Preterm Labor Prevention Watrin

Preterm Labor Prevention and Treatment Kerry Watrin MD August 2 nd 2007

Objectives: Define preterm labor and its impact Describe Risk Factors for preterm birth Name several ways to prevent preterm birth Identify and diagnose preterm labor Outline an appropriate evaluation and management algorithm for patients who present with preterm labor and PPROM Understand risks and limitations of management strategies for treating patients with preterm labor and PROM

Definitions/ Epidemiology Definitions Preterm Labor : regular contractions with cervical change at <37 weeks gestation Preterm Birth : < 37 & 0/7 days Near term or Late term : 34 & 0/7 to 36 & 6/7 weeks Very preterm : < 32 & 0/7 weeks Extremely Preterm : < 28 & 0/7 weeks Rising Rates of Preterm Birth 1981-2003 PTB < 37 weeks: increase from 9.4 to 12.3% PTB “near term”, : increased from 6.3-8.8%

Race/Ethnicity and Prematurity 2000to 2002 1.5% 10.7% White 1.4% 10.2% Asian 1.7% 11.4% Hispanic 2.0% 12.9% Native American 4.1% 17.6% Black 1.9% 11.9% All US < 32wk US < 37wk Race/Ethnicity

Preterm Birth Causes Multifactorial Spontaneous Preterm Labor (31-50%) Intact membranes PPROM (6-40%) Maternal Illness/Trauma (20-30%) Hypertensive disorders of pregnancy (12%) IUGR (2-4%) Abruption and Previa (6-9%) Structural (20-30%) Multifetal pregnancy (12-28%), Cervical Incompetence Uterine Malformations

Case #1 24 year old NA G2P1 presents at 16 weeks history of spontaneous preterm birth at 26 weeks, (no bleed, PPROM, or maternal illness) Is this patient high risk or average risk for Preterm Birth? What can I do different this pregnancy to prevent preterm birth?

Case #1 Preterm Labor Precautions Lifestyle BMI 18, wt 100 lbs, ¼ PPD tobacco, some marijuana New significant other last 1 month, not father of the baby Screening Labs: Wet Mount/Gram Stain: Bacterial Vaginosis Informed Consent Utox: negative Urine culture: no growth in 2 days Ligase Chain Reaction GC/Chlamydia: negative

Prematurity Risk Factors High Risk/Low incidence PTL after tocolysis 70% Bleeding > 20 wk OR 5.3 Twins 40% Unicornate uterus 30% Gravida 9+ 32% Incompetent cervix 25% Prior preterm birth 25%, with 25-70% Prior PPROM 29% Preterm contracts 25% High Incidence/mild risk Threaten Ab (30%) OR 4.1 Smoking (25%) OR 1.3 Black Race (9%) OR 1.5 Drug use (8%) OR 2.0 UTI/Bacteruria (5%) 2.0 Anemia (5%) OR 2.2 Chronic HTN (5%) OR 1.8 Mild PIH (5%) OR 1.7 3+ Abortions OR 2.9 Late to Care OR 2.0 Scoring systems have low predictive value

Cervical Incompetence Risks Past OB History Prior Midtrimester loss Prior Preterm delivery @ 24-30 weeks Previous cerclage History of multiple 1st Trimester TOP (  2) History of one 2 nd trimester TOP Structural Uterine DES exposure Uterine malformation Hx of Cone Biopsy Current Pregnancy multiple pregnancy

Prematurity Interventions: Lifestyle Some Effect : Nutrition, zinc, folate and caloric supplementation, Smoking cessation Drug abstinence Income support, France and Germany Unknown/Maybe : Domestic Violence screen Light duty for fatigue work Ineffective: Nutrition counseling, vitamins and minerals Hydration Patient Education to detect contractions Psychological support Harmful Nutrition, Protein supplementation Bedrest

Expected pregnancy weight gain 15+ lbs > 29 Obese 15-25 lbs 26-29 High 25-35 lbs 19.8-26 Normal 28-40 lbs <19.8 Low Recommended wt gain BMI Kg/m2 Wt/ht category

Prematurity Interventions: Medical Effective : Rx Asymptomatic Bacteriuria (1970s tetracycline) Progesterone Supplementation Cerclage if prior incompetent cervix Unknown/Maybe : STD treatment BV Rx in high risk Anticoagulant in Thrombophilias Nurse phone calls to home Ineffective : More or enhanced prenatal care Risk Scoring systems Home Uterine Monitoring Treatment of BV in low risk women Cerclage in only short cervix Peridontal Disease treatment Harmful : Antibiotics with intact membranes Tocolysis > 48 hours

Asymptomatic Bacteriuria Defined as > 100K/ml single uropathogen Urine culture is gold standard Dipstick 86% sensitive, 86% specific, 54% PPV, 97% NPV 5-10% of all pregnancies Outcomes if treated (Cochrane database) Pyelonephritis OR 0.24 (0.19-0.32) Pre-term birth OR 0.60 (0.45-0.80)

