Antibiotic Therapy for Premature Rupture of Membranes and Preterm Labor and Effect on Fetal Outcome

Abstract

In Germany almost 10 % of children are born before the end of 37th week of gestation. In at least one quarter of these cases, ascending infection of the vagina plays a causative role, particularly during the early weeks of gestation. If, in addition to the decidua, the amniotic membrane, amniotic fluid and the umbilical cord are also affected, infection not only triggers uterine contractions and premature rupture of membranes but also initiates a systemic inflammatory reaction on the part of the fetus, which can increase neonatal morbidity. Numerous studies and meta-analyses have found that antibiotic therapy prolongs pregnancy and reduces neonatal morbidity. No general benefit of antibiotic treatment was found for premature uterine contractions. But it is conceivable that a subgroup of pregnant women would benefit from antibiotic treatment. It is important to identify this subgroup of women and offer them targeted treatment. This overview summarizes the current body of evidence on antibiotic treatment for impending preterm birth and the effect on neonatal outcomes.

Zusammenfassung

In Deutschland kommen fast 10 % aller Kinder vor Vollendung der 37. Schwangerschaftswoche zur Welt. In mindestens einem Viertel davon spielt eine aszendierende Infektion aus der Vagina eine kausale Rolle, insbesondere in einem niedrigen Gestationsalter. Sind neben der Dezidua die Eihäute, das Fruchtwasser und die Nabelschnur davon betroffen, werden durch entzündliche Prozesse nicht nur Wehen oder ein vorzeitiger Blasensprung ausgelöst, sondern auch eine systemische inflammatorische Reaktion des Fetus selbst in Gang gesetzt, welche die neonatale Morbidität negativ beeinflussen kann. Als Therapiemaßnahme bei vorzeitigem Blasensprung hat sich in zahlreichen Studien und Metaanalysen eine antibiotische Behandlung bewährt, indem die Schwangerschaft prolongiert und die neonatale Morbidität reduziert werden konnte. Bei vorzeitiger Wehentätigkeit hat sich dagegen ein Benefit generell nicht nachweisen lassen. Es ist aber anzunehmen, dass es eine Subgruppe von Schwangeren gibt, die dennoch davon profitieren könnte. Es gilt diese zu identifizieren und gezielt zu behandeln. Die vorliegende Übersicht umreißt die derzeitige Evidenzlage zur antibiotischen Behandlung bei drohender Frühgeburt und zum neonatalen Outcome.

Key words

premature rupture of membranes - impending preterm birth - premature uterine contractions - antibiosis for impending preterm birth

Schlüsselwörter

vorzeitiger Blasensprung - drohende Frühgeburt - vorzeitige Wehen - Antibiose bei drohender Frühgeburt

• References

• 1 Goldenberg RL, Culhane JF, Iams JD et al. Epidemiology and causes of preterm birth. Lancet 2008; 371: 75-84
• 2 AQUA-Institut für angewandte Qualitätsförderung und Forschung im Gesundheitswesen GmbH. 2011 (a), Gesetzliche Grundlagen § 137a SGB V zur „Umsetzung der Qualitätssicherung und Darstellung der Qualität“ im deutschen Gesundheitswesen. Online: http://www.sqg.de/hintergrund/gesetzliche-grundlagen/index.html
• 3 Muglia LJ, Katz M. The enigma of spontaneous preterm birth. N Engl J Med 2010; 362: 529-535
• 4 Mercer B. Antibiotics in the management of PROM and preterm labor. Obstet Gynecol Clin North Am 2012; 39: 65-76
