_and preterm birth感染与早产课件

INFECTION AND PRETERM BIRTH Sequelae of Preterm Birth Perinatal Perinatal MortalityMortality NeurologicNeurologic HandicapHandicap (75%)(75%) (50%)(50%) (10%)(10%) Incidence of Preterm Birth in The U.S.A. 1981-1994 Time Trends in Low Birth Weight (2500 20%* *Majority associated with congenital anomalies*Majority associated with congenital anomalies Approximate Prevalence of Cerebral Palsy per 1,000 Births by Birth Weight and Gestational Age LBW-PORTLBW-PORT 0500100015002000250030003500400045005000 Birth Weight (g) / Gestational Age (wks) 0 10 20 30 40 50 Prevalence of Cerebral Palsy per 1,000 Live Births Term 230 240 250 23 273236 Survival Rate for Extremely Small Infants (5 hours 6/7 (4/6 anaerobic) They concluded that organisms could reach the amniotic fluid with intact membranes and that fever was not a reliable sign of infection in labor. Infection in the female reproductive tract can cause premature rupture of the membranes and induce premature labor. The membranes in all premature cases in this series show evidence of infection. In most instances this reaction is severe. Knox, Am J Obstet Gynecol 1950 Infection and Prematurity Elder treated 279 non-bacteriuric women with a 6- week course of 1gm tetracycline daily or a placebo beginning at 1000 per ml with anaerobic organisms predominating. “It appears that bacteria can penetrate the fetal membranes and contaminate the amniotic fluid” “In patients in premature labor, the role of unrecognized amnionitis should be reevaluated.” BobittBobitt 1:127 Percent Incidence of Chorioamnionitis in Preterm Delivery Patients 6/9 11/19 17/33 27/120 295/1526 % with Chorioamnionitis Gestational Age (weeks) Mueller-Heubach 1990 Histological Chorioamnionitis % Birthweight (g) Chellam, 1985 Patients in Labor with Intact Membranes % Positive Amniotic Fluid Cultures Gestational Age (weeks) Watts, Ob/Gyn 79:351, 1992 20/105 (19%) + Cultures 0 20 40 60 80 100 Spontaneous Indicated Chorioamnion Colonization Indicated vs. Spontaneous Delivery 1000 1000-1499 1500-2499 2500 Birthweight (grams) % Positive Cultures Etiology of Spontaneous PTB InfectionInfection OtherOther PathologiesPathologies NoNo PathologyPathology Gestational AgeGestational Age Etiology of Spontaneous Preterm Birth Single potent risk factor (Infection and placental abruption) Multiple weaker risk factors acting through usual hormonal pathways 20 weeks 36 weeks Mediating Factors cervical strength uterine contractility host defenses Histologic Chorioamnionitis Evidence of chronicity 1. Ureaplasma diagnosed by amniocentesis (PCR or culture) at 15-20 wks delivery with HCA at 24-28 wks. 2. IL-6 in amniotic fluid at 15-20 wks delivery with HCA at 32 to 34 wks. 3. FFN (a marker for membrane disruption) in vagina or cervix at 13-24 wks - associated with HCA at 29-31 wks. Recurrent Preterm Birth Women with recurrent spontaneous preterm births 32 weeks are more likely to have histologic chorioamnionitis than other women giving birth at similar gestational ages. Salafia, SMAM 2001 Bacteria Associated with Prematurity Ureaplasma Mycoplasma Gardnerella Mobiluncus Peptostreptococcus Bacteroides Low Virulence Choriodecidual bacterial colonization (endotoxins and exotoxins) Fetal tissue response Fetus Increased corticotropin-releasing hormone Increased adrenal cortisol production Myometrial contractions Chorioamnion weakening and rupture Preterm Delivery Increased prostaglandins Decreased chorionic prostaglandin dehydrogenase Chorioamnion and placenta Maternal response Decidua Increased cytokines and chemokines Neutrophil infiltration Increased metalloproteases Cervical ripening Bacterial Vaginosis and Preterm Birth Normal vaginal secretionsNormal vaginal secretionsBacterial Bacterial vaginosisvaginosis BV and Prematurity The odds ratio for preterm birth in association with BV in nearly every study ranges from 1.5 to 3.0 BV and Preterm Birth Women with BV type organisms