Bacterial Vaginosis: Clue cell

Bacterial Vaginosis Common occurs in 20%, asymptomatic in 50% Diagnosis by wet mount (3 of 4 criteria: clue cells, pH > 4.5, positive whiff test with KOH for amine odor, thin homogenous discharge) gram stain, criteria on type and amount of bacteria Increased risk of OB complications, RR or 2.3 for preterm delivery, 2.4 for PROM, 3.2 for chorioamnionitis

Bacterial Vaginosis 1995 small (n=426) high risk (prior PTB) RTC showed a 30% decrease in preterm birth with Rx using Erythromycin (14d) and Metronidazole (7d) 2000 Large trial (n= 1953) low risk for PTB diagnosis by gram stain and treatment with metronidazole 2gm stat alone, with no effect AHRQ 2001 Review I rating for “high risk women” D rating for “low risk asymptomatic women”

Bacterial Vaginitis Metronidazole potential harm Metronidazole 2006 PREMET study, 900 screened 24 and 27 weeks for fetal fibronectin, 116 positive, 100 randomized, 400mg TID Metonidazole, 11/53 treated delivered < 37 weeks vs. 18/46 control, RR 1.6 (CI 1.05-2.4) 2001 Trichomonas study, 16-23 weeks, asymptomatic, treated with 2 grams for 2 doses, PTB 60/320 treated, 31/297 placebo, RR 1.8 (CI 1.2-2.7) 2004 Meta-analysis of 4 studies, 182/1,375 treated vs. 180/1,373 control, RR 0.92 (CI 0.52-1.62) for preterm birth, no difference

Bacterial Vaginitis Clindamycin Clindamycin 2003 RTC, Clindamycin low Risk, n= 494, Showed less Preterm Birth 11/244 vs. 28/241, NNT is 17, and less late miscarriage 13-24 weeks, 2 vs. 10, NNT of 10

Prevention with Progesterone High Risk Population of 463 women with prior preterm delivery (NIH study) >50% Black, Average prior birth at 30-31 weeks, one third with more than one prior preterm delivery Exclusions: multifetal pregnancy, planned cerclage, use of heparin or progesterone, chronic HTN on meds, seizure disorder Randomized 2/1 (310/153) double blind placebo weekly IM injections of 250mg 17  hydroxyprogesterone caproate starting 16-20 weeks Groups equal except average of 1.4 vs 1.6 prior preterm births in progesterone vs placebo

Preterm outcomes and Progesterone NNT Relative Risk Placebo N=153 Progest N=306 7 0.66 (.51-.87) 62 41.1% 82 27.2% LBW < 2500 gm 12 0.58 (.37-.91) 30 19.6% 35 11.4% Delivery < 32 wk 10 0.67 (.48-.93) 47 30.7% 63 20.6% Delivery < 35 wk 5 0.66 (.54-.81) 84 54.9% 111 36.3% Delivery < 37 wk

Progesterone Outcomes With Progesterone less NEC, need for O2, Trend but not significant less RDS, and ventilatory support, birth wt < 1,500 gms No difference in fetal or neonatal death, IVH grade 3 and 4, sepsis, anomalies One infant in progesterone group with torsion of testicles and subsequent infarction

Progesterone Meta-analysis Cochrane: Jan 2006, 6 RTCs, 988 patients PTB <37 weeks, RR 0.65 (CI 0.54-0.79), PTB < 34 weeks (one study) RR 0.15 (CI .04-.64), Less LBW RR 0.63 (.49-.81), IVH RR 0.25 (.08-.82) “ Not enough evidence”, desired further information on harms and other maternal and neonatal outcomes European: May 2006, 9 studies, n > 5,800, “ women at high risk of preterm birth should be recommended progestational agent therapy” PTB < 37 weeks, RR 0.42 (CI 0.31-0.57) NNT 9, PTB < 34 weeks, RR 0.51 (CI 0.34-0.77) NNT 42, RDS RR 0.55 (CI 0.31-0.96) Harms not significant

ACOG and Progesterone “ The hormone progesterone may be used as treatment to help prevent preterm birth but should be restricted to pregnant women with a documented history of preterm birth before 37 weeks gestation”

Preterm Birth Risk Stratification Contractions: 50% of those with threatened preterm labor deliver term pregnancies, can we further define risk Biochemical Markers Fetal Fibronectin Biophysical Markers Cervical Length

Markers for Prematurity Preterm Prediction Study: Case control 28 biologic markers studied in 2,929 women at 23 weeks 50 (1.7%) delivered < 32 weeks 127 (4.3%) delivered < 35 weeks

Most Potent Predictive Markers For Preterm Birth < 32 weeks  2 positive below OR 56.5 59% of cases and 2.4% of controls Fetal Fibronectin OR 32.7 > 90 th % AFP OR 8.3 > 90 th % Alk Phos OR 6.8 < 10% Cvx (25 mm) OR 5.8 > 75% GCSF OR 5.5 Any three tests positive 20% of cases and none of controls

