OBJECTIVE:To compare different antibiotic prophylaxis administered after preterm premature rupture of membranes to determine whether any were associated with differences in obstetric and/or neonatal outcomes and/or neurodevelopmental outcomes at 2 years of corrected age. DESIGN:Prospective, nationwide, population-based EPIPAGE-2 cohort study of preterm infants. SETTING:France, 2011. SAMPLE:We included 492 women with a singleton pregnancy and a diagnosis of preterm premature rupture of membranes at 24-31 weeks. Exclusion criteria were contraindication to expectant management or indication for antibiotic therapy other than preterm premature rupture of membranes. Antibiotic prophylaxis was categorised as amoxicillin (n = 345), macrolide (n = 30), third-generation cephalosporin (n = 45) or any combinations covering Streptococcus agalactiae and >90% of Escherichia coli (n = 72), initiated within 24 hours after preterm premature rupture of membranes. METHODS:Population-averaged robust Poisson models. MAIN OUTCOME MEASURES:Survival at discharge without severe neonatal morbidity, 2-year neurodevelopment. RESULTS:With amoxicillin, macrolide, third-generation cephalosporin and combinations, 78.5%, 83.9%, 93.6% and 86.0% of neonates were discharged alive without severe morbidity. The administration of third-generation cephalosporin or any E. coli-targeting combinations was associated with improved survival without severe morbidity (adjusted risk ratio 1.25 [95% confidence interval 1.08-1.45] and 1.10 [95 % confidence interval 1.01-1.20], respectively) compared with amoxicillin. We evidenced no increase in neonatal sepsis related to third-generation cephalosporin-resistant pathogen. CONCLUSION:In preterm premature rupture of membranes at 24-31 weeks, antibiotic prophylaxis based on third-generation cephalosporin may be associated with improved survival without severe neonatal morbidity when compared with amoxicillin, with no evidence of increase in neonatal sepsis related to third-generation cephalosporin-resistant pathogen. TWEETABLE ABSTRACT:Antibiotic prophylaxis after PPROM at 24-31 weeks: 3rd-generation cephalosporins associated with improved neonatal outcomes.

BACKGROUND:The association between maternal antibiotic exposure during pregnancy and childhood obesity is still unclear. OBJECTIVES:The study aimed to evaluate the association between prenatal exposure to antibiotics and obesity at age 3 years using data from a large Japanese birth cohort. METHODS:The Japan Environment and Children's Study is a nationwide birth cohort study. In this study, singleton vaginal full-term births were included. Obesity was defined as body mass index ≥95th percentile according to child growth standards. Prenatal antibiotic exposure was defined as antimicrobial agent use during pregnancy and was collected from maternal interviews and medical record transcripts. Logistic regression analysis was performed to evaluate the association of prenatal antibiotic exposure with child obesity at 3 years. RESULTS:In the crude and adjusted models with all children, maternal antibiotic exposure during pregnancy showed a marginal relationship with child obesity at 3 years. In the analyses according to exposure period and sex, exposure to antibiotics during the second/third trimester was significantly associated with obesity at the age of 3 years in female infants, but not in male infants, although the exposure during the first trimester was not in both sexes. CONCLUSION:Maternal antibiotic exposure during mid/late pregnancy may result in child obesity.

Antibiotic use during pregnancy may affect asthma risk in offspring. However, epidemiological studies yielded conflicting findings, with an observed association possibly confounded by shared familial factors. We sought to assess the association between maternal antibiotic use during pregnancy and childhood asthma in the offspring, by accounting for time-stable familial factors.We conducted a population-based cohort study and sibling study using data from Danish nationwide registers, which comprised 407 804 liveborn singletons from 2005 to 2011. Antibiotic use during pregnancy was defined as at least one antibiotic prescription filled by the mother from 1 month prior to pregnancy up until delivery, identified in the National Prescription Registry. First-time asthma in the offspring was determined by hospital treatment or asthma medication treatment after age 5 years. We estimated hazard ratios (HRs) of asthma using Cox regression in the population-based cohort and stratified Cox regression in the sibling cohort.Approximately 36.5% of pregnant women redeemed antibiotic prescriptions. Antibiotic use during pregnancy was associated with childhood asthma in cohort analyses (HR 1.21, 95% CI 1.18-1.24), but not in sibling analyses (HR 0.96, 95% CI 0.90-1.03). In the population-based analyses, higher risks of asthma were seen with longer duration of maternal antibiotic use, a higher number of prescriptions and prescriptions of multiple types of antibiotics. All these associations disappeared in the sibling analyses.The associations observed by previous studies for prenatal exposure to antibiotics and offspring asthma risk are likely to be due to confounding factors shared within families.

BACKGROUND/OBJECTIVES:Current research suggests an association between antibiotic use in early life and later obesity. Less is known about prenatal antibiotic exposure and foetal growth. We investigated the association between prenatal antibiotic exposure and birth weight. METHODS:Data from the Danish National Birth Cohort were linked to the Danish National Medical Birth Registry. Exposure was self-reported antibiotic use in pregnancy. Outcome was registered birth weight. Multivariable linear regression models were adjusted for confounders defined a priori. RESULTS:A total of 63 300 mother-child dyads from 1996 to 2002 were included. Overall, prenatal antibiotic exposure was not associated with birth weight (-8.90 g, 95%CI: -19.5- +1.64 g, p = 0.10). Findings were similar for those born term and preterm. Antibiotic exposure in second to third trimester, compared to no exposure, was associated with lower birth weight (-12.6 g, 95%CI: -24.1 to -1.1 g, p = 0.03). In sex-stratified analyses, there were no observed associations between antibiotics and birth weight. With further stratifications, prenatal antibiotic exposure and birth weight were associated in boys who were preterm (+91.0 g, 95%CI: +6.8 g- +175.2 g, p = 0.03) but not among girls who were preterm (-44.0 g, 95%CI: -128.1 to +40.0 g, p = 0.30). CONCLUSIONS:Prenatal antibiotic exposure is not consistently associated with birth weight.

