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Endometrial endotoxin, assisted reproductive technology, and preterm birth
FERTILITY AND STERILITY威 VOL. 82, NO. 4, OCTOBER 2004
RESPONSES
Copyright ©2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A.
Endometrial endotoxin, assisted reproductive technology, and preterm birth Jay D. Iams, M.D. Division of Maternal Fetal Medicine, The Ohio State University, Columbus, Ohio
The failure of antibiotic prophylaxis to reduce preterm birth in women at risk and the increased rate of preterm birth in singleton pregnancy after ART may have a common explanation: persistent bacterial endotoxin in the endometrium, reported by Kamiyama et al. as an explanation for reduced fertility. (Fertil Steril威 2004;82: 793– 4. ©2004 by American Society for Reproductive Medicine.)
The study by Kamiyama et al. (1) in this issue of Fertility and Sterility has importance beyond its proximate implications for fertility care. Although gestational age at delivery is not supplied for the six successful pregnancies, the report suggests that two enigmatic observations in the recent prematurity literature may have a common cause. The increased rate of preterm and low birth weight infants in singleton pregnancies after IVF (2, 3) and the mixed but generally disappointing results of trials of antibiotic prophylaxis to reduce the rate of preterm birth in women with genital tract infection (4 –10) may also be sequelae of persistent bacterial endotoxin in the endometrium.
Received April 13, 2004; revised and accepted April 13, 2004. Reprint requests: Jay D. Iams, M.D., Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, 1654 Upham Drive, Columbus, Ohio 43210-1228 (FAX: 614293-8993). 0015-0282/04/$30.00 doi:10.1016/j.fertnstert.2004. 04.036
The increased incidence of preterm and low birth weight infants after ART has most often been attributed to the greater frequency of multiple gestations. However, an increase in singleton preterm births after IVF-ET is now well documented (1). The etiology of the increased risk is not readily apparent. Proposed explanations have included abnormal placental implantation and intrauterine bleeding related to intrauterine instrumentation or embryo resorption, increased iatrogenic preterm birth, preterm cervical ripening caused by elevated relaxin levels secondary to superovulation, and factors related to the cause of the often-unexplained infertility. The finding by Kamiyama et al. (1) of increased bacterial endotoxin in endometrial fluid and its effect on the success of IVF-ET supports the last of these hypotheses. The reduction in fertility in women with high levels of endotoxin is presumably the result of chronic intrauterine inflammation, a condition
that is increasingly seen as the pathway by which most early preterm births occur (11). In the obstetrical patient, inflammation is most often the consequence of genital tract infection. Although preterm birth has been linked clearly to intrauterine infection (12, 13), eradication of common organisms recovered from the upper and lower genital tract in women who deliver preterm has not been accompanied by a decline in preterm births, even when appropriate prophylactic medications were administered in the second trimester. In an attempt to select women with evidence of upper as well as lower tract infection and inflammation, Andrews et al. (4) treated women with a positive test for fetal fibronectin in cervicovaginal fluid with both metronidazole and erythromycin or placebo in a randomized blinded trial. There was no difference in the rate of preterm birth according to treatment arm, and the rate of spontaneous preterm delivery was actually increased among women with a prior preterm birth who received the antibiotics. To test the benefit of eradication of chronic intrauterine colonization of microorganisms before conception, a subsequent trial enrolled women with a preterm birth to receive placebo or metronidazole plus azithromycin every 4 months until a subsequent pregnancy occurred (14). Again, there was no reduction in pregnancy loss or preterm birth in women who received antibiotic prophylaxis. These and other studies have directed the attention of obstetrical researchers toward host factors and in particular to variations in inflam793
matory response caused by maternal and fetal genetic polymorphisms (15, 16). Kamiyama et al. (1) suggest that the persistence of bacterial endotoxin in endometrium might be the result of chronic adnexal infection. Their hypothesis should prompt a re-evaluation of studies of antibiotic prophylaxis to prevent prematurity and of the relationship between IVF-ET and preterm and low birth weight delivery in singleton pregnancies. References 1. Kamiyama S, Teruya Y, Nohara M, Kanazawa K. Impact of detection of bacterial endotoxin in menstrual effluent on the pregnancy rate in in vitro fertilization and embryo transfer. Fertil Steril 2004;82:788 –92. 2. Jackson RA, Gibson KA, Wu YW, Crough MS. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol 2004;103:551– 63. 3. Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002;346:731–7. 4. Andrews WW, Sibai BM, Thom EA, Dudley D, Ernest JM, McNellis D, et al. Randomized clinical trial of metronidazole plus erythromycin to prevent spontaneous preterm delivery in fetal fibronectin-positive women. Obstet Gynecol 2003;101:847–55. 5. Carey JC, Klebanoff MA, Hauth JC, Hillier SL, Thom EA, Ernest JM, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. N Engl J Med 2000;342:534 – 40. 6. Kekki M, Kurki T, Pelkonen J, Kurkinen-Raty M, Cacciatore B, Paavonen J. Vaginal clindamycin in preventing preterm birth and peripartal infections o asymptomatic women with bacterial vaginosis: a randomized controlled trial. Obstet Gynecol 2001;97:643– 8.