• 5 Onderdonk AB, Hecht L, Thomas F et al. Colonization of second trimester placenta parenchyma. Am J Obstet Gynecol 2008; 199: 52.e1-52.e10
• 6 Tita AT, Anrews WW. Diagnosis and management of clinical chorioamnionitis. Clin Perinatol 2010; 37: 339-354
• 7 De Felice C, Toti P, Laurini RN et al. Early neonatal brain injury in histologic chorioamnionitis. J Pediatr 2001; 138: 101-104
• 8 De Felice C, Toti P, Parrini S et al. Histologic chorioamnionitis and severitiy of illess in very low birth weight newborns. Pedriatr Crit Care Med 2005; 6: 293-302
• 9 Mehta R, Nanjundaswamy S, Shen-Schwarz S et al. Neonatal morbidity and placental pathology. Indian J Pediatr 2006; 73: 25-28
• 10 Watterberg KL, Demers LM, Scott SM et al. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 1996; 97: 210-215
• 11 Graham EM, Holcroft CJ, Rai KK et al. Neonatal cerebral white matter injury in preterm infants is associated with culture positive infections and only rarely with metabolic acidosis. Am J Obstet Gynecol 2004; 191: 1305-1310
• 12 Dammann O, Leviton A, Bartels DB et al. Lung and brain damage in preterm newborns. Are they related? How? Why?. Biol Neonate 2004; 85: 305-313
• 13 Salafia CM, Minior VK, Rosenkrantz TS et al. Maternal, placental and neonatal associations with early germinal matrix/intraventricular hemorrhage in infants born before 32 weeksʼ gestation. Am J Perinatol 1995; 12: 429-436
• 14 Been JV, Rours IG, Kornelisse RF et al. Histologic chorioamnionitis, fetal involvement, and antenatal steroids: effects on neonatal outcome in preterm infants. Am J Obstet Gynecol 2009; 201: 587.e1-587.e8
• 15 Andrews WW, Goldenberg RL, Faye-Peterson O et al. The Alabama preterm birth study: polymorphonuclear and mononuclear cell placental infiltrations, other markers of inflammation and outcomes in 23–32 week preterm newborn infants. Am J Obstet Gynecol 2006; 195: 803-808
• 16 Dempsey E, Vhen MF, Kokottis T et al. Outcome of neonates less than 30 weeksʼ gestation with histologic chorioamnionitis. Am J Perinatol 2005; 22: 155-159
• 17 Baud O, Emilie D, Pelletier E et al. Amniotic fluid concentrations of interleukin-1beta, interleukin-6 and TNF-alpha in chorioamnionitis before 32 weeks of gestation: histological associations and neonatal outcome. Br J Obstet Gynaecol 1999; 106: 72-77
• 18 Dexter SC, Pinar H, Malee MP et al. Outcome of very low birth weight infants with histopathologic chorioamnionitis. Obstet Gynecol 2000; 96: 172-177
• 19 Tauscher MK, Berg D, Brockmann M et al. Association of histologic chorioamnionitis, increased levels of cord blood cytokines, and intracerebral hemorrhage in preterm neonates. Biol Neonate 2003; 83: 166-170
• 20 Kaukola T, Herva R, Perhomaa M et al. Population cohort associating chorioamnionitis, cord inflammatory cytokines and neurologic outcome in very preterm, extremely low birth weight infants. Pediatr Res 2006; 59: 478-483
• 21 Yoon BH, Jun JK, Romero R et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal white matter lesions, and cerebral palsy. Am J Obstet Gynecol 1997; 177: 19-26
• 22 Lee J, Oh KJ, Yang HJ et al. The importance of intraamniotic inflammation in the subsequent development of atypal chronic lung disease. J Matern Fetal Neonatal Med 2009; 22: 917-923
