Predicting and Preventing Preterm Birth Steven R. Allen, MD Scott & White Hosp & Clinic Temple, TX

Educational Objectives Identify remediable risk factors for PTB Address potential “predictors” of PTB cervical ultrasonographic screening fibronectin Discuss possible role for progesterone (Rx) in pregnancy maintenance Review the potential utility of tocolysis

Significance of Preterm Birth (PTB) 12.1% of US births - rising One sixth of PTD’s occur at 24-31 weeks, with highest rate of complications * Leading cause of neonatal mortality (75%), morbidity, and health care expenditures (57% of nursery costs; 10% of all healthcare costs for children) * US Nat’t Vital Stats Reports 2000 & 2003

Mortality & morbidity related to PTB (S&W 1998-2001) % Survival % IVH Grade 3-4

Components of PTL pathophysiology Prostaglandins Inflammatory response Adrenergic response: stimulates contractions Ischemia: free radicals promote PGs Decidual hemorrhage

Group survey question Who is most likely to have a PTB? A) 34 yo P1203 (last preg preterm) B) 34 yo P1103 C) 34 yo P3003 D) 34 yo P1203 (last preg term)

Historical risk factors for PTL/PTB Prior PTB (spontaneous PTL) Low socioeconomic status Teen Age >34 Prepregnancy weight < 100-110 lb. Uterine or cervical abnormality Maternal smoking

Pregnancy complications predisposing to PTL/PTB Multiple gestation Polyhydramnios Antepartum bleeding PROM Chorioamnionitis Pyelonephritis Untreated asymptomatic bacteriuria Some specific fetal anomalies

Rationale for new PTL screening tools <50% with PTL perceive typical symptoms 10-20% of uncomplicated patients have similar symptoms PTL is diagnosed only after gross structural change of the cervix Majority of women with PTD have no currently identifiable risk factor

Summary of PTL Risk Scoring Indices 26 - 64 % 13 - 35 4 - 30 2 - 16 PTD Sensitivity Pos Screen PPV

Risk of subsequent PTB % Bakketeig, 1981

Group survey question Who is most likely to have a PTB? A) 34 yo P1203 (last preg preterm) B) 34 yo P1103 C) 34 yo P3003 D) 34 yo P1203 (last preg term)

Group survey question What “lab test” is most helpful in selecting mgmt plan for 33 yo P0010 @ 28 wks with q 4 min ctx and cx 1/2/-3 (digital exam)? A) cervical length (transabdominal scan) B) wet mount (r/o bacterial vaginosis) C) fFN D) cervical length (transvaginal scan)

Bacterial vaginosis (BV) Anaerobic bacteria predominate vaginal flora Incidence: 12-40% of pregnant women Risk factors (all non-remediable) black race younger age unmarried multiparous low socioeconomic status

Bacterial vaginosis: diagnosis Relatively alkaline pH (>4.5) Vaginal epithelial “clue cells” Release of amine odor with alkalinization of vaginal fluid (“whiff test”) Thin vaginal secretion of uniform consistency Gram stain: Nugent criteria

BV: indirect screening (Pap smear) % Green. AJOG 2000;182:1048-9

Bacterial vaginosis as a risk factor for PTB – meta analysis * * * * NS: 95%CI < 1 Leitich. AJOG 2003;189:139-47

Effect of BV treatment RR of PTD 300 mg bid AJOG 1995;173:157 250 mg tid + 333 mg tid NEJM 1995;333:1732 AJOG 1995;173:1527 Meta-analysis confirms reduction in PTB only in pts with prior PTB

Bacterial vaginosis: summary BV increases risk of PTD Screen high risk patients Systemic treatment for BV metronidazole 250 mg po tid x 7 d or clindamycin 300 mg po bid x 7 d Screening for risks of PTL by means other than historic risk factors is not beneficial in the general obstetric population ACOG Practice Bulletin # 31, 10/01

Fibronectins Ubiquitous glycoproteins, present in plasma and ECM Adhesion molecules Fetal fibronectin (fFN) contains uniquely glycosylated epitope (“oncofetal domain”) fFN located in ECM of decidua basalis and cytotrophoblasts