Other Markers of Preterm Birth < 32 weeks > 90 th % Ferritin OR 8.0 Past Hx PTB OR 4.5* Vaginal pH  5.0 OR 3.3* Chlamydia Positive OR 2.6 Low Wt, BMI <19.8 OR 2.4 History of bleeding OR 1.8 * P <.05

Fetal Fibronectin Occurs in the choriodecidual junction Decreases 16-20 wks, absent 24-34 wks Taken from the vaginal fornix for 10 seconds, not in cervix No prior coitus or vaginal exam for 24 hrs ROM or bleeding make inaccurate

Fetal Fibronectin Asymptomatic Positive (n=1,530) 18.4% delivery <34 weeks LR 4.01 (2.93 to 5.49) Negative (n=23,150) 96.8% deliver >34 weeks LR 0.78 (0.72-0.84) Symptomatic Birth in 7-10 days Positive (n=1,270) 21% deliver in 7-10d LR 5.42 (4.36-6.74) Negative (n= 5865) 1% deliver in 7-10d LR 0.25 (0.2-0.31) Delivery < 34weeks Positive (n=189) 46.6%, LR 3.64 Negative (n= 498) 93.4%, LR 0.32

Fetal Fibronectin If positive One in 5 symptomatic deliver in 7-10 days One in 5 asymptomatic will deliver by 34 wks Nearly half symptomatic deliver by 34 weeks If negative One in 100 symptomatic deliver in 7-10 days Three in 100 asymptomatic deliver < 34 weeks 6-7 in 100 symptomatic deliver < 34 weeks

Case #2 Low Risk no prior PTB at 25 weeks Size < Dates, 21cm fundal height at 25 weeks Transabdominal Ultrasound shows normal growth cervix is with 1.2 cm length and 1.2 cm wide fluid filled beaking in upper canal Transvaginal Ultrasound repeat shows 2.3 cm long cervix, with again beaking down 1.3-1.5 cm of the length, 1.0 cm from beak tip to external os One hour of tocodynometer shows no contractions Vaginal exam is 2-3 cm long, closed, firm Outpatient vaginal Fetal Fibronectin is negative What precautions for this incidental US finding?

Transvaginal Cervical Length 1996 NEJM study of 2,915 women with US at 24 weeks, repeat on 2,531 at 28 weeks 126 with preterm birth < 35 weeks, 4.3% Was a general population, 42% were nulliparous 16% had history of prior preterm birth There was only 2mm difference between parous and nulliparous women, not clinically important Mean length was 35.2mm at 24 weeks and 33.7 mm at 28 weeks

Rate of Preterm Birth <35 weeks by Cervical Length at 24 weeks 34 % < 13 mm 20 % <20 mm 8 %  25 mm Rate Delivery Length

Ultrasound Cervical Length Prediction of PTB < 35 weeks 17.2% 96.6% 94.5% 25.4% Funneling At 24 wk 17.8% 97% 92.2% 37.3% 25mm 24 weeks 16.7% 97.6% 94.7% 31.3% 20 mm 28 weeks 25.7% 96.7% 97% 23% 20mm 24 weeks PPV NPV Specificity Sensitivity Finding

Cervical Length Caveats Distinguish Average Risk versus High Risk Population studies Cervixes change from the inside out, but digital vaginal exam of Bishops ≥ 4 is significant Ultrasound Higher risk of Preterm Birth with Funneling > 25% Earlier shortening 16 versus 24 weeks More rapid rate, <3mm/week reassuring,  5mm per week concerning at 20-24 weeks

Cerclage and Short Cervix 47,123 screened at 22-25 weeks 430 with cervical length < 15mm 253 in RTC No difference in delivery before 33 weeks with placement of Shirodkar suture 22% (28 /127 cerclage), 26% (33/126 control) RR 0.84 (CI 0.54-1.31) No difference in perinatal or maternal morbidity and mortality

Role of US and Cerclage High risk with 3 prior midterm losses Serial Cervical Length Ultrasound: May have a role in management Assessments should begin no earlier than 16-20 weeks No role for history of 1 st trimester losses Cerclage Only benefit in subgroup 3 prior midtrimester losses or preterm deliveries, 33% watched, 15% cerclage with delivery before 33 weeks, n=107, total groups n=1,292 No benefit in subgroups of one prior MTL/PTD, two prior MTL/PTD, history cone biopsy or cervical amputation, twins, prior TOP/uterine anomalie ACOG Practice Bulletin #48, Nov 2003

Short Cervix and Vaginal Progesterone 2003-2006, 24,620 screened by US at 20-25 weeks for short cervix during prenatal care, 413 with cervix ≤ 15mm, 250 accepted randomization, groups equal, 200mg micronized progesterone vaginally each night, 24 to 33 and 6/7 weeks, avoid intercourse PT Birth < 34 weeks, 26/125 progesterone vs. 43/125 placebo RR 0.60 (CI 0.38-0.86), NNT = 7 Not large enough to see neonatal outcomes