• 23 Shatrov JG, Birch SC, Lam LT et al. Chorioamnionitis and cerebral palsy. Obstet Gynecol 2010; 116: 387-392
• 24 Wu YW. Systematic review of choriamnionitis and cerebral palsy. Ment Retard Dev Disabil ResRev 2002; 8: 25-29
• 25 Leviton A, Allred EN, Kuban KC et al. Microbiologic and histologic characteristics of the extremely preterm infantʼs placenta predict white matter damage and later cerebral palsy: The ELGAN study. Pediatric Research 2010; 67: 95-101
• 26 Nasef N, Shabaan A, Schurr P et al. Effect of clinical and histological chorioamnionitis on the outcome of preterm infants. Am J Perinatology 2013; 30: 59-68
• 27 Romero R, Espinoza J, Goncalves LF et al. The role of inflammation and infection in preterm birth. Semin Reprod Med 2007; 25: 21-39
• 28 Gomez R, Romero R, Ghezzi F et al. The fetal inflammatory response syndrome. Am J Obstet Gynecol 1998; 179: 194-202
• 29 Been JV, Zimmermann LJ. Histologic chorioamnionitis and respiratory outcome in preterm infants. Arch Dis Child Fetal Neonatal Ed 2009; 94: F218-F225
• 30 Yoon BH, Romero R, Park JS et al. Fetal exposure to an intraamniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol 2000; 182: 675-681
• 31 Minagawa K, Tsuji Y, Ueda H et al. Possible correlation between high levels of IL-18 in the cord blood of preterm infants and neonatal development of periventricular leukomalacia and cerebral palsy. Cytokine 2002; 17: 164-170
• 32 Hansen-Pupp I, Halli AL, Hellstrom-Westas I et al. Inflammation at birth is associated with subnormal development in very preterm infants. Pediatr Res 2009; 64: 183-188
• 33 Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med 2000; 342: 1500-1507
• 34 Onderdonk AB, Delaney ML, DuBois AM et al. Detection of bacteria in placental tissues obtained from extremely low gestational age neonates. Am J Obstet Gynecol 2008; 198: 110.e1-110.e7
• 35 Romero R, Sirtori M, Oyarzun E et al. Infection and labor. V: Prevalence, microbiology, and clinical significance of intraamnonic infection in women with preterm labor and intact membranes. Am J Obstet Gynecol 1989; 161: 817-824
• 36 Romero R, Gonzales R, Sepulveda W et al. Infection and labor. VIII. Microbial invasion of the amniotic cavity in patients with suspected cervical incompetence: prevalence and clinical significance. Am J Obstet Gynecol 1992; 167: 1086-1091
• 37 Romero R, Yoon BH, Mazor M et al. A comparative study of the diagnostic performance of amniotic fluid glucose, white blood cell count, interleukin-6, and gram stain in the detection of microbial invasion in patients with preterm premature rupture of membranes. Am J Obstet Gynecol 1993; 169: 839-851
• 38 Yoon BH, Romero R, Park JS et al. Microbial invasion of the amniotic cavity with Ureaplasma urealyticum is associated with a robust host response in fetal, amniotic, and maternal compartments. Am J Obstet Gynecol 1998; 179: 1254-1260
• 39 Yoon BH, Chang JW, Romero R. Isolation of Ureaplasma urealyticum from the amniotic cavity and adverse outcome in preterm labor. Obstet Gynecol 1998; 92: 77-82
• 40 Lee SE, Romero R, Park CW et al. The frequency and significance of intraamniotic inflammation in patients with cervical insufficiency. Am J Obstet Gynecol 2008; 198: 633.e1-633.e8