Fetal fibronectin fFN rarely present (3-4%) in cervical/ vaginal secretions of women without PTL/PROM fFN common in cervical/vaginal secretions of women with PTL (50%) or PROM (94%) HYPOTHESIS: mechanical or inflammatory damage to placenta or membranes releases fFN into cervical/vaginal secretions

fFN as a predictor of PTD among women with PTL (n=192) AJOG 1995;173:141

Survival curve after fFN testing for threatened PTL % Days after fFN test Peaceman. AJOG 1997;177:13-18

fFN as a predictor of PTB Meta-analysis; 13 studies; n=22,390 Asymptomatic; predicting PTB < 34 wks Symptomatic; Predicting PTB < 11 d Honest. BMJ. 2002;325:1-10

Impact of fFN assay on admissions for PTL Cohort study with a historical control cohort 24-34.9 wks with signs or symptoms of PTL fFN results in 24-48 hr No difference in neonatal outcome * * * AJOG 1999;180:581 * p<0.001

fFN NOT strictly related to infection/inflammation Many studies evaluating risk included women with multiple gestation or uterine anomalies (without obvious risk of infection) fFN present in cervical/vaginal secretions at term

Fibronectin: summary fFN is fairly sensitive marker for PTD in high risk patients (55-97%) High short term NPV (71-100%) may identify women not needing tocolysis Screening not recommended

Group survey question What “lab test” is most helpful in selecting mgmt plan for 33 yo P0010 @ 28 wks with q 4 min ctx and cx 1/2/-3 (digital exam)? A) cervical length (transabdominal scan) B) wet mount (r/o bacterial vaginosis) C) fFN D) cervical length (transvaginal scan)

Group survey question Which patient is most likely to threaten PTB? A) 28 yo P0 @ 17 wks with cx 1dil/2.5 long on US B) 28 yo P0111 @ 17 wks with cx 1 dil/2.5 long C) 28 yo P2002 @ 29 wks with cx 1 dil/2.5 long D) 28 yo P2002 @ 29 wks with cx cl/4 long

Hypothesis: cervical competence is a continuous variable Most human features are continuous, not categorical Cervical resistance to delivery varies at term Bishop score varies duration of normal labor varies Prior PTL predicts subsequent PTL

Cervical length at 24 wks measured by TVUS 800 600 No. of Women 400 200 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 Length of Cervix (mm) 5 25 75 1 10 50 Percentile NEJM 1996;334:567

Cervical length correlates with PTB 800 14 Relative Risk of PTB 12 600 10 8 No. of Women 400 6 4 200 2 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 Length of Cervix (mm) 5 25 75 1 10 50 Percentile NEJM 1996;334:567

Predictive value of cervical length with threatened PTD NPV PPV % Obstet Gynecol 1993;82:829

Predictive value of cervical “funneling” with threatened PTD ‘Funneling” present in half of women studied with preterm contractions Funneling correlates with cervical length, but is not as good a predictor of PTD Funneling may vary over time, and thus be less reproducible than cervical length

US cervical canal measurement: summary Cervical length correlates inversely with PTD risk Identification of abnormal cervix does not determine etiology or direct treatment Routine screening not recommended

Effectiveness of cerclage for sonographically shortened cervix Meta-analysis 6 studies (2 RCT) n=357; mostly hi risk for PTB (3 studies, n=212) Inclusion: cx < 2.5 cm long, dil < 2 cm, or funneling RR (all NS) Belej-Rak. AJOG 2003;189:1679-87

Preterm Prediction Study NICHD; MFM Units Network “No screening test (except history) recommended for low-risk patient” % Low risk pts; n=2197 Iams. AJOG 2001;184:652-5

Group survey question Which patient is most likely to threaten PTB? A) 28 yo P0 @ 17 wks with cx 1dil/2.5 long on US B) 28 yo P0111 @ 17 wks with cx 1 dil/2.5 long C) 28 yo P2002 @ 29 wks with cx 1 dil/2.5 long D) 28 yo P2002 @ 29 wks with cx cl/4 long

Group survey question What is best prophylaxis for P0202 (prior PTB x 2 @ 28-29 wks after spontaneous PTL)? A) Bedrest B) Terbutaline pump C) 17-OH Progesterone 250 mg IM q wk D) Progesterone suppository 100 mg pv qd

Progesterone Steroid hormone – “for gestation” Progesterone production rises from 2-3 mg/d at ovulation to 30 mg/d 1 wk later Progesterone production during pregnancy: 300 – 400 mg/d during 3rd TM (ovary  placenta) Hydrophobic – diffuses thru plasma membrane, binds to cytoplasmic receptor, then moves to nucleus to function as a transcription factor

