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  • INFECTION AND PRETERM BIRTH

  • Sequelae of Preterm BirthPerinatal MortalityNeurologicHandicap(75%)(50%)(10%)

  • Incidence of Preterm Birth in The U.S.A.1981-1994

  • Time Trends in Low Birth Weight (
  • UAB Infants with Birthweights 1000 GramsMean BWSurvival1975900 gms17%1980860 gms48%1985820 gms56%1990804 gms74%

  • Distribution of Neonatal MortalityBWT (gms) Distribution250020%**Majority associated with congenital anomalies

  • Approximate Prevalence of Cerebral Palsy per 1,000 Births by Birth Weight and Gestational AgeLBW-PORT0500100015002000250030003500400045005000Birth Weight (g) / Gestational Age (wks)01020304050Prevalence of Cerebral Palsy per 1,000 Live BirthsTerm23024025023 273236

  • Survival Rate for Extremely Small Infants (
  • Prevalence of Disability Among Extremely Small Survivors (
  • Percentage of Extremely Small (
  • Cerebral Palsy in
  • Etiology of Preterm Birth50%30%20%SpontaneousPreterm LaborPreterm Birth for Maternal or Fetal IndicationsPremature Rupture of Membranes

  • REVIEW OF INTERVENTIONS TO PREVENT PRETERM BIRTHPrenatal careRisk screeningNutrition counselingCaloric supplementationProtein supplementationIron supplementationMost labor inhibiting agentsDrug, alcohol and tobacco cessation programsBed restHydrationHome uterine activity monitoringCommonly used interventions which have not been shown to reduce preterm birth include:

  • INFECTION AND PRETERM BIRTH

  • SURGICAL PATHOLOGY REPORTClinical History34 year old white female with an intrauterine pregnancy at 25 and 3/7th weeks.Microscopic DescriptionSections of the free fetal membranes show severe, necrotizing chorioamnionitis. Both umbilical arteries as well as the umbilical vein exhibit funisitis.

  • Infection and LaborIn 1927, Harris and Brown reported culturing women undergoing C-section with intact membranes. STATUSRESULTS (# POSITIVE) No labor0/21Labor 5 hours6/7 (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 PrematurityElder treated 279 non-bacteriuric women with a 6-week course of 1gm tetracycline daily or a placebo beginning at
  • Infection and Preterm LaborIn 1977 Bobitt and Ledger performed amniocenteses on 10 women in preterm labor with intact membranes. 7 had colony counts >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. Bobitt & Ledger, 1977 J Reprod Med

  • Intrauterine InfectionClinical chorioamnionitisSub-clinical chorioamnionitisOrganisms in amniotic fluid and membranesOrganisms only in membranes

  • Of women with positive chorioamnion cultures, only 50% also have positive amniotic fluid cultures.

  • INFECTION AND PREMATURITYOnly 8% of women with histologic chorioamnionitis have clinical signs (fever and uterine tenderness) prior to delivery. Gusick 1985

  • ChorioamnionitisHistologic studies suggest a clear progression of granulocyte infiltration:Maternal GranulocytesDecidua Chorion Amnion Amniotic fluidUmbilical CordUmbilical vessels Whartons Jelly Amniotic fluid Granulocytes in AF likely represent both a maternal and fetal response.

  • FunisitisPrior to 1970, funisitis was thought to represent a sign of asphyxiaIn 1970, Cassady showed that funisitis was associated with intrauterine infection - not asphyxiaThe only proven intrauterine and fetal infection occurring in the absence of funisitis was Group B strepOverbach and Cassady, Pediatrics 1970

  • ChorioamnionitisFunisitis is present in about half the cases of histologic chorioamnionitis and is almost never seen alone.This suggests that the etiologic infection almost always starts in the chorioamnion.

