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Effect of Prenatal Antibiotic Exposure on Neonatal Outcomes of Preterm Infants

  • Kim, Hyunjoo (Department of Pediatrics, Korea University Anam Hospital, Korea University College of Medicine) ;
  • Choe, Young June (Department of Pediatrics, Korea University Anam Hospital, Korea University College of Medicine) ;
  • Cho, Hannah (Department of Pediatrics, Korea University Anam Hospital, Korea University College of Medicine) ;
  • Heo, Ju Sun (Department of Pediatrics, Korea University Anam Hospital, Korea University College of Medicine)
  • Received : 2021.10.04
  • Accepted : 2022.01.16
  • Published : 2021.12.25

Abstract

Purpose: Antibiotic exposure during pregnancy may affect the fetus and newborn in many ways. This study investigated the impact of prenatal antibiotic exposure duration on neonatal outcomes in very preterm (VP) or very low birth weight (VLBW) infants. Methods: From September 2015 to December 2020, preterm infants with gestational age less than 32 weeks or with a BW less than 1,500 g who were admitted to the neonatal intensive care unit, and their mothers were enrolled. Prenatal antibiotic exposure was defined as antibiotics received by mothers before delivery, and the patients were categorized into the non-antibiotic group, short-duration (SD; ≤7 days) group, or long-duration (LD; >7 days) groups. Results: A total of 93 of 145 infants were exposed to prenatal antibiotics, among which 35 (37.6%) were in the SD group and 58 (62.4%) were in the LD group. Infants in the LD group had a significantly higher birth weight-for-gestational-age (BW/GA) Z-score than those in the non-antibiotic group, even after the adjustment for confounding factors (beta, 0.258; standard error, 0.149; P<0.001). Multivariate logistic regression analysis showed that prolonged prenatal antibiotic exposure was independently associated with death (adjusted odds ratio [aOR], 8.926; 95% confidence interval [CI], 1.482-53.775) and composite outcomes of death, necrotizing enterocolitis (NEC), and late-onset sepsis (LOS) (aOR, 2.375; 95% CI, 1.027-5.492). Conclusions: Prolonged prenatal antibiotic exposure could increase the BW/GA Z-score and the risk of death and composite outcomes of death, NEC, and LOS in VP or VLBW infants.

목적: 산모의 산전 항생제 사용은 여러가지 면에서 태아 및 신생아에 영향을 미칠 수 있다. 본 연구에서는 극소 미숙아 또는 극소 저체중출생아에서 산모의 산전 항생제 투여 기간이 신생아 예후에 미치는 영향에 대해 조사하였다. 방법: 2015년 9월부터 2020년 12월까지 고려대학교 안암병원에서 출생한 재태주수 32주 미만 또는 출생 체중 1,500 gram 미만인 신생아 및 산모를 대상으로 의무기록을 후향적으로 분석하였다. 산모의 산전 항생제 투여 기간에 따라 미투여 군, 7일 이하 군, 7일 초과 군의 세 군으로 나누어 산모의 특성, 환아의 특성 및 합병증 등을 비교 분석하였다. 결과: 총 145명 중 93명의 환아가 산전 항생제에 노출되었으며, 그 중 35명(37.6%)는 7일 이하 군, 58명(62.4%)는 7일 초과 군이었다. 7일 초과 군은 미투여 군에 비해 재태 연령에 따른 출생체중의 Z-score가 교란변수 보정 후에도 유의미하게 높았다(beta, 0.258; standard error, 0.149; P<0.001). 다변량 로지스틱 회귀 분석에서 7일 초과 군은 사망(adjusted odds ratio [aOR], 8.926; 95% confidence interval [CI], 1.482-53.775), 그리고 사망, 괴사성 장염, 후기 패혈증의 복합 평가 결과와 연관이 있었다(aOR, 2.375; 95% CI, 1.027-5.492). 결론: 산모의 장기간 산전 항생제 투여는, 극소 미숙아 또는 극소 저체중출생아에서 재태 연령에 따른 출생체중의 Z score을 증가시키며, 사망 뿐 아니라 사망, 괴사성 장염, 후기 패혈증의 복합 평가 결과의 위험도를 증가시킬 수 있다.