Antibiotics are widely used during pregnancy. Recent epidemiological studies suggest that maternal exposure to antibiotics during pregnancy is associated with increased risks of various diseases in offspring; host-microbiome interactions are considered to be involved in pathogenesis, as antibiotic-induced perturbations (dysbiosis) of the maternal microbiome can be transmitted to offspring. We reviewed the current status of antibiotic usage during pregnancy, transmission of maternal antibiotic-induced dysbiosis to offspring, and several diseases in offspring reported to be associated with maternal antibiotic exposure. Antibiotics must be properly used when necessary. While the adverse effect of maternal antibiotic exposure during pregnancy on the health of offspring has been demonstrated by several studies, more robust clinical evidence is necessary to define the best practice for antibiotic use during pregnancy. Epidemiologic studies have limitations in establishing causal links beyond associations; animal studies provide benefits in examining these links, however, microbiomes, gestation courses, and aging vary between host species. Understanding the underlying mechanisms of epidemiologic findings as well as the healthy microbiome during pregnancy and early life in humans would contribute to developing future microbial interventions for restoring antibiotic-induced dysbiosis during pregnancy.

BACKGROUND:Allergies are a serious public health issue, and prevalences are rising worldwide. The role of antibiotics in the development of allergies has repeatedly been discussed, as results remain inconsistent. The aim of this study was to investigate the association between pre- and post-natal antibiotic exposure and subsequent development of allergies (atopic dermatitis, food allergy, asthma, atopic sensitization and allergic rhinitis). METHODS:A total of 1080 children who participated in a European birth cohort study (PASTURE) were included in this analysis. Data on antibiotic exposure during pregnancy and/or first year of life and allergic diseases were collected by questionnaires from pregnancy up to 6 years of age and analysed by performing logistic regressions. To take into account reverse causation, we included models, where children with diagnosis or symptoms of the respective disease in the first year of life were excluded. RESULTS:Antibiotic exposure in utero was significantly and positively associated with atopic dermatitis and food allergy. The strongest effect was on diseases with onset within the first year of life (for atopic dermatitis: aOR 1.66, 95% CI 1.11-2.48 and for food allergy: aOR 3.01, 95% CI 1.22-7.47). Antibiotics in the first year of life were positively associated with atopic dermatitis up to 4 years (aOR 2.73, 95% CI 1.66-4.49) and also suggested a dose-response relationship. A tendency was observed with asthma between 3 and 6 years (aOR 1.65, 95% CI 0.95-2.86). CONCLUSIONS:Our findings show positive associations between exposure to antibiotics and allergies, mainly atopic dermatitis and food allergy within the first year of life, after prenatal exposure, and atopic dermatitis and asthma after post-natal exposure to antibiotics in children born in rural settings.

BACKGROUND:As 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. METHODS:In 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. RESULTS:Only 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. CONCLUSIONS:Intentional 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.

OBJECTIVE:This study aimed to investigate whether antibiotic exposure during pregnancy and infancy was associated with childhood overweight or obesity. METHODS:PubMed, Embase, and Cochrane Library databases were searched from the inception date to April 18, 2019, to identify observational studies that investigated the association between antibiotic exposure during pregnancy and infancy and childhood overweight or obesity. After study selection and data extraction, the meta-analysis was conducted using Stata software version 12.0 (StataCorp LP, College Station, Texas). The evaluation of the methodological quality was carried out by AMSTAR 2 (Bruyère Research Institute, Ottawa, Ontario, Canada). RESULTS:A total of 23 observational studies involving 1,253,035 participants were included. The meta-analysis showed that prenatal exposure to antibiotics was not significantly associated with childhood overweight or obesity, whereas an increased risk of overweight or obesity was seen in subgroup analysis of the second trimester (risk ratio = 1.13; 95% CI: 1.06-1.22; P = 0.001). In contrast, antibiotic exposure during infancy could increase the risk of childhood overweight or obesity (risk ratio = 1.14; 95% CI: 1.06-1.23; P = 0.001). CONCLUSIONS:This meta-analysis found that antibiotic exposure during the second trimester and infancy could increase the risk of childhood overweight or obesity.