  • Intrauterine Infection and Preterm LaborRelationship to Gestational Age

  • 010203040506070809010021-2425-2829-3233-3637-4041-44Weeks GestationPrevalence at Delivery of Histologic Chorioamnionitis at Different Stages of Gestation Russell, P.Am J Diag Gyn Obst. 1979;1:127Percent

  • Incidence of Chorioamnionitis in Preterm Delivery Patients% with ChorioamnionitisGestational 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, 199220/105 (19%) + Cultures

  • 020406080100SpontaneousIndicatedChorioamnion Colonization Indicated vs. Spontaneous Delivery
  • Etiology of Spontaneous PTBInfectionOther PathologiesNo PathologyGestational Age

  • Etiology of Spontaneous Preterm BirthSingle potentrisk factor(Infection and placental abruption)Multiple weaker risk factors acting through usual hormonal pathways20 weeks 36 weeksMediating Factors cervical strength uterine contractility host defenses

  • Histologic ChorioamnionitisEvidence of chronicity1. 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
  • Recurrent Preterm BirthWomen with recurrent spontaneous preterm births
  • Bacteria Associated with PrematurityUreaplasmaMycoplasmaGardnerellaMobiluncusPeptostreptococcusBacteroidesLow Virulence

  • Choriodecidual bacterial colonization(endotoxins and exotoxins)Fetal tissueresponseFetusIncreased corticotropin-releasinghormoneIncreased adrenalcortisol productionMyometrialcontractionsChorioamnion weakening and rupturePreterm DeliveryIncreasedprostaglandinsDecreased chorionicprostaglandindehydrogenaseChorioamnionand placentaMaternal responseDeciduaIncreased cytokinesand chemokinesNeutrophilinfiltrationIncreased metalloproteasesCervicalripening

  • Bacterial VaginosisandPreterm Birth

  • Normal vaginal secretionsBacterial vaginosis

  • BV and PrematurityThe 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 gardnerella, bacteroides and mycoplasma in the vagina early in pregnancy were significantly more likely to have these organisms in the amniotic fluid at the time of delivery.

    VIP Study Krohn, 1996

  • BACTERIAL VAGINOSISKorn et al., in non-pregnant women, showed that BV was associated with plasma cell endometritis as well as with endometrial colonization by a number of organisms which are present in excessive numbers in women with BV.

  • Association of BV with Plasma Cell EndometritisMetritis (%)Positive NegativeKorn et al., Obstet Gynecol 1995;85:387-90Bacterial Vaginosis

  • GENITAL INFECTIONS IN PREGNANT WOMEN BY RACEVIP Study, Am J Obstet Gynecol, 1996ChlamydiaGonorrheaTrichomonasGroup 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 FibronectinA basement membrane proteinProduced primarily by fetal tissue, the placenta and membranes.It may help to adhere the placenta and membranes to the decidua.

  • FETAL FIBRONECTINA marker for upper genital tract basement membrane disruption

  • INFECTION AND PRETERM BIRTH

  • FFN AND PRETERM BIRTHDelivery (weeks)OR
  • ASSOCIATION OF FFN AND INFECTION1. FFN is twice as common in women with BV2. FFN was 16-20 fold more common in women who developed clinical chorioamnionitis3. All women with FFN has histologic chorioamnionitis4. FFN was 6 fold more common in women whose infants developed sepsis

  • TIMINGEventGestational Age (Weeks SD)

    Screening for FFN23.9 .06

    Clinical Chorioamnionitis30.6 4.1

  • SPECULATIONAt 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 LaborandPreterm Birth

  • Antibiotics in Women with Preterm Labor and Intact MembranesDelayed Improved Infant StudyAntibiotic NDeliveryOutcome MacGregor, 1986Erythromycin17Yes NoMorales, 1988Erythromycin, Ampicillin150Yes NoWinkler, 1988Erythromycin 19Yes - Newton, 1989Erythromycin / Ampicillin95 No NoMacGregor, 1991Clindamycin103Yes NoMcCaul, 1992Ampicillin40 No NoRomero, 1993Ampicillin / Amoxicillin / Erythromycin275 No NoCox, 1995Ampicillin / Amoxicillin78 No NoGordon, 1995Ceftizoximine117 No No

  • Antibiotics in Women with Preterm Labor and Intact MembranesMeta-analysis of existing RCTs These results do not support the routine use of antibiotics in women in preterm labor

    Egarter et al, 1996

  • Antibiotics and Preterm BirthLabor with Intact MembranesStudy GroupPlacebo Group Outcomen=43n=38 BWT (x) (g)23182093Days to delivery (median) 15 2.5*Delivery
  • Antibiotics and Preterm Birth Labor with Intact MembranesAntibioticsPlaceboOutcome(n=59) (n=51)P value Days to delivery (x)4827.01GA at delivery (wks) (x)3734.01Birth
  • Antibiotics in Women with Preterm Labor and Intact MembranesThe most promising studies used metronidazole.the organisms found in upper tract infection associated with early preterm labor are likely to be more responsive to this antibiotic.Additional RCTs to test the efficacy of metronidazole to reduce early preterm birth in laboring women are indicated.