Contractions and Bishops Score And birth before 35 weeks 306 high risk women, singleton pregnancy with prior PTB or 2 nd trimester bleeding Contractions  4 per hour RR was with 3.0 but not significant, At 24 weeks CI (0.6-14.6) At 28 weeks CI (1.0- 8.7) Sens 6.7%, Specificity 92.3%, PPV 25%, NPV 84.7% 75% deliver at term Bishops Score  4 Significant only at 22-24 weeks OR 2.4 (CI 1.7-10.6) Sens 32 %, Specificity 91.4%, PPV 42.1%, NPV 87.4%

Threatened Preterm Labor Preterm Labor due to what? Treat reversible causes, such as UTI, Consider occult trauma of domestic violence, contractions of substance abuse Watch for PPROM, about 1/3 of preterm birth For Idiopathic Preterm Labor Four Categories Inflammation/ Infection Uterine Over-distension/ Structural Decidual Hemorrhage/ Bleeding Premature activation of normal initiators of labor

Idiopathic Preterm Contractions in Triage 179 randomized, singletons, 20-34 weeks, no ROM, no maternal of fetal complication, reassuring FHT 3 contractions/30 min,  1cm dilated,  80% effaced Eligible for discharge when contractions < 2 in 30 minutes, no digital cervical change, one hour apart, Preterm labor if cervical change of dilation of 1 cm or effacement of 25% Terbutaline with 1-2 hour less triage stay No significant outcome differences between Observation, Hydration of 500cc crystalloid then 200 cc/hour, Terbutaline one Subcutaneous dose of 0.25mg

Contractions what to do? 4 (7%) 4 (6%) 5 (9%) PTB < 34 wks $687 $966 $717 Mean cost < 24 hours 5 (8%) 8 (13%) 7 (13%) admitted 8 (13%) 8 (13%) 10 (18%) More tocolysis 79% 57% 64% Triage < 4hrs 4.1  5.1 hrs 6.0  5.7 hrs 5.2  5.1 hrs Mean time to discharge Terbutaline x1, n=61 Hydration N=62 Observation N=56

Case #2 now with contractions Presents 28 weeks with contractions every 5 minutes, Repeat exams and labs Digital cervix some change 1 cm long, medium consistency, posterior, -3 station, closed Fetal Fibronectin now positive US length repeated slightly progressed, 1.2 cm length, 0.7 cm from tip of funnel to external os, GBS culture done, (at 24 hours is positive) Hematocrit 29.5 What approach now with short US cervix, positive fetal fibronectin, and slight clinical shortening?

Case #2, Threatened PTL in High Risk (contracts, +FFN, short cervix) GBS prophylaxis: Penicillin Given Terbutaline 0.25mg SQ/dose tocolysis to allow 48 hours steroids Given Betamethasone 12mg IM q 24 hours times 2 doses ? FeSO4 325mg TID Observe in hospital with level 3 NICU

The Recommendations MMWR, Vol 51 (RR-11)

CDC GBS algorithm for Threatened Preterm Delivery Suggested algorithm for management of threatened preterm delivery (labor or rupture of membranes at <37 weeks’ gestation) which does not proceed rapidly to delivery: Culture and start IV antibiotics Culture negative at 48 hrs: stop antibiotics Culture positive: no data on duration of antibiotics before active labor, when active labor begins give IAP Culture negative and undelivered within 4 wks: re-screen

Agents for intrapartum prophylaxis Recommended agents for women with documented penicillin allergy: Not at high risk for anaphylaxis: cefazolin At high risk for anaphylaxis: Clindamycin or erythromycin if susceptibility testing feasible Vancomycin if erythromycin or clindamycin not options

Antenatal Steroids Intact Membranes and PTL 24-34 weeks Cochrane shows benefit 26 to 34 & 6/7 weeks PPROM and no chorioamnionitis, 24-32 wk Single course recommended Cochrane 2006 Doses 2 doses Betamethasone 12mg q 24 hours 4 doses Dexamethasone 6mg q 12 hours

Antenatal Steroids Cochrane 2006, 21 studies, n = 3,885 women, 4,629 newborns, showing less Neonatal Death: RR 0.69 (CI .58-.81) RDS: RR 0.66 (CI .59-.73) IVH: RR 0.54 (CI .43-.69) NEC: RR 0.46 (CI .29-.74) NICU Ventilator RR 0.80 (CI .65-.99) Neonatal Sepsis RR 0.56 (CI .38-.85) Develop Delay RR 0.49 (CI .24-1.00)