Keywords

References

  1. Bookstaver PB, Bland CM, Griffin B, Stover KR, Eiland LS, McLaughlin M. A review of antibiotic use in pregnancy. Pharmacotherapy 2015;35:1052-62. https://doi.org/10.1002/phar.1649
  2. Broe A, Pottegard A, Lamont RF, Jorgensen JS, Damkier P. Increasing use of antibiotics in pregnancy during the period 2000-2010: prevalence, timing, category, and demographics. BJOG 2014;121:988-96. https://doi.org/10.1111/1471-0528.12806
  3. Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin No. 199: use of prophylactic antibiotics in labor and delivery. Obstet Gynecol 2018;132:e103-19. https://doi.org/10.1097/AOG.0000000000002833
  4. World Health Organization. WHO recommendations for prevention and treatment of maternal peripartum infections. Geneva: World Health Organization; 2015.
  5. Prelabor rupture of membranes: ACOG practice bulletin, number 217. Obstet Gynecol 2020;135:e80-97. https://doi.org/10.1097/aog.0000000000003700
  6. Bizzarro MJ, Dembry LM, Baltimore RS, Gallagher PG. Changing patterns in neonatal Escherichia coli sepsis and ampicillin resistance in the era of intrapartum antibiotic prophylaxis. Pediatrics 2008;121:689-96. https://doi.org/10.1542/peds.2007-2171
  7. Didier C, Streicher MP, Chognot D, Campagni R, Schnebelen A, Messer J, et al. Late-onset neonatal infections: incidences and pathogens in the era of antenatal antibiotics. Eur J Pediatr 2012;171:681-7. https://doi.org/10.1007/s00431-011-1639-7
  8. Weintraub AS, Ferrara L, Deluca L, Moshier E, Green RS, Oakman E, et al. Antenatal antibiotic exposure in preterm infants with necrotizing enterocolitis. J Perinatol 2012;32:705-9. https://doi.org/10.1038/jp.2011.180
  9. Mercer BM, Miodovnik M, Thurnau GR, Goldenberg RL, Das AF, Ramsey RD, et al. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes. A randomized controlled trial. JAMA 1997;278:989-95. https://doi.org/10.1001/jama.1997.03550120049032
  10. Reed BD, Schibler KR, Deshmukh H, Ambalavanan N, Morrow AL. The impact of maternal antibiotics on neonatal disease. J Pediatr 2018;197:97-103.e3. https://doi.org/10.1016/j.jpeds.2018.01.056
  11. Fenton TR, Kim JH. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr 2013;13:59. https://doi.org/10.1186/1471-2431-13-59
  12. Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986;33:179-201. https://doi.org/10.1016/s0031-3955(16)34975-6
  13. Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005;116:1353-60. https://doi.org/10.1542/peds.2005-0249
  14. Bizzarro MJ, Raskind C, Baltimore RS, Gallagher PG. Seventy-five years of neonatal sepsis at Yale: 1928-2003. Pediatrics 2005;116:595-602. https://doi.org/10.1542/peds.2005-0552
  15. Chiang MF, Quinn GE, Fielder AR, Ostmo SR, Chan RVP, Berrocal A, et al. International classification of retinopathy of prematurity, third edition. Ophthalmology 2021;128:e51-68. https://doi.org/10.1016/j.ophtha.2021.05.031
  16. de Jonge L, Bos HJ, van Langen IM, de Jong-van den Berg LT, Bakker MK. Antibiotics prescribed before, during and after pregnancy in the Netherlands: a drug utilization study. Pharmacoepidemiol Drug Saf 2014;23:60-8. https://doi.org/10.1002/pds.3492
  17. Kim SY, Kwon HS, Lee J, Sul AR, Ko HS, Yang JI. Questionnaire survey on the management of pregnant women with preterm premature rupture of membranes. Obstet Gynecol Sci 2020;63:286-92. https://doi.org/10.5468/ogs.2020.63.3.286
  18. Kenyon SL, Taylor DJ, Tarnow-Mordi W; ORACLE Collaborative Group. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. Lancet 2001;357:979-88. https://doi.org/10.1016/S0140-6736(00)04233-1
  19. Lee J, Romero R, Kim SM, Chaemsaithong P, Yoon BH. A new antibiotic regimen treats and prevents intra-amniotic inflammation/infection in patients with preterm PROM. J Matern Fetal Neonatal Med 2016;29:2727-37.
  20. Oh KJ, Lee KA, Sohn YK, Park CW, Hong JS, Romero R, et al. Intraamniotic infection with genital mycoplasmas exhibits a more intense inflammatory response than intraamniotic infection with other microorganisms in patients with preterm premature rupture of membranes. Am J Obstet Gynecol 2010;203:211.e1-8. https://doi.org/10.1016/j.ajog.2010.03.035
  21. Redelinghuys MJ, Ehlers MM, Dreyer AW, Lombaard HA, Kock MM. Antimicrobial susceptibility patterns of Ureaplasma species and Mycoplasma hominis in pregnant women. BMC Infect Dis 2014;14:171. https://doi.org/10.1186/1471-2334-14-171
