system to commensal gut bacteria and luminal antigens. GAPs are inhibited by epidermal growth factor receptor (EGFR) signaling, colonic GAPs are closed prior to postnatal day (P) 10 in mice when luminal EGF levels from breast milk are high, then open after P10 when breast milk EGF levels decline. When colonic GAPs are opened inappropriately due to low levels of EGF prior to P10 or dysbiosis of the gut microbiota after weaning, they can facilitate pathological bacterial translocation. Pups of dams treated with ampicillin and neomycin in their drinking water from pup P1–8 had significantly more open GAPs in the small intestine (SI) compared to controls. These data suggest that MAT creates a permissive environment for SI GAPs in the neonatal period which could allow pathologic bacterial translocation. MAT pups weighed significantly less and were significantly hypoglycemic compared to pups from control dams, after weaning MAT pups recover to a normal weight. We hypothesize that MAT pups have reduced intestinal EGFR signaling, leading to stunted growth and irregular opening of GAPs in the SI and colon. These data suggest maternal antibiotic treatment may be a risk factor for sepsis and growth failure in premature neonates.

Fungal infection and neurodevelopmental outcomes at 18-30 months in preterm infants.

Invasive fungal infection (IFI) is associated with significant mortality and morbidity among preterm infants but there has been no population-based study of long-term neurodevelopmental outcomes. The objective of this study was to examine population-based incidence trends as well as mortality, short term in-hospital morbidity and long-term neurodevelopmental outcomes among preterm infants with IFI, non-fungal infections (NFI) and no infections in Canada. We conducted a retrospective cohort study of 8,408 infants born at <29 weeks gestational age (GA), admitted to Canadian Neonatal Network neonatal intensive care units (NICU) from April 2009 to December 2017, and followed up at 18-30 months corrected age (CA) in Canadian Neonatal Follow-Up Network clinics. We compared mortality, long term neurodevelopmental outcomes and short term in-hospital morbidity among 3 groups of infants (IFI, NFI, and no infections). The incidence of IFI was 1.3%, non-IFI 26.9% and no infections 71.7%. IFI incidence varied between 0.93% and 1.94% across the study period with no significant trend over time. Infants of higher gestational age were significantly (p < 0.01) less likely to have IFI. Among infants with IFI, NFI and no infections, the incidence of the significant neurodevelopmental impairment (sNDI) was 44.26%, 21.63% and 14.84% respectively, while mortality was 50%, 25.35% and 22.25% respectively. Even after risk adjustment for confounders (GA, Score for Neonatal Acute Physiology Version II, ruptured membranes >24 h, maternal antibiotic treatment, antenatal steroid use, cesarean section), infants with IFI had significantly higher odds of sNDI than NFI (aOR: 2.19; 95% CI: 1.23, 3.91) or no infections (aOR: 2.97; 95% CI: 1.55, 5.71), and higher odds of mortality than NFI (aOR: 1.55; 95% CI: 1.07, 2.26) or no infections (aOR: 1.45; 95% CI: 0.97, 2.17). Preterm infants with invasive fungal infections have significantly higher incidence of mortality and adverse neurodevelopmental outcomes than those with non-invasive fungal infections and no infections.

Histologic chorioamnionitis in extremely preterm births, microbiological findings and infant outcome