Repeat courses of Antenatal Steroids Cochrane 2006 subgroup weekly repeats, n = 5-900 Less perinatal death RR 0.63 (.48-.92) NNT 7 Less RDS RR 0.55 (.43-.72) NNT 9 Less Chronic Lung RR 0.72 (.54-.96) NNT 15 Lancet 2006, RTC single repeat dose, n = 982 Less RDS RR 0.82 (.71-.95) NNT = 12 Severe lung disease RR 0.60 (.42-.79) NNT = 12 Pediatrics Feb 2007, single repeat dose, n = 249 No difference in neonatal death, RDS or IVH Increased RDS if delivers in first 24 hours after second dose of steroids

Tocolytics: Ca Channel Blockers: dihydropryridines Cochrance 12 trials of 1,029 versus any tocolytic, 9 versus betamemetics, Outcomes Less birth in 48 hrs (vs  agonist) RR 0.72 Less birth in 7 days RR 0.76 (0.60-0.97) Less birth < 34 weeks RR 0.83 (0.69-99) Less RDS RR 0.63 (0.46-.88) NNT 14 Less NEC RR 0.21 (0.05-0.96) Less IVH RR 0.59 (0.36-.98) NNT 13 Less Adverse Effects NNT of 3 Conclusion: “calcium channel blockers should be preferred to betamimetics”

Tocolytics: Magnesium Sulfate Cochrane with 9 of 23 trials of 2000 women No difference in birth < 48 hrs RR 0.85 CI 0.58-1.25), 11 trials of 881 women No difference in birth < 37 or <34 weeks Increase risk of fetal and pediatric mortality RR 7.82 (1.20-6.62), 7 trials 727 infants No difference in neonatal morbidity Non-significant reduction in CP in one trial of 99 infants RR 0.14, (CI 0.01-2.60) Conclusion: Mg Sulfate is ineffective as tocolysis and has increased infant mortality

Tocolytics:  - mimetics 2004 Cochrane Review: 17 trials, 11 trials with 1,320 women are placebo controlled No benefit for Perinatal death RR 0.84 (CI 0.46-1.55) Neonatal death RR 1.00 (CI 0.48-2.09) RDS RR 0.87 (CI 0.71-1.08)

Tocolytics:  - mimetics Did reduce delivery within 48 hours 118/541  mimetic, 158/460 Control OR 0.56, (CI 0.42-0.74) Allows time for antenatal steroids Had more side-effects requiring discontinuation of treatment 3 RTCs, 25/88 (28%)  mimetic, 0/86 control OR 11.5 (CI 4.8-27.5)

COX Inhibitors 2005 Cochrane review: 13 trials of 713 women, 10 trials of indomethacin Trials are small, and there is insufficient evidence Placebo controlled one trial 36 women Birth < 37 weeks, 3/18 indomethacin vs. 14/18 placebo, RR 0.21 (CI 0.07-.62) Versus another tocolytic, 3 trials 168 women Birth < 37 weeks, 13/85 COX vs 24/83 other, RR 0.53 (CI .31-.94)

Tocolytics: ACOG 5/2003 “ All have demonstrated limited benefit”, “may prolong pregnancy 2-7 days- Level A “ No clear first-line tocolytic drug” Level A “ Neither maintenance treatment nor repeated acute tocolysis improve perinatal outcome, neither should be undertaken” Level A “ Bedrest, pelvic rest, hydration, antibiotics should not be routinely recommended” Level B Goals of tocolytic therapy Allow administration of steroids, Level A Allow Maternal transport to tertiary care facility, level A Allow for imminent GBS chemoprophylaxis, Level A

Tocolytics Uncontrolled thyroid or Diabetes Cardiac arrhythmia 0.25mg SQ q 20min-3hr Hold if P>120 Mimetic Terbutaline Myasthenia gravis Also using Calcium channel Blocker 4-6 gm IV bolus in 20 min, then 2-3gm/hr Mag Sulfate Renal failure, Active Ulcer Coagulation disorders NSAID asthma trigger 50 rectal, 50-100 mg PO, then 25-50 orally q6 x 48 hrs NSAID Indomethacin (<32 weeks) Maternal hypotension Also using Magnesium 30-40 mg load PO 10-20 q 4-6hrs CCB Nifedipine Contra- indication Dose and Route Agent

Case #3, PPROM 30 year old G4P3 at 30 weeks feels a “pop and gush” and has leakage of clear fluid from the vagina Her risk factors include previous PPROM at 32 weeks, smoker, anorexia nervosa but no vaginal infections What is the management approach?