Background:The early life microbiome contributes to immune development. Antibiotics during pregnancy alter the microbiome and may influence disease risks in the offspring. We investigated the relationship between maternal antibiotic exposure before and during pregnancy, and risk of childhood hospitalization with infection. Methods:We used population-based Danish national databases for pregnancies between 1995 and 2009. Infants were followed from birth until their first infection-related hospitalization, death, 14th birthday, emigration or end-2009. Exposure was maternal antibiotics prescribed before and during pregnancy. Outcome was infection-related hospitalization. Results:141 359 (18%) mothers had at least one antibiotic prescription during pregnancy, 230 886 (29.4% of those with complete data) in the 18 months before pregnancy. Of 776 657 live-born singletons, 443 546 infection-related hospitalizations occurred in 222 524 (28.6%) children. Pregnancy antibiotic exposure was associated with increased risk of childhood infection-related hospitalization [hazard ratio (HR) 1.18, 95% confidence interval (CI) 1.17-1.19]. In mothers prescribed antibiotics only during pregnancy whose child did not receive pre-hospitalization antibiotics, this association was present only in those born vaginally. Higher risks of infection-related hospitalization occurred when pregnancy antibiotic prescriptions were closer to birth and in mothers receiving more pregnancy antibiotics. Children born to mothers exposed to antibiotics before (but not during) pregnancy also had increased risk of infection-related hospitalization (HR 1.10, 95% CI 1.07-1.12). Conclusions:Antibiotic exposure before or during pregnancy was associated with increased risk of childhood hospitalized infections. Alteration of the maternally derived microbiome and shared heritable and environmental determinants are possible contributory mechanisms.

BACKGROUND:Our microbial companions (the "microbiota") are extremely important for the preservation of human health. Although changes in bacterial communities (dysbiosis) are commonly associated with disease, such changes have also been described in healthy pregnancies, where the microbiome plays an essential role in maternal and child health outcomes, including normal immune and metabolic function in later life. Nevertheless, this new understanding of the importance of the microbiome has not yet influenced contemporary clinical practice regarding antibiotic use during pregnancy. DISCUSSION:Antibiotic treatment during pregnancy is widespread in Western countries, and accounts for 80 % of prescribed medications in pregnancy. However, antibiotic treatment, while at times lifesaving, can also have detrimental consequences. A single course of antibiotics perturbs bacterial communities, with evidence that the microbial ecosystem does not return completely to baseline following treatment. Antibiotics in pregnancy should be used only when indicated, choosing those with the narrowest range possible. Bacteria are essential for normal human development and, while antibiotic treatment during pregnancy has an important role in controlling and preventing infections, it may have undesired effects regarding the maternal and fetoplacental microbiomes. We expect that microbiota manipulation in pregnancy, through the use of probiotics and fecal microbiota transplantation, will be the subject of increasing clinical interest.

OBJECTIVE:To investigate whether maternal exposure to quinolones, fluoroquinolones and specifically ciprofloxacin is associated with major malformations and other adverse pregnancy outcomes. METHODS:MEDLINE/PubMed, Embase and Reprotox® databases were searched. Observational studies with an exposed and control group were included. RESULTS:Analysis of 8 cohort and 2 case-control studies showed no significant increases in rates of major malformations for quinolone (OR, 1.04; 95% CI 0.89-1.21), fluoroquinolone (RR, 0.89; 95% CI 0.70-1.14) and ciprofloxacin exposure (RR, 0.72; 95% CI 0.43-1.19). For fluoroquinolones, live birth rate was significantly decreased (RD, -0.04; 95% CI -0.08 to -0.01) whereas elective termination rate (RD, 0.04; 95% CI 0.02-0.05) was significantly increased. CONCLUSIONS:Quinolone, fluoroquinolone and ciprofloxacin exposure were not associated with a significant increase in major malformations and adverse pregnancy outcomes, other than significantly decreased live birth rate and increased elective termination rate which may be the indicators of misperceived teratogenic risk.

Antibiotic use during pregnancy is associated with increased asthma risk in children. Since approximately 25% of women use antibiotics during pregnancy, it is important to identify the pathways involved in this phenomenon. We investigate how mother-to-offspring transfer of antibiotic-induced gut microbial dysbiosis influences immune system development along the gut-lung axis. Using a mouse model of maternal antibiotic exposure during pregnancy, we immunophenotyped offspring in early life and after asthma induction. In early life, prenatal-antibiotic exposed offspring exhibited gut microbial dysbiosis, intestinal inflammation (increased fecal lipocalin-2 and IgA), and dysregulated intestinal ILC3 subtypes. Intestinal barrier dysfunction in the offspring was indicated by a FITC-dextran intestinal permeability assay and circulating lipopolysaccharide. This was accompanied by increased T-helper (Th)17 cell percentages in the offspring's blood and lungs in both early life and after allergy induction. Lung tissue additionally showed increased percentages of RORγt T-regulatory (Treg) cells at both time points. Our investigation of the gut-lung axis identifies early-life gut dysbiosis, intestinal inflammation, and barrier dysfunction as a possible developmental programming event promoting increased expression of RORγt in blood and lung CD4 T cells that may contribute to increased asthma risk.

Studies in mice suggest that early life represents a critical time window, where antibiotics may exert profound and lasting effects on the gut microbiota and metabolism. We aimed to test the hypothesis that prenatal antibiotic exposure is associated with increased risk of childhood overweight in a population-based cohort study. We linked 43,365 mother-child dyads from a nationwide cohort of pregnant women and their offspring to the Danish National Prescription Registry. Linear and logistic regression models were used to examine associations between prenatal exposure to antibiotics and BMI z-score and overweight (including obesity) at age seven and 11 years. Prenatal antibiotic exposure and childhood overweight were both associated with high pre-pregnancy BMI, maternal diabetes, multi-parity, smoking, low socioeconomic status, high paternal BMI, and short duration of breastfeeding. After adjustment for confounders, no associations were observed between prenatal antibiotic exposure and odds of overweight at age seven and 11 years. Whereas no association was observed between broad-spectrum antibiotics and overweight at age 11 years, exposure to broad-spectrum antibiotics was associated with higher odds of overweight at age seven years with an odds ratio of 1.27 (95% CI, 1.05-1.53) for ampicillin and an odds ratio of 1.56 (95% CI, 1.23-1.97) for amoxicillin. As we did not account for underlying infections, the observed associations with early childhood overweight could be explained by confounding by indication. In conclusion, our population-based study suggests that prenatal exposure to narrow-spectrum antibiotics is not associated with overweight in offspring. Exposure to some broad-spectrum antibiotics may increase the odds of overweight in early childhood, but the association does not persist in later childhood.