• 41 Egawa T, Morioka I, Morisawa T et al. Ureaplasma urealyticum and Mycoplasma hominis presence in umbilical cord is associated with pathogenesis of funisitis. Kobe J Med Sci 2007; 53: 241-249
• 42 Oh KJ, Lee KA, Sohn YK 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.e1-211.e8
• 43 Goldenberg RL, Andrews WW, Goepfert AR et al. The Alabama Preterm Birth Study: umbilical cord blood Ureaplasma urealyticum and Mycoplasma hominis cultures in very preterm newborn infants. Am J Obstet Gynecol 2008; 198: 43.e1-43.e5
• 44 Choi SJ, Park SD, Jang IH et al. The prevalence of vaginal microorganisms in pregnant women with preterm labor and preterm birth. Ann Lab Med 2012; 32: 194-200
• 45 Capoccia R, Greub G, Baud D. Ureaplasma urealyticum, Mycoplasma hominis and adverse pregnancy outcomes. Curr Opin Infect Dis 2013; 26: 231-240
• 46 Eschenbach DA, Nugent RP, Rao AV et al. A randomized placebo-controlled trial of erythromycin for the treatment of Ureaplasma urealyticum to prevent premature delivery. The Vaginal Infections and Prematurity Study Group. Am J Obstet Gynecol 1991; 164: 734-742
• 47 Raynes Greenow CH, Roberts CL, Bell JC et al. Antibiotics for ureaplasma in the vagina in pregnancy. Cochrane Database Syt Rev 2011; (9) CD003767
• 48 Steel JH, Malatos S, Kennea N et al. Bacteria and inflammatory cells in fetal membranes do not always cause preterm labor. Pediatr Res 2005; 57: 404-411
• 49 Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture of membranes. Cochrane Database Syst Rev 2010; (8) CD001058
• 50 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: 979-988
• 51 Mercer B, Miodovnik M, Thurnau G et al. The NICHD-MFMU Network. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes: a randomized controlled trial. JAMA 1997; 278: 989-995
• 52 Lockwood CJ, Costigan K, Ghidini A et al. Double-blind placebo-controlled trial of piperacillin prophylaxis in preterm membrane rupture. Am J Obstet Gynecol 1993; 169: 970-976
• 53 Amon E, Lewis SV, Sibai BM et al. Ampicillin prophylaxis in preterm premature rupture of the membranes: a prospective randomized study. Am J Obstet Gynecol 1988; 159: 539-543
• 54 Christmas JT, Cox SM, Andrews W et al. Expectant management of preterm ruptured membranes: effects of antimicrobial therapy. Obstet Gynecol 1992; 80: 759-762
• 55 Fuhr N, Becker C, van Baalen A et al. Antibiotic therapy for preterm premature rupture of membranes: results of a multicenter study. J Perinat Med 2009; 34: 203-206
• 56 Johnson MM, Sanchez-Ramos L, Vaughn AJ et al. Antibiotic therapy in preterm premature rupture of the membranes: a randomized prospective double-blind study. Am J Obstet Gynecol 1990; 163: 743-747
• 57 Owen J, Groome LJ, Hauth JC. Randomized trial of prophylactic antibiotic therapy after preterm amnion rupture. Am J Obstet Gynecol 1993; 169: 976-981
• 58 Segel SY, Miles AM, Clothier B et al. Duration of antibiotic therapy after preterm premature rupture of fetal membranes. Am J Obstet Gynecol 2003; 189: 799-802
• 59 Lewis DF, Adair CD, Robichaux AG et al. Antibiotic therapy in preterm premature rupture of fetal membranes. Am J Obstet Gynecol 2003; 189: 799-802
• 60 Yudin MH, van Schalkwyk J, Van Eyck N et al. Antibiotic therapy in preterm premature rupture of membranes. J Obstet Gynaecol Can 2009; 31: 863-867
• 61 AWMF Leitlinie Nr. 015/029 Empfehlungen zum Vorgehen beim vorzeitigen Blasensprung.
