Sequelae of Preterm Birth (75%) Perinatal Mortality (10%) (50%) Neurologic Handicap
Time Trends in Low Birth Weight (<1,500 g) by Race/Ethnicity - United States, 1970-1990
UAB Infants with Birthweights £1000 Grams Mean BW Survival 1975 900 gms 17% 1980 860 gms 48% 1985 820 gms 56% 1990 804 gms 74%
Distribution of Neonatal Mortality BWT (gms) Distribution <1000 60% 1000-2500 20% >2500 20%* *Majority associated with congenital anomalies
Approximate Prevalence of Cerebral Palsy per 1,000 Births by Birth Weight and Gestational Age 250 240 230 50 40 30 Prevalence of Cerebral Palsy per 1,000 Live Births 20 10 0 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 32 36 23 27 Term Birth Weight (g) / Gestational Age (wks) LBW-PORT
Survival Rate for Extremely Small Infants (<800g)in Relation to Mid-Year of Birth 80 60 40 Survivors per Livebirth, % 20 0 1975 1980 1985 1990 Mid-Year of Birth Lorenz, 1998
70 60 50 40 Disabled Infants per Survivor, % 30 20 10 0 1975 1980 1985 1990 Prevalence of Disability Among Extremely Small Survivors (<800g) in Relation to Mid-Year of Birth Mid-Year of Birth Lorenz, 1998
20 15 Disabled Infants per Livebirth, % 10 5 0 1975 1980 1985 1990 Mid-Year of Birth Percentage of Extremely Small (<800g) Livebirths Surviving with at Least One Disability in Relation to Mid-Year of Birth Lorenz, 1998
Cerebral Palsy in <1000gm infants Year 1960 1985 1997 <1000g births (n) 20,000 20,000 20,000 Survival (%) 1 40 80 Survivors (n) 200 8,000 16,000 Survivors with CP* (n) 16 640 1280 Survivors with Any Disability** (n) 32 1280 2560 *Assuming an 8% incidence in survivors consistently over time. **Assuming a 16% incidence in survivors consistently over time.
Etiology of Preterm Birth Preterm Birth for Maternal or Fetal Indications Spontaneous Preterm Labor 20% 50% 30% Premature Rupture of Membranes
Prenatal care Risk screening Nutrition counseling Caloric supplementation Protein supplementation Iron supplementation Most labor inhibiting agents Drug, alcohol and tobacco cessation programs Bed rest Hydration Home uterine activity monitoring REVIEW OF INTERVENTIONS TO PREVENT PRETERM BIRTH Commonly used interventions which have not been shown to reduce preterm birth include:
SURGICAL PATHOLOGY REPORT Clinical History 34 year old white female with an intrauterine pregnancy at 25 and 3/7th weeks. Microscopic Description Sections of the free fetal membranes show severe, necrotizing chorioamnionitis. Both umbilical arteries as well as the umbilical vein exhibit funisitis.
Infection and Labor In 1927, Harris and Brown reported culturing women undergoing C-section with intact membranes. STATUS RESULTS (# POSITIVE) No labor 0/21 Labor <5 hours 0/5 Labor >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 <32 weeks gestation. Tetracycline treated women had fewer preterm births. Elder, 1971
Infection and Preterm Labor In 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, 1977J Reprod Med
Intrauterine Infection • Clinical chorioamnionitis • Sub-clinical chorioamnionitis • Organisms in amniotic fluid and membranes • Organisms only in membranes
Of women with positive chorioamnion cultures, only 50% also have positive amniotic fluid cultures.
INFECTION AND PREMATURITY Only 8% of women with histologic chorioamnionitis have clinical signs (fever and uterine tenderness) prior to delivery.Gusick 1985
Chorioamnionitis Histologic studies suggest a clear progression of granulocyte infiltration: Maternal Granulocytes Decidua Chorion Amnion Amniotic fluid Umbilical Cord Umbilical vessels Wharton’s Jelly Amniotic fluid Granulocytes in AF likely represent both a maternal and fetal response.
Funisitis • Prior to 1970, funisitis was thought to represent a sign of asphyxia • In 1970, Cassady showed that funisitis was associated with intrauterine infection - not asphyxia • The only proven intrauterine and fetal infection occurring in the absence of funisitis was Group B strep Overbach and Cassady, Pediatrics 1970
Chorioamnionitis • Funisitis 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 Labor Relationship to Gestational Age
Prevalence at Delivery of Histologic Chorioamnionitis at Different Stages of Gestation 100 90 80 70 60 Percent 50 40 30 20 10 0 21-24 25-28 29-32 33-36 37-40 41-44 Weeks Gestation Russell, P. Am J Diag Gyn Obst. 1979;1:127
6/9 11/19 17/33 27/120 295/1526 Incidence of Chorioamnionitis in Preterm Delivery Patients % with Chorioamnionitis Gestational Age (weeks) Mueller-Heubach 1990
Histological Chorioamnionitis % Birthweight (g) Chellam, 1985
Patients in Labor with Intact Membranes Watts, Ob/Gyn 79:351, 1992 20/105 (19%) + Cultures % Positive Amniotic Fluid Cultures Gestational Age (weeks)
Chorioamnion Colonization Indicated vs. Spontaneous Delivery 100 Spontaneous 80 Indicated 60 % Positive Cultures 40 20 0 <1000 1000-1499 1500-2499 ³ 2500 Birthweight (grams)
Etiology of Spontaneous PTB OtherPathologies NoPathology Infection Gestational Age
Etiology of Spontaneous Preterm Birth Multiple weaker risk factors acting through usual hormonal pathways Single potent risk factor (Infection and placental abruption) 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 Maternal response Chorioamnion and placenta Fetus Decidua Increased corticotropin-releasing hormone Decreased chorionic prostaglandin dehydrogenase Increased cytokines and chemokines Increased adrenal cortisol production Increased prostaglandins Neutrophil infiltration Increased metalloproteases Myometrial contractions Cervical ripening Chorioamnion weakening and rupture Preterm Delivery
Normal vaginal secretions Bacterial vaginosis
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 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 VAGINOSIS Korn 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 Endometritis Metritis (%) Positive Negative Bacterial Vaginosis Korn et al., Obstet Gynecol 1995;85:387-90
GENITAL INFECTIONS IN PREGNANT WOMEN BY RACE Chlamydia Gonorrhea Trichomonas Group B Mycoplasma Bacterial Strep vaginosis VIP Study, Am J Obstet Gynecol, 1996
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 • A basement membrane protein • Produced primarily by fetal tissue, the placenta and membranes. • It may help to adhere the placenta and membranes to the decidua.
FETAL FIBRONECTIN A marker for upper genital tract basement membrane disruption
III IV II II I I INFECTION AND PRETERM BIRTH
FFN AND PRETERM BIRTH Delivery (weeks) OR <28 60 <30 42 <32 23 <35 11 <37 5 +Goldenberg AJOG 1995