such as Women with BV type organisms such as gardnerella, bacteroides and mycoplasma gardnerella, bacteroides and mycoplasma in the vagina early in pregnancy were in the vagina early in pregnancy were significantly more likely to have these significantly more likely to have these organisms in the amniotic fluid at the time organisms in the amniotic fluid at the time of delivery.of delivery. VIP StudyVIP Study KrohnKrohn, 1996, 1996 BACTERIAL VAGINOSIS KornKorn et al., in non-pregnant women, showed et al., in non-pregnant women, showed that BV was associated with plasma cellthat BV was associated with plasma cell endometritisendometritis as well as with endometrial as well as with endometrial colonization by a number of organisms colonization by a number of organisms which are present in excessive numbers in which are present in excessive numbers in women with BV.women with BV. Association of BV with Plasma Cell Endometritis Metritis (%) Positive Negative Korn et al., Obstet Gynecol 1995;85:387-90 Bacterial Vaginosis VIP Study, Am J Obstet Gynecol, 1996VIP Study, Am J Obstet Gynecol, 1996 GENITAL INFECTIONS IN PREGNANT WOMEN BY RACE ChlamydiaGonorrheaTrichomonasGroup B MycoplasmaBacterial Strep vaginosis Nearly 50% of the excess preterm births and mortality in black versus white infants is explained by the increase in vaginal and intrauterine infections in black women Fetal Fibronectin lA basement membrane protein lProduced primarily by fetal tissue, the placenta and membranes. lIt may help to adhere the placenta and membranes to the decidua. FETAL FIBRONECTIN A marker for upper genital tract basement membrane disruption IIII I I III IV INFECTION AND PRETERM BIRTHINFECTION AND PRETERM BIRTH FFN AND PRETERM BIRTH Delivery (weeks)OR 28 60 30 42 32 23 35 11 37 5 +Goldenberg AJOG 1995 ASSOCIATION OF FFN AND INFECTION 1. FFN is twice as common in women with BV 2. FFN was 16-20 fold more common in women who developed clinical chorioamnionitis 3. All women with FFN has histologic chorioamnionitis 4. FFN was 6 fold more common in women whose infants developed sepsis TIMING EventGestational Age (Weeks SD) Screening for FFN23.9 .06 Clinical Chorioamnionitis30.6 4.1 SPECULATION lAt 24 weeks, FFN in the vagina or cervix is a marker for an asymptomatic upper genital tract infection which later manifests itself as spontaneous preterm labor or PROM frequently in conjunction with a perinatal infection. Is pregnancy an antibiotic- deficient state? Antibiotics in Labor and Preterm Birth Antibiotics in Women with Preterm Labor and Intact Membranes Delayed Improved Infant StudyAntibiotic NDeliveryOutcome MacGregor, 1986Erythromycin 17Yes No Morales, 1988Erythromycin, Ampicillin150Yes No Winkler, 1988Erythromycin 19Yes - Newton, 1989Erythromycin / Ampicillin95 No No MacGregor, 1991Clindamycin 103Yes No McCaul, 1992 Ampicillin40 No No Romero, 1993Ampicillin / Amoxicillin / Erythromycin275 No No Cox, 1995 Ampicillin / Amoxicillin78 No No Gordon, 1995Ceftizoximine117 No No Antibiotics in Women with Preterm Labor and Intact Membranes lMeta-analysis of existing RCTs lThese results do not support the routine use of antibiotics in women in preterm labor EgarterEgarter et al, 1996 et al, 1996 Antibiotics and Preterm Birth Labor with Intact Membranes Study GroupPlacebo Group Outcomen=43n=38 BWT (x) (g)23182093Days to delivery (median) 15 2.5* Delivery 7 days (%)37%63%* NEC (%)0% 13%* *p.05 greater prolongation occurred in 30 week pregnancies MetronidazoleMetronidazole and and Ampicillin Ampicillin for 6 days at 30 weeks in a RCT for 6 days at 30 weeks in a RCT Norman et al (South Africa), Br JNorman et al (South Africa), Br J Obstet Gynaecol Obstet Gynaecol, 1994, 1994 Antibiotics and Preterm Birth Labor with Intact Membranes AntibioticsPlacebo Outcome(n=59) (n=51)P value Days to delivery (x)4827 .01 GA at delivery (wks) (x)3734.01 Birth 37 weeks (%)42% 65% .01 BWT (g) (x)2662 2370.08 NICU Admission (%)40% 63% .03 Neonatal sepsis (%)10% 22% .18 Ampicillin and Metronidazole for 8 days at 30 weeks in a RCT SvareSvare et al (Denmark), Br J et al (Denmark), Br J Ob Gyn Ob Gyn 1997 1997 Antibiotics in Women with Preterm Labor and Intact Membranes lThe most promising studies used metronidazole. lthe organisms found in upper tract infection associated with early preterm labor are likely to be more responsive to this antibiotic. lAdditional RCTs to test the efficacy of metronidazole to reduce early preterm birth in laboring women are indicated. Antibiotics Prior to Labor and Preterm Birth A Randomized Trial of Cefamet-Pivoxil in High Risk Pregnant Women in Nairobi NumberNumber EGA at RxEGA at Rx BirthweightBirthweight LBW (2500g)LBW (2500g) PP EndometritisPP Endometritis AntibioticsAntibiotics 160160 30 wks 30 wks 29272927 18.7%18.7% 17.3%17.3% PlaceboPlacebo 160160 30 wks 30 wks 27722772 32.8%32.8% 31.6%31.6% Gichangi, Am J ObGyn, 1997 P P .04.04 .01.01 .03.03 Rakai Study of Mass STD Treatment During Pregnancy OutcomeOutcome Neonatal DeathNeonatal Death Preterm deliveryPreterm delivery T. T. vagvag B.V.B.V. Maternal NG/CTMaternal NG/CT Infant NG/CTInfant NG/CT R.R.R.R. 0.800.80 0.730.73 0.280.28 0.380.38 0.420.42 0.380.38 95% C.I.95% C.I. 0.69-0.940.69-0.94 0.54-0.990.54-0.99 0.17-0.460.17-0.46 0.21-0.680.21-0.68 0.25-0.700.25-0.70 0.21-0.680.21-0.68 *There was no difference in maternal HIV acquisition or in MCT of HIV or in stillbirths, spontaneous Ab or maternal death. BV AND PRETERM BIRTH WHAT ARE WE TREATING?WHAT ARE WE TREATING? BV and Prematurity Randomized trial of metronidazole in 80 women with BV and a previous PTB Rx = 18% Placebo = 39% p = .05 MoralesMorales 1994 1994 BV and Prematurity Randomized trial of metronidazole and erythromycin in women with BV and at high risk for PTB Rx = 23% Placebo = 37% p = .001 Hauth Hauth 19941994 BV During pregnancy at 14-26 weeks, During pregnancy at 14-26 weeks, intravaginalintravaginal 2% 2% Clindamycin Clindamycin cream cream cured BV (86%), but had no effect on cured BV (86%), but had no effect on the rate of preterm delivery - the rate of preterm delivery - 15%15% vs vs. 13.5% for placebo 13.5% for placebo. OR 1.1 (0.7-1.7).OR 1.1 (0.7-1.7). IndonesiaIndonesia Joesoef Joesoef SER 1995 SER 1995 BV Treatment and Spontaneous Preterm Birth MetronidazolePlacebo OR BV Positive11/242 (4.5%) 15/238 (6.3%) 0.71 (0.3-1.7) BV Positive and Prior PTB1/17 (5.9%) 6/17 (35.3%) 0.11 (0.0-1.2) BV Positive and Negative and Prior PTB2/22 (9.1%)10/24 (42%)0.14 (0.0-0.8) McDonald, 1997McDonald, 1997 Br JBr J Obstet Gynaecol Obstet Gynaecol BV and Preterm Birth Treating asymptomatic predominantly low-risk women with BV with two doses of 2 gm of metronidazole 48 hours apart, on two occasions did not reduce preterm birth A randomized trial of antibiotics in 700 women positive for fFN showed no benefit in reducing spontaneous preterm birth. Metronidazole to Prevent Preterm Birth Among Asymptomatic Pregnant Women with Trichomonas Vaginalis NICHD MFMU Network Preterm Birth - Antibiotic Treatment lOld literature: oral tetracycline during pregnancy reduced SPB lTreatment of BV in high risk women with oral metro. and erythro. has reduced SPB lTopical treatment of BV has not reduced SPB lIn women in SPL, penicillin-type antibiotics have not generally reduced SPB lTreatment of women in SPL with metro. and amp. has reduced SPB PREMATURITY “The treatment of premature labor is identical with that already described for term labor and does not require further mention.” Williams 1908Williams 1908 Markers for Infection Markers for Infection Amniotic FluidAmniotic Fluid Plasma/SerumPlasma/Serum Vaginal FluidVaginal Fluid Cervical FluidCervical Fluid UrineUrine Saliva Saliva Markers of Intrauterine Infection in Asymptomatic Women in Routine Prenatal Care Amniotic Fluid High interleukin-6 Cervix or Vagina Bacterial vaginosis High interleukin-6 High ferritin High feta