794
Iams
Endometrial endotoxin, ART, and preterm birth
7. Klebanoff MA, Carey JC, Hauth JC, Hillier SL, Nugent RP, Thom EA, et al. Failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection. N Engl J Med 2001;345:487–93. 8. Lamont RF, Duncan SL, Mandal D, Bassett P. Intravaginal clindamycin to reduce preterm birth in women with abnormal genital tract flora. Obstet Gynecol 2003;101:516 –22. 9. McDonald H, Brocklehurst P, Parsons J, Vigneswaran R. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev 2003;2:CD000262. 10. Thinkhamrop J, Hofmeyr GJ, Adetoro O, Lumbiganon P. Prophylactic antibiotic administration in pregnancy to prevent infectious morbidity and mortality (Cochrane Review). In: The Cochrane Library, Issue 3, 2004. Chichester, UK: Wiley & Sons. 11. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med 2000;342:1500 –7. 12. Hillier SL, Martius J, Krohn M, Kiviat N, Holmes KK, Eschenbach DA. A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med 1988;319:972– 8. 13. Watts DH, Krohn MA, Hillier SL, Eschenbach DA. The association of occult amniotic fluid infection with gestational age and neonatal outcome among women in preterm labor. Obstet Gynecol 1992;79: 351–7. 14. Andrews WW, Goldenberg RL, Hauth JC, Cliver S. Interconceptional antibiotics to prevent spontaneous preterm birth: a randomized trial [abstract 5]. Am J Obstet Gynecol 2003;189:S57. 15. Roberts AK, Monzon-Bordonaba F, Van Deerlin PG, Holder J, Macones GA, Morgan MA, et al. Association of polymorphism within the promoter of the tumor necrosis factor-alpha gene with increased risk of preterm premature rupture of the fetal membranes. Am J Obstet Gynecol 1999;180:1297–302. 16. Hao K, Wang X, Niu T, Xu X, Li A, Chang W, et al. A candidate gene association study on preterm delivery: application of high-throughput genotyping technology and advanced statistical methods. Hum Mol Genet 2004;13:683–91.
Vol. 82, No. 4, October 2004
RESPONSES
Copyright ©2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A.
Endometrial endotoxin, assisted reproductive technology, and preterm birth Jay D. Iams, M.D. Division of Maternal Fetal Medicine, The Ohio State University, Columbus, Ohio
The failure of antibiotic prophylaxis to reduce preterm birth in women at risk and the increased rate of preterm birth in singleton pregnancy after ART may have a common explanation: persistent bacterial endotoxin in the endometrium, reported by Kamiyama et al. as an explanation for reduced fertility. (Fertil Steril威 2004;82: 793– 4. ©2004 by American Society for Reproductive Medicine.)
The study by Kamiyama et al. (1) in this issue of Fertility and Sterility has importance beyond its proximate implications for fertility care. Although gestational age at delivery is not supplied for the six successful pregnancies, the report suggests that two enigmatic observations in the recent prematurity literature may have a common cause. The increased rate of preterm and low birth weight infants in singleton pregnancies after IVF (2, 3) and the mixed but generally disappointing results of trials of antibiotic prophylaxis to reduce the rate of preterm birth in women with genital tract infection (4 –10) may also be sequelae of persistent bacterial endotoxin in the endometrium.