Incidence and Natural Hx PROM @ term 10 % PPROM 2 % Prolonged > 24 hours 10% of term Prolonged latency > 48 hrs 62% of preterm Chorioamnionitis will develop in 10% of those lasting beyond 24 hours at term, and in 25% of expectantly managed preterm Increased incidence of abruption, cord accident, infection

PROM Risks Malnutrition, esp vit C and zinc Smoking and substance abuse Infections esp staph aureus, GBS, Chlamydia, GC, Trichomonas, Bacteroides 1st and 3rd Timester Bleeding Incompetent cervix Genetic weak collagen Overdistension or trauma PPROM recurs 25%

Diagnosis Typical History , “pop and gush” 90.3% specific Nitrazine , ( false positive for blood, BV, semen, turns at pH 6.4-6.8) 98.9% sensitive, and 90.3% accurate Fern, 87% accurate, onset after 20 weeks,ok with meconium or blood unless 1 to 1 ratio, cervical mucous (fine) vs amniotic (coarse), Pooling

Diagnosis AFI , to be used as an adjunct if suspicious, Amniocentesis with instillation of indigo carmine dye Vaginal Pool lung maturity tests, PG accurate, LS will decrease with blood, (accurate if Hct <3) and Meconium, FLM not tested on vag pool Cultures, GBS, GC, Chlamydia, wet mount

Sterile Speculum The time clock starts with the first digital exam Studies have shown that infection rate rises with the number of digital exams (  3 is statistically significant, and 7 exams is worse than 3) visual estimation on sterile speculum is accurate for cervical effacement and dilation Keep our fingers out of there !!! Accurate Dates, term (>34 weeks) vs preterm <34 weeks Presentation, breech or unstable lie with polyhydramnios with risk of cord prolapse, premie breech calls for C/section route of delivery, use Leopolds or bedside Ultrasound

Assessment of Fetal Lung Maturity L/S Ratio  2.0/1 (Lecithin/Sphingomyelin) Predictive value for mature 95-100%, Predictive valule for immature 33-50% L/S of blood in 2.0, meconium interferes, should process within one hour decreases with time Phosphastidylglycerol (PG), present Predictive value for mature 95-100% Predictive value for immature 23-53% Not effected by blood/meconium, ok vaginal pool Flourescence Polarization (FLM)  55 mg/g Predictive value for mature 96-100% Predictive value for immature 47-61% Vaginal pool accuracy not known, affected by blood and meconium

Expectant vs Intervene Fetal risks prematurity with RDS, IVH, NEC etc asphyxia due to cord compression, prolapse, or placental abruption neonatal sepsis in micropremies, aplasic lungs Maternal Risks infections, chorioamnionitis, sepsis abruption

Antibiotics for Preterm PROM 2003 Cochrane 22 trials, >6,000 women, Maternal Benefits Less chorioamnionitis : RR 0.57 (CI 0.37-0.86) Neonatal Benefits Prolonged latency : > 48 hours RR 0.71, (CI 0.58 to 0.87), > 7 days RR 0.80, (CI 0.71 to 0.90) Neonatal infection : RR 0.68, (CI 0.53 to 0.87) US abnormality at discharge : RR 0.82, (CI 0.68 to 0.98) Oxygen need: RR 0.88, (CI 0.81 to 0.96) Neonatal Harms NEC with Amoxicillin Clavulanate: RR 4.60, 95% CI 1.98 to 10.72

4/07 ACOG PPROM 34-36 weeks, “near term ”: same as term, proceed to delivery, GBS chemoprophylaxis 32-33 & 6/7 weeks : expectant management, antibiotics to prolong latency, GBS chemoprophylaxis, +/- steroids < 32 weeks : expectant management, single course steroids, antibiotics to prolong latency, GBS chemoprophylaxis Antibiotics: recommend 7 total days, with 1st 48 hours Ampicilln/Amoxicillin and Erythromycin IV, then 5 more days PO

PPROM Interventions Antenatal steroids Recommend use in PPROM @  30-32 weeks Cochrane 2006 Subgroup Analysis Less neonatal death RR 0.58 (.43-.80) NNT 15 Less RDS RR 0.67 (.55-.82) NNT 10 Less NEC RR 0.39 (.18-.86) NNT 23 No difference in chorioamnionitis

PPROM interventions Antibiotics goals GBS prophylaxis Prolong latency >48hrs, 73%, >7d to 41% less chorio 16 vs 25%, neonatal + blood culture 2 vs 10%, & neonate infxn 11 vs 15% same abnormal cranial US, death, RDS, NEC

Oracle 1 trial 4826 women <37 weeks randomized to erythromycin, 250mg QID augmentin, 250/125mg QID both or placebo Gives short term benefit without short term harm Delivery delay 48 hours 98.8% treated vs 95.6% control NNT = 33 Delivery delay by 7 days 63.3% treated vs 57.7% control NNT = 18

Oracle 1 trial No significant differences in treat vs placebo for Low birth weight rate RDS Need for O2 at 36 weeks post conception Positive neonatal blood cultures Short term harm Augmentin with more necrotizing colitis 1.8% Augmentin vs 0.7%, NNH = 91 Long term harm unknown Histologic chorioamnionitis is correlated with more US neonatal brain abnormalities, ? If we keep them in longer how will they do in kindergarten

Cerebral Palsy Retrospective Case control study mentioned in discussion in Oracle 1 trial 59 born < 32 weeks with Cerebral palsy Risk factors Prolonged ROM > 24 hours OR 2.3 (1.2-4.3) Chorioamnionitis OR 4.2 (1.4-12.0) Maternal infection OR 2.3 (1.2-4.5)

