A Cohort Study On Association Of β-diketone Antibiotic Exposure During Pregnancy And Overweight Or Obesity In Infants At 18 Months Of Age

ObjectiveTo describe the exposure level of β-diketone antibiotics across different pregnancy in Ma’anshan city,and explore the relationship between β-diketone antibiotic exposure during pregnancy and overweight or obesity,and gender differences in infants at 18 months of age.MethodsBased on the Ma’anshan Birth Cohort(MABC),the cohort recruited 3 474 pregnant women(all aged over 18 years and gestational age less than 14 weeks)who underwent the first birth examination from May 2013 to September 2014.Self-made questionnaires were used by uniformly trained investigators to conduct surveys and follow-ups and collect general demographic information of the mothers in the first trimester(mean 10weeks),the second trimester(mean 26 weeks)and the third trimester(mean 34 weeks).Birth information related to single live births was collected at the time of delivery.Questionnaire follow-up and physical measurements were performed at 42 days,3months,6 months,9 months,12 months,and 18 months of age.Urine samples from pregnant women were collected in the morning,and a total of 41 antibiotics and 2metabolites were screened in urine samples through Shimadzu LC system coupled to a triple quadrupole mass spectrometer API 5500.In the study,tetracyclines and fluoroquinolones were selected for data analysis because of their higher detection rates and mainly from animal food.Among the 3 474 pregnant women,participants who presented with absence of unhealthy fetuses and multiple births(n = 201),missed children’s BMI(body mass index)data at 18 months(n = 585)and missed urine samples(n = 69)were excluded from the study,2 613 subjects were included ultimately.Among them,2 458 pregnant women were included in the first trimester,2 514 pregnant women were included in the second trimester,and 2 436 pregnant women were included in the third trimester.Statistically the detection frequency and concentration of urinary antibiotics were described.The intraclass correlation coefficient(ICC)and its confidence interval(95%CI)were used to evaluate the time difference of antibiotic exposure risk during three trimesters.Spearman’s rank correlation coefficient(SCC)was employed to evaluate the pairwise correlation between antibiotic concentrations adjusted by urinary creatinine.The liner mixed model(LMM)was used to examine the associations of repeated measures of BMI z-score from birth to 18months(42 days,3 months,6 months,9 months,12 months and 18months)with prenatal antibiotic exposure.Then,generalized evaluation equation model(GEE)was constructed to estimate trimester-specific urinary antibiotic concentrations in relation to early-childhood BMI z-score at 18 months.We used binary logistic regression to assess the relationship between prenatal antibiotic exposure and overweight or obesity in infants at 18 months of age.Restricted cubic spline(RCS)was performed to simulate the association between antibiotic concentrations and overweight or obesity in infants.ResultsThe total detection frequency of antibiotics in 2 613 pregnant women during pregnancy reached up to 93.4%.From the first trimester to third trimester,the detection frequency of tetracyclines ranged from 43.6% to 54.4%,and the detection frequency of fluoroquinolones ranged from 61.2% to 71.2%.The detection rate of β-diketone antibiotics synthesized by tetracyclines and fluoroquinolones was from 76.0% to 85.1%.The detection rate of oxytetracycline,tetracycline,doxycycline,ofloxacin,enrofloxacin and ciprofloxacin in each trimester were more than 10%.In addition,the maximum concentration of fluoroquinolones during the whole pregnancy exceeds 1 000 ng/m L,much higher than other antibiotics.In the study,the prevalence of overweight or obesity among infants at 18 months of age was 20.6%.After adjusting for all confounding factors,exposure to higher concentrations of doxycycline(OR = 2.44,95% CI = 1.03,5.57)and tetracyclines(OR =2.39,95% CI = 1.08,5.30)in the first trimester might be risk factors for overweight or obesity in infants,however,the higher concentrations of ciprofloxacin exposure(OR =0.38,95% CI = 0.15,0.97)was associated with overweight or obesity restriction.Exposure to the higher concentrations of ciprofloxacin in the second trimester was 2.83times(95%CI = 2.20,6.65)more likely to lead to overweight or obesity than the nonexposed group.Pregnant women exposed to higher concentrations of enrofloxacin(OR =0.13,95% CI = 0.02,0.65)and ciprofloxacin(OR = 0.35,95% CI = 0.12,0.98)in the third trimester were associated with overweight or obesity in infants at 18 months of age(P < 0.05).In males,tetracycline(OR = 1.78,95% CI = 1.10,2.88)in the lower concentration group and tetracyclines(OR = 1.57,95% CI = 1.08,2.27)in the higher concentration group in the first trimester showed statistically significantly increased risks of overweight and obesity.However,ciprofloxacin(OR = 0.59,95% CI = 0.38,0.91)and fluoroquinolones(OR = 0.66,95% CI = 0.44,0.97)in the higher concentration group were negatively correlated with overweight or obesity in infants.Exposure to ciprofloxacin(OR = 0.32,95% CI = 0.14,0.70)and enrofloxacin(OR = 0.55,95% CI =0.34,0.89)in the third trimester were statistically associated with overweight or obesity restriction in infants.In females,tetracyclines at lower concentrations(OR = 1.66,95%CI =1.21,2.28)and β-diketone Antibiotics(OR = 1.56,95% CI =1.01,2.39,OR = 1.54,95% CI =1.01,2.36,respectively)at lower concentrations and higher concentrations were associated with increased risks of overweight or obesity in infants.ConclusionThe majority of pregnant women continued to be exposed to lower doses of β-diketone antibiotics throughout the whole pregnancy,and nearly half were exposed to two or more single β-diketone antibiotics in a single pregnancy.Through the analysis of the relationship between antibiotic exposure and overweight and obesity,we found that tetracycline,oxytetracycline,tetracyclines and β-diketone Antibiotics could increase the risk of overweight or obesity,while enrofloxacin and ciprofloxacin were protective factors.Moreover,there were significant gender differences in the association between antibiotic exposure and overweight or obesity in infants.Tetracycline and tetracyclines may increase the risk of overweight or obesity in males,whereas enrofloxacin and ciprofloxacin were protective factors for overweight or obesity.In addition,tetracyclines and β-diketone antibiotics may increase the risk of overweight or obesity in females.