• 62 McGregor IA, French JL, Reller LB et al. Adjunctive erythromycin treatment for idiopathic preterm labour: Results of a randomized, double blinded, placebo-controlled trial. Am J Obst Gynecol 1986; 154: 98-103
• 63 McGregor IA, French I, Seo K. Adjunctive clindamycin therapy for preterm labor: results of a double-blinded placebo-controlled trial. Am J Obstet Gynecol 1991; 165: 867-875
• 64 Morales WJ, Angel JL, OʼBrien WF et al. A randomized study of antibiotic therapy in idiopathic preterm labor. Obstet Gynecol 1988; 72: 829-833
• 65 Norman K, Pattinson RC, de Souza J et al. Ampicillin and metronidazole treatment in preterm labour: a multicentre, randomised controlled trial. Br J Obstet Gynecol 1994; 101: 404-408
• 66 Nadisaukiene R, Bergström S, Kilda A. Ampicillin in the treatment of preterm labor: a randomised, placebo-controlled study. Gynecol Obstet Invest 1996; 41: 89-92
• 67 Svare J, Langhoff-Roos J, Andersen LF et al. Ampicillin-metronidazole treatment in idiopathic preterm labour: a randomised controlled multicentre trial. Br J Obstet Gynaecol 1997; 104: 892-897
• 68 Oyarzún E, Gómez R, Rioseco A et al. Antibiotic treatment in preterm labor and intact membranes; a randomized, double-blinded, placebo-controlled trial. J Matern Fetal Med 1998; 7: 105-110
• 69 Newton ER, Dinsmoor MJ, Gibbs RS. A randomized, blinded, placebo-controlled trial of antibiotics in idiopathic preterm labor. Obstet Gynecol 1989; 74: 562-566
• 70 Romero R, Sibai B, Caritis S et al. Antibiotic treatment of preterm labour with intact membranes: a multicenter, randomized double blind, placebo-controlled trial. Am J Obstet Gynecol 1993; 169: 764-774
• 71 Watts DH, Krohn MA, Hillier SL et al. Randomized trial of antibiotics in addition to tocolytic therapy to treat preterm labor. Infect Dis Obstet Gynecol 1994; 1: 220-227
• 72 Gordon M, Samuels P, Shubert P et al. A randomized, prospective study of adjunctive ceftizoxime in preterm labour. Am J Obstet Gynecol 1995; 172: 1546-1552
• 73 Cox SM, Bohman Van R, Sherman ML et al. Randomized investigation of antimicrobials for the prevention of preterm birth. Am J Obstet Gynecol 1996; 174: 206-210
• 74 Kenyon SL, Taylor DJ, Tarnow-Mordi W et al. Broad-spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomized trial. Lancet 2001; 357: 989-994
• 75 King J, Flenady V. Prophylactic antibiotics for inhibiting preterm labour with intact membranes. Cochrane Database Syst Rev 2002; (4) CD000246
• 76 Ovalle A, Romero R, Gómez R et al. Antibiotic administration to patients with preterm labor and intact membranes: is there a beneficial effect in patients with endocervical inflammation?. J Matern Fetal Neonatal Med 2006; 19: 453-464
• 77 Peaceman AM, Andrews WW, Thorp JM et al. Fetal fibronectin as a predictor of preterm birth in patients with symptoms. Am J Obstet Gynecol 1997; 177: 13-16
• 78 Sukchaya K, Phupong V. A comparative study of positive rate of placental alpha-microglobulin 1 test in pre-term pregnant women with and without uterine contraction. J Obstet Gynaecol 2013; 33: 566-568
• 79 Andrews WW, Sibai BM, Thom EA et al. Randomized clinical trial of metronidazole plus erythromycin to prevent spontaneous preterm delivery in fetal fibronectin-positive women. Obstet Gynecol 2003; 101: 847-855
• 80 Shennan A, Crawshaw S, Briley A et al. A randomized controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET Study. BJOG 2006; 113: 65-74
• 81 Hendler J, Andrews WW, Carey CJ et al. The relationship between resolution of asymptomatic bacterial vaginosis and spontaneous preterm birth in fetal fibronectin-positive women. Am J Obstet Gynecol 2007; 197: 488.e1-488.e5