OBJECTIVE:The benefits of antibiotic treatment during pregnancy are immediate, but there may be long-term risks to the developing child. Prior studies show an association between early life antibiotics and obesity, but few have examined this risk during pregnancy. SUBJECTS:To evaluate the association of maternal antibiotic exposure during pregnancy on childhood BMI-z at 5 years, we conducted a retrospective cohort analysis. Using electronic health record data from seven health systems in PCORnet, a national distributed clinical research network, we included children with same-day height and weight measures who could be linked to mothers with vital measurements during pregnancy. The primary independent variable was maternal outpatient antibiotic prescriptions during pregnancy (any versus none). We examined dose response (number of antibiotic episodes), spectrum and class of antibiotics, and antibiotic episodes by trimester. The primary outcome was child age- and sex-specific BMI-z at age 5 years. RESULTS:The final sample was 53,320 mother-child pairs. During pregnancy, 29.9% of mothers received antibiotics. In adjusted models, maternal outpatient antibiotic prescriptions during pregnancy were not associated with child BMI-z at age 5 years (β = 0.00, 95% CI -0.03, 0.02). When evaluating timing during pregnancy, dose-response, spectrum and class of antibiotics, there were no associations of maternal antibiotics with child BMI-z at age 5 years. CONCLUSION:In this large observational cohort, provision of antibiotics during pregnancy was not associated with childhood BMI-z at 5 years.

BACKGROUND:Studies on potential maternal thyrotoxicity related to tetracycline antibiotics exposure during pregnancy are lacking. Based on a large prospective cohort study, this study aimed to examine the associations between tetracycline antibiotics exposure in maternal urine and maternal thyroid hormone parameters. METHODS:Based on the Ma'anshan Birth Cohort study, urine and serum samples of 2969 pregnant women were collected in the first, second and third trimesters. Tetracycline antibiotics, including oxytetracycline, chlorotetracycline, tetracycline and doxycycline in urine samples, as well as free thyroxine (FT4), thyroid stimulating hormone (TSH), total triiodothyronine (TT3) and total thyroxine (TT4) levels in serum samples, were measured. Linear mixed models and multivariate linear regression models were employed to examine associations between tetracycline antibiotics exposure during pregnancy and maternal thyroid hormone parameters. RESULTS:The detection rates of four individual tetracycline antibiotics and all antibiotics (sum of four individual tetracycline antibiotics) in the three trimesters were 5.0%-52.3%, and the 95th percentile concentration ranged from 0.11 to 4.84 ng/mL. After adjusting for potential confounding factors, the repeated measures analyses indicated that pregnant women exposed to doxycycline and all antibiotics during the entire pregnancy were negatively associated with serum FT4 and TT4 levels but positively associated with serum TSH and TT3 levels. Trimester-stratified analyses found that doxycycline and all antibiotics exposure during the first trimester were negatively associated with serum FT4 and TT4 levels, while doxycycline was positively associated with TSH levels. In the third trimester, a significant association was only found between all antibiotics and TSH levels. CONCLUSIONS:Our results suggest that exposure of pregnant women to tetracycline antibiotics is associated with maternal thyroid hormone parameters, and the first trimester might be the most critical window. More studies are needed to substantiate our findings and determine the underlying biological mechanisms.

OBJECTIVES:To assess the impact of gestational antibiotics on the risk of preterm birth, since a healthy maternal microbiome may be protective. METHODS:Population-based cohort study including all first pregnancies in Sweden (2006-16). The association between gestational and recent pre-conception systemic antibiotics and preterm birth was assessed by multivariable logistic regression presented as ORs and 95% CIs, adjusted for comorbidities (hypo- and hyperthyroidism, hypertension, or diabetes mellitus pre-gestation), trimester, antibiotic class and treatment duration. RESULTS:Compared with non-users, antibiotic exposure was associated with increased risks of preterm birth in mothers with comorbidities (OR = 1.32, 95% CI 1.18-1.48) and without (OR = 1.09, 95% CI 1.06-1.13). Pre-conception use showed no association, while risk was increased for first and second trimester use and decreased for third trimester use. The increased risks were seen for the following antibiotic groups in mothers without and with comorbidities, respectively: macrolides, lincosamides and streptogramins (OR = 1.63, 95% CI 1.45-1.83; OR = 2.48, 95% CI 1.72-3.56); quinolones (OR = 1.60, 95% CI 1.32-1.94; OR = 2.11, 95% CI 1.12-4.03); non-penicillin β-lactams (OR = 1.15, 95% CI 1.07-1.24; OR = 1.39, 95% CI 1.07-1.83); other antibacterials (OR = 1.09, 95% CI 1.03-1.14; 1.38, 95% CI 1.16-1.63); and penicillins (OR = 1.04, 95% CI 1.01-1.08; 1.23, 95% CI 1.09-1.40). Antibiotic indications were not available, which could also affect preterm birth. CONCLUSIONS:Antibiotic use during pregnancy was associated with an increased risk of preterm birth, especially in mothers with chronic diseases.