Received April 13, 2004; revised and accepted April 13, 2004. Reprint requests: Jay D. Iams, M.D., Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, 1654 Upham Drive, Columbus, Ohio 43210-1228 (FAX: 614293-8993). 0015-0282/04/$30.00 doi:10.1016/j.fertnstert.2004. 04.036
The increased incidence of preterm and low birth weight infants after ART has most often been attributed to the greater frequency of multiple gestations. However, an increase in singleton preterm births after IVF-ET is now well documented (1). The etiology of the increased risk is not readily apparent. Proposed explanations have included abnormal placental implantation and intrauterine bleeding related to intrauterine instrumentation or embryo resorption, increased iatrogenic preterm birth, preterm cervical ripening caused by elevated relaxin levels secondary to superovulation, and factors related to the cause of the often-unexplained infertility. The finding by Kamiyama et al. (1) of increased bacterial endotoxin in endometrial fluid and its effect on the success of IVF-ET supports the last of these hypotheses. The reduction in fertility in women with high levels of endotoxin is presumably the result of chronic intrauterine inflammation, a condition
that is increasingly seen as the pathway by which most early preterm births occur (11). In the obstetrical patient, inflammation is most often the consequence of genital tract infection. Although preterm birth has been linked clearly to intrauterine infection (12, 13), eradication of common organisms recovered from the upper and lower genital tract in women who deliver preterm has not been accompanied by a decline in preterm births, even when appropriate prophylactic medications were administered in the second trimester. In an attempt to select women with evidence of upper as well as lower tract infection and inflammation, Andrews et al. (4) treated women with a positive test for fetal fibronectin in cervicovaginal fluid with both metronidazole and erythromycin or placebo in a randomized blinded trial. There was no difference in the rate of preterm birth according to treatment arm, and the rate of spontaneous preterm delivery was actually increased among women with a prior preterm birth who received the antibiotics. To test the benefit of eradication of chronic intrauterine colonization of microorganisms before conception, a subsequent trial enrolled women with a preterm birth to receive placebo or metronidazole plus azithromycin every 4 months until a subsequent pregnancy occurred (14). Again, there was no reduction in pregnancy loss or preterm birth in women who received antibiotic prophylaxis. These and other studies have directed the attention of obstetrical researchers toward host factors and in particular to variations in inflam793
matory response caused by maternal and fetal genetic polymorphisms (15, 16). Kamiyama et al. (1) suggest that the persistence of bacterial endotoxin in endometrium might be the result of chronic adnexal infection. Their hypothesis should prompt a re-evaluation of studies of antibiotic prophylaxis to prevent prematurity and of the relationship between IVF-ET and preterm and low birth weight delivery in singleton pregnancies. References 1. Kamiyama S, Teruya Y, Nohara M, Kanazawa K. Impact of detection of bacterial endotoxin in menstrual effluent on the pregnancy rate in in vitro fertilization and embryo transfer. Fertil Steril 2004;82:788 –92. 2. Jackson RA, Gibson KA, Wu YW, Crough MS. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol 2004;103:551– 63. 3. Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002;346:731–7. 4. Andrews WW, Sibai BM, Thom EA, Dudley D, Ernest JM, McNellis D, et al. Randomized clinical trial of metronidazole plus erythromycin to prevent spontaneous preterm delivery in fetal fibronectin-positive women. Obstet Gynecol 2003;101:847–55. 5. Carey JC, Klebanoff MA, Hauth JC, Hillier SL, Thom EA, Ernest JM, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. N Engl J Med 2000;342:534 – 40. 6. Kekki M, Kurki T, Pelkonen J, Kurkinen-Raty M, Cacciatore B, Paavonen J. Vaginal clindamycin in preventing preterm birth and peripartal infections o asymptomatic women with bacterial vaginosis: a randomized controlled trial. Obstet Gynecol 2001;97:643– 8.
794
Iams
Endometrial endotoxin, ART, and preterm birth
7. Klebanoff MA, Carey JC, Hauth JC, Hillier SL, Nugent RP, Thom EA, et al. Failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection. N Engl J Med 2001;345:487–93. 8. Lamont RF, Duncan SL, Mandal D, Bassett P. Intravaginal clindamycin to reduce preterm birth in women with abnormal genital tract flora. Obstet Gynecol 2003;101:516 –22. 9. McDonald H, Brocklehurst P, Parsons J, Vigneswaran R. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev 2003;2:CD000262. 10. Thinkhamrop J, Hofmeyr GJ, Adetoro O, Lumbiganon P. Prophylactic antibiotic administration in pregnancy to prevent infectious morbidity and mortality (Cochrane Review). In: The Cochrane Library, Issue 3, 2004. Chichester, UK: Wiley & Sons. 11. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med 2000;342:1500 –7. 12. Hillier SL, Martius J, Krohn M, Kiviat N, Holmes KK, Eschenbach DA. A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med 1988;319:972– 8. 13. Watts DH, Krohn MA, Hillier SL, Eschenbach DA. The association of occult amniotic fluid infection with gestational age and neonatal outcome among women in preterm labor. Obstet Gynecol 1992;79: 351–7. 14. Andrews WW, Goldenberg RL, Hauth JC, Cliver S. Interconceptional antibiotics to prevent spontaneous preterm birth: a randomized trial [abstract 5]. Am J Obstet Gynecol 2003;189:S57. 15. Roberts AK, Monzon-Bordonaba F, Van Deerlin PG, Holder J, Macones GA, Morgan MA, et al. Association of polymorphism within the promoter of the tumor necrosis factor-alpha gene with increased risk of preterm premature rupture of the fetal membranes. Am J Obstet Gynecol 1999;180:1297–302. 16. Hao K, Wang X, Niu T, Xu X, Li A, Chang W, et al. A candidate gene association study on preterm delivery: application of high-throughput genotyping technology and advanced statistical methods. Hum Mol Genet 2004;13:683–91.
Vol. 82, No. 4, October 2004