Conclusions Preterm birth has multi-factorial causes For prevention of Preterm Birth Optimize lifestyle and nutrition Screen for asymptomatic Bacteriuria Progesterone holds promise in high risk populations Threatened Preterm Labor is a common problem, yet 50% deliver at term Before using reactive tocolytics evaluate for possible causes, Preterm contractions due to what? Interventions that are bottom-line in threatened preterm labor are: Antenatal steroids Maternal Transport and delivery at tertiary care center GBS prophylaxis

Conclusions Prevent PPROM with good nutrition, smoking and drug cessation, rx infections secure the diagnosis & keep your fingers out of there secure the dates, transfer premies to appropriate level NICU/maternal unit, induce near-term PROM ≥ 34 weeks Antibiotic and Steroid use Betamethasone  32 weeks Erythromycin for 48 hours for latency for steroids <32 weeks GBS prophylaxis

References Epidemiology/Reviews Hollier, Lisa, Preventing Preterm Birth, What works, what doesn’t, Obstetrical and Gynecological Survey, 2005, Vol 60, #2, p124-131 Siman, H & Caritis S, Review Article, Drug Therapy, Prevention of Preterm Delivery, NEJM 2007, Aug 2 nd , 357; p 477-87 Tonse, R, Epidemiology of Late Preterm (Near-term) Births; Clinical Perinatology 2006, 33: p751-763 ACOG Practice Bulletins : October 2001, #31, Assessment of Risk Factors for Preterm Birth May 2003, #43, Management of Preterm Labor Nov 2003, #48, Cervical Insufficiency April 2007, #80 Premature Rupture of the Membranes

References: Cochrane Reviews: Anotayanonth, S et al, Betamimetics for inhibiting preterm labour, Oct 18 th 2004 Crowther, C et al, Magnesium Sulfate for preventing preterm birth in threatened preterm labor, Oct 21 st 2002 King, J et al, Cyclo-oxygenase (COX) inhibitors for treating pretem labour, Feb 2 nd 2005 King, J et al, Calcium Channel Blockers for inhibiting Preterm Labor, Jan 20 th , 2003 Roberts D, Dalziel, S; Antenatal Steroids for accelerating fetal lung maturation in women at risk of preterm birth, May 15 th 2006

References Preterm Labor Iams, J Prediction and Early Detection of Preterm Labor, OB/Gyn 2003: 101: 402-12 Slattery, M and Morrison J, Preterm delivery, Lancet, Vol 360, 11/9/2002, p 1489-1497 Gerdingen, D, Premature Labor Part 1; Risk Assessment, Etiologic Factors and Diagnosis, Journal American Board of Family Practice, Sept-Oct 1992 Vo 5, #5, p 498 Goldenberg, R and Rouse D, Prevention of Premature Birth, NEJM, July 30, 1998, Vol339, #5, P 313-320 Cervical Length Iams, J et al, The length of the cervix and the risk of spontaneous premature delivery, NEJM, Vol 334, #9, p567-96 Meekai S To, et al, Cervical cerclage for prevention of preterm delivery in women with short cervix: randomized controlled trial, Lancet, Vol 363, June 5 th 2004, p 1849-53

References Fetal Fibronectin Goldenberg, R et al, The Preterm Prediction Study: Toward a multiple marker test for spontaneous preterm birth,Am J Ob Gyn Sept 2001, Vol 185, #3, p 643-651 Honest, H, Accuracy of cervicovaginal fetal fibronectin test in predicting risk of spontaneous preterm birth: systemic review, BMJ, Vol 325, Aug 10 2002, p1-10 Tocolysis Gyetvai, Kristen, et al, Tocolytics for Preterm Labor: A Systematic Review, OB/Gyn Vol 94 (5 part 2) Nov 1999, p 869-877

References Infections: BV Hauth, J Reduced Incidence of Preterm Delivery with Metronidazole and Erythromycin in women with Bacterial Vaginosis, NEJM Dec 28, 1995, p 1732-1736 Carey, C et al, Metronidazole to prevent preterm delivery in pregnant women with asymptomatic Bacterial Vaginosis NEJM, Vol 342 (8) Feb 24 th 2000, pp 534-540 Riggs M & Klebanoff M, Treatment of vaginal infections to prevent preterm birth: a Meta-Analysis, Clinical Obstetrics and Gynecology, 2004 Vol47, #4, p796-807 Shennan A, et al, A Randomized controlled trial of metronidazole for prevention of preterm birth in women with positive Cevicovaginal fetal fibronectin: the PREMET study, BJOG 2006, 113:, p 65-74

References Infections BV USPSTF, Screening for Bacterial Vaginosis in Pregnancy, Recommendations and Rationale, Amer Fam Physician, March 15 th , 2002, Vol 65, #6 p 1147-1150 Ugwumadu, A et al, Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomised controlled trial, Lancet vol 361, 3/22/2003, p 983-988 Infections 2002 revised group B strep prevention guidelines. MMWR in Volume 51, RR-11.August 16 th 2002