BACKGROUND:Increasing studies suggest that antibiotic exposure during pregnancy may increase the risk of childhood allergic diseases; however, controversy still exists. Thus, we conducted this meta-analysis to evaluate the association between antibiotic use during pregnancy and childhood asthma/wheeze, eczema/atopic dermatitis, and food allergy. METHODS:CENTRAL, EMBASE, and PubMed were searched for studies up to July 20, 2020. Cohort studies and case-control studies that estimated the association of antibiotic exposure in pregnancy with the risk of childhood asthma/wheeze, eczema/atopic dermatitis, and food allergy were included. A random-effects model or fixed-effects model was used to calculate the pooled estimates. The quality of the included studies was assessed by the Newcastle-Ottawa Scale (NOS). Stata12.0 software was used to analyze the association through a meta-analysis. RESULTS:A total of 26 studies were included in the meta-analysis. The results showed that maternal antibiotic exposure in pregnancy and the summary OR for the risk of childhood asthma/wheeze was 1.29 (95% CI = 1.16-1.43), the summary OR for eczema/atopic dermatitis was 1.62 (95% CI = 1.16-2.27), and the pooled OR for food allergy was 1.36 (95% CI = 0.94-1.96). CONCLUSIONS:Our results indicated that maternal antibiotic use during pregnancy might increase the risk of asthma/wheeze and eczema/atopic dermatitis but not food allergy in children. Further studies with larger sample size and robust multivariable adjustment are needed to confirm our findings. Nevertheless, the appropriate use of antibiotics during pregnancy is incredibly important, and healthcare professionals should be selective when prescribing antibiotics for pregnant women.

The use of antibiotics to prevent infections during the antepartum, intrapartum, and postpartum periods is different than the use of antibiotics to treat established infections. For many years, the use of prophylactic antibiotics was thought to have few adverse consequences. Concerns about the emergence of resistant strains of common bacteria, in addition to the emergence of strains with increased virulence, have resulted in increased scrutiny of the use of antibiotics, particularly in the hospital setting. Awareness of the potential adverse effects of resistant bacterial infections on neonates has been growing. Attention has been focused on the effect of mode of delivery or early antibiotic exposure on the neonatal oral and gut microbiome, which is essential for immune development. Finally, cost is a consideration in the use and choice of prophylactic agents. The purpose of this Practice Bulletin is to present a review of clinical situations in which prophylactic antibiotics are frequently prescribed and to weigh the evidence that supports the use of antibiotics in these scenarios. This Practice Bulletin is updated to reflect a limited change to clarify and provide additional information on recommendations from recent consensus guidelines for antimicrobial prophylaxis in surgery and the prevention of surgical site infection. The following practices related to cesarean delivery include preoperative skin and vaginal cleansing, weight-based dosage for cefazolin antibiotic prophylaxis, the addition of adjunctive azithromycin antibiotic prophylaxis, and antibiotic selection and dosage for women with a penicillin allergy.

OBJECTIVE:To evaluate the association between antibiotic use during pregnancy or early infancy and the risk of neurodevelopmental disorders in children. DESIGN:Nationwide population based cohort study and sibling analysis. SETTING:Korea's National Health Insurance Service mother-child linked database, 2008-21. PARTICIPANTS:All children live born between 2009 and 2020, followed up until 2021 to compare those with and without antibiotic exposure during pregnancy or early infancy (first six months of life). MAIN OUTCOMES MEASURES:Autism spectrum disorder, intellectual disorder, language disorder, and epilepsy in children. After 1:1 propensity score matching based on many potential confounders, hazard ratios with 95% confidence interval were estimated using Cox proportional hazard models. A sibling analysis additionally accounted for unmeasured familial factors. RESULTS:After propensity score matching, 1 961 744 children were identified for the pregnancy analysis and 1 609 774 children were identified for the early infancy analysis. Although antibiotic exposure during pregnancy was associated with increased risks of all four neurodevelopmental disorders in the overall cohort, these estimates were attenuated towards the null in the sibling analyses (hazard ratio for autism spectrum disorder 1.06, 95% confidence interval 1.01 to 1.12; intellectual disorder 1.00, 0.93 to 1.07; language disorder 1.05, 1.02 to 1.09; and epilepsy 1.03, 0.98 to 1.08). Likewise, no association was observed between antibiotic exposure during early infancy and autism spectrum disorder (hazard ratio 1.00, 0.96 to 1.03), intellectual disorder (1.07, 0.98 to 1.15), and language disorder (1.04, 1.00 to 1.08) in the sibling analyses; however, a small increased risk of epilepsy was observed (1.13, 1.09 to 1.18). The results generally remained consistent across several subgroup and sensitivity analyses, except for slightly elevated risks observed among children who used antibiotics during very early life and those who used antibiotics for more than 15 days. CONCLUSIONS:In this large cohort study, antibiotic exposure during pregnancy or early infancy was not associated with an increased risk of autism spectrum disorder, intellectual disorder, or language disorder in children. However, elevated risks were observed in several subgroups such as children using antibiotics during very early life and those with long term antibiotic use, which warrants attention and further investigation. Moreover, antibiotic use during infancy was modestly associated with epilepsy, even after control for indications and familial factors. When prescribing antibiotics to pregnant women and infants, clinicians should carefully balance the benefits of use against potential risks.