Progesterone: relaxes myometrium Inhibits gap junction formation Decreases number of oxytocin receptors Immunusuppression

Prevention of recurrent PTB by 17-OH Progesterone caproate Multicenter; n=463 RCT; dbl blind Inclusion: singleton, prior PTB Wkly injection, 16-20 until 36 wks; 17-OH prog caproate or placebo 17-OH-P assoc’d with neonatal risk reduction: NEC, IVH, & O2 need % Meis. NEJM 2003;348:2379-2385

Prevention of PTB by vaginal administration of progesterone % undelivered RCT; n=142 Inclusion: singleton + prior PTB, cerclage, or uterine anomaly Nightly vag suppository @ 24-34 wks: prog100 mg or placebo Wkly ctx monitoring: lower for prog group (p0.01) PTB < 34 wks lower for prog (2.7 vs 18.5%; p<0.05) P=0.03 Wks EGA da Fonseca. AJOG 2003;188:419-24

Can Progesterone prevent PTB? Multiple gestation Polyhydramnios Antepartum bleeding PROM Chorioamnionitis Pyelonephritis Untreated ASB Some fetal anomalies Prior PTB (spontaneous PTL) Low SES Teen Age >34 Prepregnancy weight < 100-110 lb. Uterine or cervical abnormality Maternal smoking

Group survey question What is best prophylaxis for P0202 (prior PTB x 2 @ 28-29 wks after spontaneous PTL)? A) Bedrest B) Terbutaline pump C) 17-OH Progesterone 250 mg IM q wk D) Progesterone suppository 100 mg pv qd

Group survey question Which of the following is not a contraindication to tocolysis: A) Preeclampsia B) Abruption C) Gastroschisis D) Chorioamnionitis

Contraindications to tocolysis Absolute Severe preeclampsia Severe abruption Severe bleeding Chorioamnionitis Fetal death Fetal anomaly incompatible with life Severe fetal growth restriction Relative Mild CHTN Mild abruption Stable placenta previa Maternal disease – cardiac, hyperthyroid, uncontolled DM Fetal distress Mild fetal growth restriction Cx > 5 cm Fetal anomaly Creasy & Resnick, Mat-Fetal Med

Group survey question Which of the following is not a contraindication to tocolysis: A) Preeclampsia B) Abruption C) Gastroschisis D) Chorioamnionitis

Group survey question What is best 1st line tocolytic agent? A) MgSO4 B) nifedipine C) ritodrine D) indomethacin

Mechanisms of tocolytic agents

? ? Tocolysis Rationale PROPHYLACTIC Prevent PTL/PTB Women at risk THERAPEUTIC Prevent PTB Acute PTL Prolong 48 h for steroids Improve neonatal outcome MAINTENANCE After acute treatment Prevent recurrent PTL ? ?

Effect of tocolytics to prevent PTB Meta-analysis1966-1999 OR for delivery at term Many of these studies were performed before widespread corticosteroid use – perhaps contributing to lack of proven improved neonatal outcomes Berkman. AJOG 2003;188:1648-59

Tocolysis Limited benefits – have a plan Don’t forget fetal risks (?benefits) Upcoming considerations Atosiban Selective COX-2 inhibition

MgSO4 for neuroprotection RR * p<0.05 RCT; n=1047 Inclusion: EGA < 30 wks; PTB anticipated in < 24h Mg 4g bolus + 1 g/h (not managed for tocolysis; median administration duration 3+ hrs) * * Crowther. JAMA 2003;290:2669-76

Group survey question What is best 1st line tocolytic agent? A) MgSO4 B) nifedipine C) ritodrine D) indomethacin

PTB prediction and prevention: Conclusions PTD has multifactorial etiology Identification of patients at risk does not: determine etiology direct therapy* necessarily result in improved outcome* * Possible exceptions: 17OHP for treatment BV as contributing risk factor

PTB prediction and prevention: Conclusions Routine screening (BV, US, fFN) not indicated for low risk patients Systemic treatment for BV ’s risk for PTD if hi risk For patients at high risk for PTD, measurement of cervical length and fFN may be useful because of their high NPV Consider progesterone supplementation for women at high risk for PTB Use tocolytics within bounds of reasonable goals