References Preterm Contractions and Digital Cervix Iams, J et al, Requency of uterine contractions and the risk of spontaneous preterm birth NEJM 2002: 346: 250-5 Guinn, D et Al Management options in women with preterm uterine contractions: a randomized controlled trial, Am J Obstet Gynecol Vol 177, #4, 1997, p 814-815 Other Crowther, C et al, Neonatal Respiratory Distress Syndrome after Repeat exposure to antenatal corticosteroids: a randomized controlled trial; Lancet 2006, 367, p1913-19 Peltoniemi, O et al, Randomized Trial of a single repeat dose of betamethasone treatment in imminant preterm birth, Peds Feb 2007, vol 119, #2, p 290-298

References: Progesterone Meis, P et al, Prevention of Recurrent Preterm Delivery by 17 Alpha-Hydroxyprogesterone Caproate, NEJM Vol 348 #24, June 12 th 2003, p 2379-85 Da Fonseca, E et al, Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: A randomized placebo controlled double blind study, Am J OB Gyn, Vol 188 (2) Feb 2003, pp 419-424 Coomarssamy, A et al, Progesterone and the prevention of preterm birth, a critical review of the evidence, European J OB/Gyn, 2006, 129: p111-118 Dodd, JM et al, Prenatal administration of progesterone for preventing preterm birth, Cochrane, Jan 25 th 2006

References PPROM Hartling, l et al, A systematic review of intentional delivery in women with premature prelabor rupture of membranes, j of Mat-fetal and Neonatal Med, March 2006 19 (3), 177-187 Wu, Y et al, Chorioamnionitis as a risk factor for Cerebral Palsy, a meta-analysis, JAMA, 2000, 284: p1417-24 Grier, M et al, Do antibiotics improve neonatal outcomes in PPROM, J of Fam Prac, Vol 50(7), July 2001, p626 Kenyon et al, Broad-Spectrum antibiotics for preterm prelabour rupture of fetal membranes: The ORACLE I randomized trial, Lancet 2001; 357: 979-88 Naef, R et al, PROM at 34 to 37 weeks gestation: aggressive vs conservative management, Am J OB/Gyn 1998; 178: 126-30

References Progesterone: Fonseca, E et al, Progesterone and the Risk of Preterm Birth among women with a Short Cervix, NEJM, 2007, Aug 2 nd , 357; p 462-9 Rouse, D et al, A Trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins, NEJM, 2007, Aug 2 nd , 357; 454-61

PROM @ 34-37, “Near-term” Naef, AmJOB/Gyn, Jan 1998, p126 prospective randomized 120 patients RDS - 3 induce/ 3 expectant Neonate mech vent, 2 induce/ 3 expectant Chorioamnionitis 2% induce / 16% expectant significant to p=0.007 neonatal sepsis 0 induce / 3 expectant NS

PPROM 30-36 weeks: Metanalysis 4 studies, 389 women, 391 babies 1987-98, no steroids, no tocolysis, only one study gave antibiotics as GBS prophylaxis Intentional delivery with Less chorioamnionitis RR .16 (CI .10-.23) NNT 6 Maternal shorter length of stay, 1.4 days shorter No difference (induce/wait) in RDS 33/191 vs 36/200, IVH 6 vs 3, NEC 1 vs 2 Confirmed Neonatal sepsis 11/191 to 12/200 NICU stay 11 vs 11.7 days Perinatal mortality 0/191 to 3/200 (2 anomalies)

Risk of Preterm Birth < 35 weeks compared to cervical length of the 75% 1.0 1.0 75% 40 mm 9.5 6.7 10% 26 mm 13.9 9.5 5% 22 mm 24.9 14 1% 13 mm 28 weeks RR of PTB 24 weeks RR of PTB Percentile On Curve Length

Lifestyle: Drug Screening Self Report 3,142 Washington women, 40% participation Ever used IV Drugs 2% Ever Cocaine 15% Ever methamphetamine 11% This Pregnancy Marijuana 7% ETOH binge or daily use 2% Tobacco 18%

Vaginal Progesterone RTC of 142 High Risk singletons with prior preterm delivery in Brazil Vaginal Progesterone 100mg nightly 24-34 weeks 13/70 (18.6%) Placebo and 2/72 (2.8%) progesterone delivered before 34 weeks, RR of 0.11, NNT of 4

Tocolytics:  - mimetics 2004 Systematic Review OR 0.79 CI (0.61-1.01) 5 RTC 55%, 332/601  mimetic 65%, 332/525 placebo LBW < 2,500 gms OR 0.76 CI (0.57-1.01) 6 RTC 18%, 117/639  mimetic 25%, 140/565 placebo RDS OR 1.08 CI (0.72-1.62) 7 RTC 9%, 62/682  mimetic 8%, 48/604 placebo Perinatal Mortality OR Sample Finding

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