PURPOSE:The prevalence of atopic diseases has increased in recent decades. A possible link between antibiotic use during pregnancy and childhood atopic disease has been proposed. The aim of this study is to explore the association of antibiotic exposure during pregnancy with childhood atopic diseases from a nationwide, population-based perspective. METHODS:This was a nationwide population-based cohort study. Taiwan's National Health Insurance Research Database was the main source of data. The pairing of mothers and children was achieved by linking the NHIRD with the Taiwan Maternal and Child Health Database. This study enrolled the first-time pregnancies from 2004 to 2010. Infants of multiple delivery, preterm delivery, and death before 5 years old were excluded. All participants were followed up at least for 5 years. Antenatal antibiotics prescribed to mothers during the pregnancy period were reviewed. Children with more than two outpatient visits, or one admission, with a main diagnosis of asthma, allergic rhinitis, or atopic dermatitis were regarded as having an atopic disease. RESULTS:A total of 900,584 children were enrolled in this study. The adjusted hazard ratios of antibiotic exposure during pregnancy to childhood atopic diseases were 1.12 for atopic dermatitis, 1.06 for asthma, and 1.08 for allergic rhinitis, all of which reached statistical significance. The trimester effect was not significant. There was a trend showing the higher the number of times a child was prenatally exposed to antibiotics, the higher the hazard ratio was for childhood atopic diseases. CONCLUSIONS:Prenatal antibiotic exposure might increase the risk of childhood atopic diseases in a dose-dependent manner.

During pregnancy, untreated sexually transmitted or urinary tract infections are associated with significant morbidity, including low birth weight, preterm birth, and spontaneous abortion. Approximately one in four women will be prescribed an antibiotic during pregnancy, accounting for nearly 80% of prescription medications in pregnant women. Antibiotic exposures during pregnancy have been associated with both short-term (e.g., congenital abnormalities) and long-term effects (e.g., changes in gut microbiome, asthma, atopic dermatitis) in the newborn. However, it is estimated that only 10% of medications have sufficient data related to safe and effective use in pregnancy. Antibiotics such as beta-lactams, vancomycin, nitrofurantoin, metronidazole, clindamycin, and fosfomycin are generally considered safe and effective in pregnancy. Fluoroquinolones and tetracyclines are generally avoided in pregnancy. Physiologic changes in pregnancy lead to an increase in glomerular filtration rate, increase in total body volume, and enhanced cardiac output. These changes may lead to pharmacokinetic alterations in antibiotics that require dose adjustment or careful monitoring and assessment.

BACKGROUND:Urinary tract infections (UTIs) are the most common infection among pregnant women and have been associated with maternal and foetal complications. Antimicrobial exposure during pregnancy is not without risk. International guidelines recommend a single screen-and-treat approach to asymptomatic bacteriuria (ASB); however, this approach has been questioned by recent studies. OBJECTIVES:The aim of this narrative review was to assess the pathophysiology, current risk factors and management of UTI during pregnancy, its impact on pregnancy outcomes, and to develop recommendations on the best use of antimicrobials. SOURCES:PubMed, Cochrane database, and ClinicalTrials.gov. CONTENT:Owing to the physiological changes related to pregnancy, pregnant women are at higher risk of UTI. All types of UTIs combined have been estimated to affect approximately 2% to 15% of women. ASB affects 2% to 7% of pregnant women. Recent studies do not provide good-quality evidence for an association between ASB and acute pyelonephritis if ASB is untreated. There is low-to-moderate-quality evidence that treatment of ASB results in a reduction in the incidence of low birth weight and preterm birth, which justifies screening practices for ASB with only a single urine culture in the first trimester. If the clinician opts for treatment, a short course of β-lactams, nitrofurantoin, or fosfomycin should be favoured. Studies on cystitis during pregnancy are limited. Acute pyelonephritis has been shown to be associated with increased maternal complications and in some studies has also been associated with preterm delivery and low birth weight. Preferred antimicrobials for the management of pyelonephritis are amoxicillin combined with an aminoglycoside, third-generation cephalosporins, or carbapenems. Studies on recurrent UTIs during pregnancy are limited, making it difficult to draw conclusions regarding prophylactic measures. IMPLICATIONS:Further research is required to understand the true incidence of ASB-related complications and the benefit and modalities of screening for ASB and to further explore prophylactic measures.

OBJECTIVE:To compare maternal vascular indices and hemodynamic parameters at 35-37 weeks' gestation in pregnancies complicated by delivery of a small-for-gestational-age (SGA) or growth-restricted (FGR) neonate. METHODS:This was a prospective observational study of women with a singleton pregnancy attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation. The visit included recording of maternal demographic characteristics, medical history, vascular indices and hemodynamic parameters, which were obtained using a non-invasive operator-independent device and included pulse-wave velocity, augmentation index, cardiac output, stroke volume, central systolic and diastolic blood pressure, total peripheral resistance and heart rate. Women with hypertensive disorders of pregnancy were excluded. SGA was diagnosed if birth weight was < 10 percentile. FGR was diagnosed if, in addition to birth weight < 10 percentile, at the 35-37-week scan, uterine artery or umbilical artery pulsatility index (PI) was > 95 percentile or fetal middle cerebral artery PI was < 5 percentile. RESULTS:Among the 6413 women included in the study, there were 605 (9.4%) cases of SGA, 133 (2.1%) cases of FGR and 5675 (88.5%) cases that were unaffected by SGA or FGR. Women with SGA or FGR, compared to unaffected pregnancies, had increased peripheral vascular resistance and reduced cardiac output. Central systolic and diastolic blood pressure were increased in the FGR group compared with the unaffected group. Aortic stiffness, as assessed by pulse-wave velocity, and augmentation index did not differ between affected and unaffected pregnancies. In the FGR group, compared with the SGA group, central systolic and diastolic blood pressure were higher, whereas heart rate was lower. CONCLUSIONS:SGA and FGR pregnancies exhibit deranged maternal hemodynamic responses compared with unaffected pregnancies. Pregnancies with FGR have higher central blood pressure compared to those with SGA, but it remains unclear whether these differences are driven by the size of the fetus or pathological fetal growth. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