• 82 Kenyon S, Pike K, Jones DR et al. Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes; 7-year follow-up of the ORACLE trial. Lancet 2008; 372: 1310-1318
• 83 Kenyon S, Pike K, Jones DR et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet 2008; 372: 1319-1327
• 84 Marlow N, Pike K, Bower E et al. Characteristics of children with cerebral palsy in the ORACLE children study. Dev Med Child Neurol 2012; 54: 640-646
• 85 Kenyon S, Taylor DJ. The effect of the publication of a major clinical trial in a high impact journal on clinical practise: the ORACLE Trial experience. BJOG 2002; 109: 1341-1343
• 86 Kenyon S, Pike K, Jones D et al. Has publication of the results of the ORACLE Children Study changed practice in the UK?. BJOG 2010; 117: 1344-1349
• 87 Bizarro MJ, Dembry LM, Baltimore RS et al. Changing patterns in neonatal Escherichia coli sepsis and ampicillin resistance in the era of intrapartum antibiotic prophylaxis. Pediatrics 2008; 121: 689-696
• 88 Wright AJ, Unger S, Coleman BL et al. Maternal antibiotic exposure and risk of antibiotic resistance in neonatal early-onset sepsis: a case-cohort study. Pediatr Infect Dis J 2012; 31: 1206-1208
• 89 Thomas W, Speer CP. Chorioamnionitis: important risk factor or innocent bystander for neonatal outcome?. Neonatology 2011; 99: 177-187
• 90 Lahra MM, Beeby PJ, Jeffery HE. Intrauterine inflammation, neonatal sepsis, and chronic lung disease: a 13-year hospital cohort study. Pediatrics 2009; 123: 1314-1319
• 91 Chau V, Poskitt KJ, McFadden DE et al. Effect of chorioamnionitis on brain development and injury in premature newborns. Ann Neurol 2009; 66: 155-164
• 92 Perrone G, Anceschi MM, Capri O et al. Maternal C-reactive protein at hospital admission is a simple predictor of funisitis in preterm premature rupture of membranes. Gynecol Obstet Invest 2012; 74: 95-99
• 93 Canzeroni BJ, Grotegut CA, Swamy GK et al. Maternal serum interleukin-6 levels predict impending funisitis in preterm premature rupture of membranes after completion of antibiotics. J Matern Fetal Neonat Med 2012; 25: 1329-1332
• 94 Mercer BM, Crouse DT, Goldenberg RL et al. The antibiotic treatment of PPROM study: systemic maternal and fetal markers and perinatal outcomes. Am J Obstet Gynecol 2012; 206: 145.e1-145.e9
• 95 Gotsch F, Romero R, Kusanovic JP et al. The anti-inflammatory limb of the immune response in preterm labor, intra-amniotic infection/inflammation, and spontaneous parturition at term: A role for interleukin-10. J Matern Fetal Neonat Med 2008; 21: 529-547
• 96 Sadowsky DW, Novy MJ, Witkin SS et al. Dexamethasone or interleukin-10 blocks interleukin-1beta-induced uterine contractions in pregnant rhesus monkeys. Am J Obstet Gynecol 2003; 188: 252-263
• 97 Rodts-Palenik S, Wyatt-Ashmead J, Pang Y et al. Maternal infection-induced white matter injury is reduced by treatment with interleukin-10. Am J Obstet Gynecol 2004; 191: 1387-1392
• 98 Mesples B, Plaisant F, Gressens P. Effects of interleukin-10 on neonatal excitotoxic brain lesions in mice. Brain Res Dev Brain Res 2003; 141: 25-32
• 99 Miller SP, Mayer EE, Clyman RI et al. Prolonged indomethacin exposure is associated with decreased white matter injury detected with magnetic resonance imaging in premature newborns at 24–28 weeksʼ gestation at birth. Pediatrics 2006; 117: 1626-1631
• 100 Hoyme UB, Saling E. Efficient prematurity prevention is possible by pH-self measurement and immediate therapy of threatening ascending infection. Eur J Obstet Gynecol Reprod Biol 2004; 10: 148-153
• 101 Brocklehurst P, Gordon A, Heatley E et al. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev 2013; (1) CD000262