Background Histologic chorioamnionitis (HCA) is most often caused by ascending bacterial infection originating from the cervicovaginal tract. Objectives To investigate whether HCA with a fetal inflammatory response (FIR) has a worse clinical outcome than HCA alone. Further, if FIR or a positive maternal microbiologic culture obtained prior to birth were related to adverse neonatal outcomes in a cohort of extremely preterm (EP) neonates. Methods Prospective observational cohort study recruiting EP singleton pregnancies (gestational age at birth ≤28 weeks) with confirmed HCA. FIR was defined by fetal neutrophils in the chorionic vessels and/or umbilical vessels. Positive culture was defined as growth of potentially pathogenic bacteria in a sample from the cervicovaginal tract prior to birth, or if a cervicovaginal culture was lacking, a culture result from the placenta was used. Logistic regression was used to estimate odds ratios and 95% confidence intervals for the associations between FIR, a positive culture result and adverse outcomes, defined as bronchopulmonary dysplasia (BPD), brain pathology assessed by magnetic resonance imaging, retinopathy of prematurity, necrotizing enterocolitis, early-onset neonatal sepsis, and perinatal death. A composite outcome variable included one or more adverse outcomes. Results We included 71 cases with HCA, of which 51 (72%) had FIR. Maternal age, rate of clinical chorioamnionitis (CCA), preterm pre-labor rupture of membranes (PPROM), the number of women receiving antenatal steroids and antibiotics, and the rate of positive maternal cultures of potentially pathogenic bacteria were all significantly higher in the HCA with FIR. Neonates in the FIR group had significantly higher levels of blood leukocytes compared to those without. FIR was associated with a longer interval from PPROM to delivery (log-rank test: p = .022). Microbiological sampling had been performed in 63 (89%) cases, of which 60 (95%) were cervicovaginal samples. No associations were found between a positive culture and adverse neonatal outcomes, in contrast to FIR, that was significantly associated to BPD and brain pathology. Conclusions In a cohort of EP pregnancies with confirmed HCA, the presence of FIR was associated with advanced maternal age, CCA, PPROM, antenatal steroids and antibiotics, and a positive maternal culture of potentially pathogenic bacteria. However, the presence of FIR, and not a positive culture, was associated with adverse neonatal outcomes.

Cross-sectional study of the proportion of antibiotic use during childbirth in full-term deliveries in Finland

PurposeIn developed countries, data on the frequency of antibiotics given to mothers during childbirth are limited beyond the overall effect of all various prophylactic indications. Also, data on the impact of such antibiotics to the well-being of term babies are scarce. We aimed to characterize the frequency of antibiotic use during childbirth of term pregnancy. Secondly, we assessed whether the use of antibiotics was associated with any symptoms in infants.MethodsThis was a cross-sectional study of 1019 term deliveries of women participating in the prospective Health and Early Life Microbiota (HELMi) birth cohort study between March 2016 and March 2018 in the capital region of Finland. The data on antibiotic use were collected from the hospital records.ResultsIn total, 37% of the mothers received antibiotics during childbirth and 100% in Caesarean Sects. (17% of the deliveries). Less than 5% of antibiotics were non-prophylactic. In vaginal deliveries, the most common indication (18%) was prophylaxis for Group B Streptococcus. The most frequently used antibiotics were cefuroxime (22%) and benzylpenicillin (15%), and 56% received only one dose. In infants exposed to antibiotics during delivery, defecation frequency was higher during the first months (p-value < 0.0001- 0.0145), and weight gain was higher at the age of three months (p-value 0.0371).ConclusionMore than every third new-born in a developed country is exposed to antibiotics during birth. Our findings support the hypothesis that maternal antibiotics given during birth have an impact on the well-being of the infants. These findings should inform current policies for prophylactic antibiotics in childbirth.

Fetal-neonatal exposure to antibiotics and NEC development: A systematic review and meta-analysis.

Fetal and neonatal exposure to antibiotics may contribute to the development of necrotizing enterocolitis (NEC) in preterm infants. This systematic review and meta-analysis investigate whether exposure to third trimester maternal antibiotics (MAB) and/or prolongation of empirical antibiotics (PEAB) are associated with NEC development in preterms. We included observational and randomized controlled studies, including those on preterm or very low birth weight (VLBW) infants, from MEDLINE and EMBASE, published between 1990 and June 2021. Exposure was defined as third trimester MAB and/or PEAB. The two reviewers independently performed study selection, data extraction, and quality assessment. Three cohort studies compared third trimester MAB with no antibiotics. MAB was associated with lower NEC incidence, unadjusted pooled odds ratio (OR) is 0.57 (95% CI: 0.35-0.93). Twelve cohort studies showed that PEAB was associated with an increased risk of NEC. Ten observational cohort studies show an unadjusted OR of 2.72 (1.65-4.47), and two case-control studies show an unadjusted mean difference of 2.31 (0.94-3.68). Moderate to substantial heterogeneity was observed but decreased in studies with low risk of bias and large sample size. Evidence suggests an association between MAB and decreased risk of NEC and an association between PEAB and increased risk of NEC. Further studies should confirm these associations and explore causality. identifier [CRD42022304937].