OBJECTIVES:Fetuses with late-onset growth restriction (FGR) have a higher risk of suboptimal neurocognitive performance after birth. Previous studies have reported that impaired brain and cortical development can start in utero. The primary aim of this study was to report midline structure growth and cortical development in fetuses with late-onset FGR according to its severity; the secondary aim was to elucidate whether the severity of FGR, as defined by the presence of abnormal Doppler findings, plays a role in affecting brain growth and maturation. METHODS:This was a prospective observational study that included fetuses with late-onset FGR (defined according to the Delphi FGR criteria) undergoing neurosonography between 32 and 34 weeks' gestation. Midline structure (corpus callosum (CC) and cerebellar vermis (CV)) length and cortical development, including the depth of the Sylvian (SF), parieto-occipital (POF) and calcarine (CF) fissures, were compared between late-onset FGR, small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) fetuses. Subgroup analysis according to the severity of FGR (normal vs abnormal fetal Doppler) was also performed. Univariate analysis was used to analyze the data. RESULTS:A total of 52 late-onset FGR fetuses with normal Doppler findings, 60 late-onset FGR fetuses with abnormal Doppler findings, 64 SGA fetuses and 100 AGA fetuses were included in the analysis. When comparing AGA controls with SGA fetuses, late-onset FGR fetuses with normal Doppler findings and late-onset FGR fetuses with abnormal Doppler findings, there was a progressive and significant reduction in the absolute values of the following parameters: CC length (median (interquartile range (IQR)), 43.5 (28.9-56.1) mm vs 41.9 (27.8-51.8) mm vs 38.5 (29.1-50.5) mm vs 31.7 (23.8-40.2) mm; K = 26.68; P < 0.0001), SF depth (median (IQR), 14.5 (10.7-16.8) mm vs 12.7 (9.8-15.1) mm vs 11.9 (9.1-13.4) mm vs 8.3 (6.7-10.3) mm; K = 75.82; P < 0.0001), POF depth (median (IQR), 8.6 (6.3-11.1) mm vs 8.1 (5.6-10.4) mm vs 7.8 (6.1-9.3) mm vs 6.6 (4.2-8.0) mm; K = 45.06; P < 0.0001) and CF depth (median (IQR), 9.3 (6.7-11.5) mm vs 8.2 (5.7-10.7) mm vs 7.7 (5.2-9.4) mm vs 6.3 (4.5-7.2) mm; K = 46.14; P < 0.0001). Absolute CV length was significantly higher in AGA fetuses compared with all other groups, although the same progressive pattern was not noted (median (IQR), 24.9 (17.6-29.2) mm vs 21.6 (15.2-26.1) mm vs 19.1 (13.8-25.9) mm vs 21.0 (13.5-25.8) mm; K = 16.72; P = 0.0008). When the neurosonographic variables were corrected for fetal head circumference, a significant difference in the CC length and SF, POF and CF depths, but not CV length, was observed only in late-onset FGR fetuses with abnormal Doppler findings when compared with AGA and SGA fetuses. CONCLUSIONS:Fetuses with late-onset FGR had shorter CC length and delayed cortical development when compared with AGA fetuses. After controlling for fetal head circumference, these differences remained significant only in late-onset FGR fetuses with abnormal Doppler. These findings support the existence of a link between brain development and impaired placental function. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

BACKGROUND:The ORACLE II trial compared the use of erythromycin and/or amoxicillin-clavulanate (co-amoxiclav) with that of placebo for women in spontaneous preterm labour and intact membranes, without overt signs of clinical infection, by use of a factorial randomised design. The aim of the present study--the ORACLE Children Study II--was to determine the long-term effects on children after exposure to antibiotics in this clinical situation. METHODS:We assessed children at age 7 years born to the 4221 women who had completed the ORACLE II study and who were eligible for follow-up with a structured parental questionnaire to assess the child's health status. Functional impairment was defined as the presence of any level of functional impairment (severe, moderate, or mild) derived from the mark III Multi-Attribute Health Status classification system. Educational outcomes were assessed with national curriculum test results for children resident in England. FINDINGS:Outcome was determined for 3196 (71%) eligible children. Overall, a greater proportion of children whose mothers had been prescribed erythromycin, with or without co-amoxiclav, had any functional impairment than did those whose mothers had received no erythromycin (658 [42.3%] of 1554 children vs 574 [38.3%] of 1498; odds ratio 1.18, 95% CI 1.02-1.37). Co-amoxiclav (with or without erythromycin) had no effect on the proportion of children with any functional impairment, compared with receipt of no co-amoxiclav (624 [40.7%] of 1523 vs 608 [40.0%] of 1520; 1.03, 0.89-1.19). No effects were seen with either antibiotic on the number of deaths, other medical conditions, behavioural patterns, or educational attainment. However, more children whose mothers had received erythromycin or co-amoxiclav developed cerebral palsy than did those born to mothers who received no erythromycin or no co-amoxiclav, respectively (erythromycin: 53 [3.3%] of 1611 vs 27 [1.7%] of 1562, 1.93, 1.21-3.09; co-amoxiclav: 50 [3.2%] of 1587 vs 30 [1.9%] of 1586, 1.69, 1.07-2.67). The number needed to harm with erythromycin was 64 (95% CI 37-209) and with co-amoxiclav 79 (42-591). INTERPRETATION:The prescription of erythromycin for women in spontaneous preterm labour with intact membranes was associated with an increase in functional impairment among their children at 7 years of age. The risk of cerebral palsy was increased by either antibiotic, although the overall risk of this condition was low. FUNDING:UK Medical Research Council.