  22. Park HS, Ahn BJ, Jun JK. Placental transfer of clarithromycin in human pregnancies with preterm premature rupture of membranes. J Perinat Med 2012;40:641-6.
  23. Aghaali M, Hashemi-Nazari SS. Association between early antibiotic exposure and risk of childhood weight gain and obesity: a systematic review and meta-analysis. J Pediatr Endocrinol Metab 2019;32:439-45. https://doi.org/10.1515/jpem-2018-0437
  24. Mueller NT, Rifas-Shiman SL, Blaser MJ, Gillman MW, Hivert MF. Association of prenatal antibiotics with foetal size and cord blood leptin and adiponectin. Pediatr Obes 2017;12:129-36. https://doi.org/10.1111/ijpo.12119
  25. Zhang M, Differding MK, Benjamin-Neelon SE, Ostbye T, Hoyo C, Mueller NT. Association of prenatal antibiotics with measures of infant adiposity and the gut microbiome. Ann Clin Microbiol Antimicrob 2019;18:18. https://doi.org/10.1186/s12941-019-0318-9
  26. Collado MC, Rautava S, Aakko J, Isolauri E, Salminen S. Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci Rep 2016;6:23129. https://doi.org/10.1038/srep23129
  27. Nogacka AM, Salazar N, Arboleya S, Suarez M, Fernandez N, Solis G, et al. Early microbiota, antibiotics and health. Cell Mol Life Sci 2018;75:83-91. https://doi.org/10.1007/s00018-017-2670-2
  28. Pacifici GM. Placental transfer of antibiotics administered to the mother: a review. Int J Clin Pharmacol Ther 2006;44:57-63. https://doi.org/10.5414/CPP44057
  29. Dai Z, Wu Z, Hang S, Zhu W, Wu G. Amino acid metabolism in intestinal bacteria and its potential implications for mammalian reproduction. Mol Hum Reprod 2015;21:389-409. https://doi.org/10.1093/molehr/gav003
  30. Mikkelsen KH, Allin KH, Knop FK. Effect of antibiotics on gut microbiota, glucose metabolism and body weight regulation: a review of the literature. Diabetes Obes Metab 2016;18:444-53. https://doi.org/10.1111/dom.12637
  31. Nogues P, Dos Santos E, Jammes H, Berveiller P, Arnould L, Vialard F, et al. Maternal obesity influences expression and DNA methylation of the adiponectin and leptin systems in human third-trimester placenta. Clin Epigenetics 2019;11:20. https://doi.org/10.1186/s13148-019-0612-6
  32. Josefson JL, Zeiss DM, Rademaker AW, Metzger BE. Maternal leptin predicts adiposity of the neonate. Horm Res Paediatr 2014;81:13-9. https://doi.org/10.1159/000355387
  33. Khan I, Azhar EI, Abbas AT, Kumosani T, Barbour EK, Raoult D, et al. Metagenomic analysis of antibiotic-induced changes in gut microbiota in a pregnant rat model. Front Pharmacol 2016;7:104. https://doi.org/10.3389/fphar.2016.00104
  34. Andrews RE, Coe KL. Clinical presentation and multifactorial pathogenesis of necrotizing enterocolitis in the preterm infant. Adv Neonatal Care 2021;21:349-55. https://doi.org/10.1097/ANC.0000000000000880
  35. Zeissig S, Blumberg RS. Life at the beginning: perturbation of the microbiota by antibiotics in early life and its role in health and disease. Nat Immunol 2014;15:307-10. https://doi.org/10.1038/ni.2847
  36. Deshmukh HS, Liu Y, Menkiti OR, Mei J, Dai N, O'Leary CE, et al. The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat Med 2014;20:524-30. https://doi.org/10.1038/nm.3542
  37. Romagano MP, Fofah O, Swaminarayan D, Williams S, Apuzzio JJ, Gittens-Williams L. Maternal antepartum antibiotic administration and patterns of bacterial resistance in early preterm neonates. J Matern Fetal Neonatal Med 2020;1-5.
  38. Patangia DV, Ryan CA, Dempsey E, Stanton C, Ross RP. Vertical transfer of antibiotics and antibiotic resistant strains across the mother/baby axis. Trends Microbiol 2022;30:47-56. https://doi.org/10.1016/j.tim.2021.05.006
  39. Hayes K, O'Halloran F, Cotter L. A review of antibiotic resistance in group B streptococcus: the story so far. Crit Rev Microbiol 2020;46:253-69. https://doi.org/10.1080/1040841X.2020.1758626
  40. Doenhardt M, Seipolt B, Mense L, Winkler JL, Thurmer A, Rudiger M, et al. Neonatal and young infant sepsis by group B streptococci and Escherichia coli: a single-center retrospective analysis in Germany-GBS screening implementation gaps and reduction in antibiotic resistance. Eur J Pediatr 2020;179:1769-77. https://doi.org/10.1007/s00431-020-03659-8