  • Antibiotics Prior to Laborand Preterm Birth

  • A Randomized Trial of Cefamet-Pivoxil in High Risk Pregnant Women in Nairobi

    NumberEGA at RxBirthweightLBW (

  • Rakai Study of Mass STD Treatment During Pregnancy

    OutcomeNeonatal DeathPreterm deliveryT. vagB.V.Maternal NG/CTInfant NG/CTR.R.0.800.730.280.380.420.3895% C.I.0.69-0.940.54-0.990.17-0.460.21-0.680.25-0.700.21-0.68*There was no difference in maternal HIV acquisition or in MCT of HIV or in stillbirths, spontaneous Ab or maternal death.

  • BV AND PRETERM BIRTHWHAT ARE WE TREATING?

  • BV and PrematurityRandomized trial of metronidazole in 80 women with BV and a previous PTBRx = 18%Placebo = 39% p =
  • BV and PrematurityRandomized trial of metronidazole and erythromycin in women with BV and at high risk for PTBRx = 23%Placebo = 37% p =
  • BVDuring pregnancy at 14-26 weeks, intravaginal 2% Clindamycin cream cured BV (86%), but had no effect on the rate of preterm delivery - 15% vs. 13.5% for placebo. OR 1.1 (0.7-1.7). Indonesia Joesoef SER 1995

  • BV Treatment and Spontaneous Preterm BirthMetronidazolePlaceboOR 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, 1997Br J Obstet Gynaecol

  • BV and Preterm BirthTreating 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 VaginalisNICHD MFMU Network

  • Preterm Birth - Antibiotic TreatmentOld literature: oral tetracycline during pregnancy reduced SPBTreatment of BV in high risk women with oral metro. and erythro. has reduced SPBTopical treatment of BV has not reduced SPBIn women in SPL, penicillin-type antibiotics have not generally reduced SPBTreatment of women in SPL with metro. and amp. has reduced SPB

  • PREMATURITYThe treatment of premature labor is identical with that already described for term labor and does not require further mention.Williams 1908

  • Markers for Infection

    Amniotic FluidPlasma/SerumVaginal FluidCervical FluidUrine Saliva

  • Markers of Intrauterine Infection in Asymptomatic Women in Routine Prenatal CareAmniotic FluidHigh interleukin-6Cervix or VaginaBacterial vaginosisHigh interleukin-6High ferritinHigh fetal fibronectinHigh -FPHigh HCGHigh ProlactinHigh CICPSerumHigh GCSFHigh ferritin

  • Markers of Intrauterine Infection in Pregnant Women

    Women Presenting in LaborAmniotic FluidBacteriaLow glucoseHigh wt-cell countHigh GCSFHigh IL-1High IL-6Cervix or VaginaBacterial vaginosisHigh GCSFHigh TNF-High IL-1High IL-6High IL-8High fetal fibronectinSerumHigh GCSFHigh IL-6High TNF-High C-reactive protein

  • Research QuestionsWhen do bacteria invade the uterus?What is the infection status of the uterus prior to conception? What Mechanical and molecular mechanisms are associated with uterine invasion? What are the protective mechanisms?

  • Why is the rate of genital tract infection so high in black women?Lack of access to treatment?Douching or other behaviors?Immunological differences?Greater risk of exposure?What strategies work to reduce these differences?

  • And what role does genetics play?None?Differences in immune response?Differences in chorioamnion membrane strength or ability to repair (keloids)?Differences in uterine muscle contractility?

  • Research QuestionsWhich markers best predict current intrauterine infection?Which interventions (i.e., antibiotics, anti-inflammatory agents) will reduce preterm birth and neonatal damage associated with intrauterine infection?

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