Although modern clinical practices such as cesarean sections and perinatal antibiotics have improved infant survival, treatment with broad-spectrum antibiotics alters intestinal microbiota and causes dysbiosis. Infants exposed to perinatal antibiotics have an increased likelihood of life-threatening infections, including pneumonia. Here, we investigated how the gut microbiota sculpt pulmonary immune responses, promoting recovery and resolution of infection in newborn rhesus macaques. Early-life antibiotic exposure interrupted the maturation of intestinal commensal bacteria and disrupted the developmental trajectory of the pulmonary immune system, as assessed by single-cell proteomic and transcriptomic analyses. Early-life antibiotic exposure rendered newborn macaques more susceptible to bacterial pneumonia, concurrent with increases in neutrophil senescence and hyperinflammation, broad inflammatory cytokine signaling, and macrophage dysfunction. This pathogenic reprogramming of pulmonary immunity was further reflected by a hyperinflammatory signature in all pulmonary immune cell subsets coupled with a global loss of tissue-protective, homeostatic pathways in the lungs of dysbiotic newborns. Fecal microbiota transfer was associated with partial correction of the broad immune maladaptations and protection against severe pneumonia. These data demonstrate the importance of intestinal microbiota in programming pulmonary immunity and support the idea that gut microbiota promote the balance between pathways driving tissue repair and inflammatory responses associated with clinical recovery from infection in infants. Our results highlight a potential role for microbial transfer for immune support in these at-risk infants.

Antibody-mediated responses play a critical role in vaccine-mediated immunity. However, for reasons that are poorly understood, these responses are highly variable between individuals. Using a mouse model, we report that antibiotic-driven intestinal dysbiosis, specifically in early life, leads to significantly impaired antibody responses to five different adjuvanted and live vaccines. Restoration of the commensal microbiota following antibiotic exposure rescues these impaired responses. In contrast, antibiotic-treated adult mice do not exhibit impaired antibody responses to vaccination. Interestingly, in contrast to impaired antibody responses, immunized mice exposed to early-life antibiotics display significantly enhanced T cell cytokine recall responses upon ex vivo restimulation with the vaccine antigen. Our results demonstrate that, in mice, antibiotic-driven dysregulation of the gut microbiota in early life can modulate immune responses to vaccines that are routinely administered to infants worldwide.

OBJECTIVE:Earlier studies on antibiotics exposure and development of IBD (Crohn's disease (CD) and ulcerative colitis (UC)) may have been biased by familial factors and gastroenteritis. We aimed to estimate the association between antibiotics during pregnancy or infantile age and very early onset (VEO) IBD. DESIGN:In this cohort study of 827 239 children born in Sweden between 2006 and 2013, we examined the link between exposure to systemic antibiotics and VEO-IBD (diagnosis <6 years of age), using Cox proportional hazard regression models. Information on antibiotics and IBD was retrieved from the nationwide population-based Swedish Prescribed Drug Register and the National Patient Register. We specifically examined potential confounding from parental IBD and gastroenteritis. RESULTS:Children exposed to antibiotics during pregnancy were at increased risk of IBD compared with general population controls (adjusted HR (aHR) 1.93; 95% CI 1.06 to 3.50). Corresponding aHRs were 2.48 (95% CI 1.01 to 6.08) for CD and 1.25 (95% CI 0.47 to 3.26) for UC, respectively. For antibiotics in infantile age, the aHR for IBD was 1.11 (95% CI 0.57 to 2.15); for CD 0.72 (95% CI 0.27 to 1.92) and 1.23 (95% CI 0.45 to 3.39) for UC. Excluding children with gastroenteritis 12 months prior to the first IBD diagnosis retained similar aHR for antibiotics during pregnancy and CD, while the association no longer remained significant for IBD. CONCLUSION:We found that exposure to antibiotics during pregnancy, but not in infantile age, is associated with an increased risk of VEO-IBD regardless of gastroenteritis. The risk increase for exposure in pregnancy may be due to changes in the microbiota.

Perinatal exposure to penicillin may result in long-lasting gut and behavioral changes.

The gut microbiota operates at the interface of host-environment interactions to influence human homoeostasis and metabolic networks. Environmental factors that unbalance gut microbial ecosystems can therefore shape physiological and disease-associated responses across somatic tissues. However, the systemic impact of the gut microbiome on the germline-and consequently on the F offspring it gives rise to-is unexplored. Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory 'gut-germline axis' in males, which is sensitive to environmental exposures and programmes offspring fitness through impacting placenta function.