Preterm Labor Prevention and Treatment

Kerry Watrin MD

August 2nd 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

Race/Ethnicity US

< 37wk

US

< 32wk

All 11.9% 1.9%

Black 17.6% 4.1%

Native American 12.9% 2.0%

Hispanic 11.4% 1.7%

Asian 10.2% 1.4%

White 10.7% 1.5%

2000to 2002

Preterm Birth CausesMultifactorial

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 2nd

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

Wt/ht category

BMI

Kg/m2

Recommended wt gain

Low <19.8 28-40 lbs

Normal 19.8-26 25-35 lbs

High 26-29 15-25 lbs

Obese > 29 15+ lbs

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 VaginitisMetronidazole 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 VaginitisClindamycin

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

Progest

N=306

Placebo

N=153

Relative Risk

NNT

Delivery < 37 wk

111

36.3%

84

54.9%

0.66

(.54-.81)

5

Delivery < 35 wk

63

20.6%

47

30.7%

0.67

(.48-.93)

10

Delivery < 32 wk

35

11.4%

30

19.6%

0.58

(.37-.91)

12

LBW < 2500 gm

82

27.2%

62

41.1%

0.66

(.51-.87)

7

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 belowOR 56.5– 59% of cases and 2.4% of controls

Fetal Fibronectin OR 32.7 > 90th % AFP OR 8.3 > 90th % 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

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 #2Low 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

Length Rate Delivery

25 mm 8 %

<20 mm 20 %

< 13 mm 34 %

Ultrasound Cervical LengthPrediction of PTB < 35 weeks

Finding Sensitivity Specificity NPV PPV

20mm

24 weeks

23% 97% 96.7% 25.7%

20 mm

28 weeks

31.3% 94.7% 97.6% 16.7%

25mm

24 weeks

37.3% 92.2% 97% 17.8%

Funneling

At 24 wk

25.4% 94.5% 96.6% 17.2%

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 1st 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 ScoreAnd birth before 35 weeks

306 high risk women, singleton pregnancy with prior PTB or 2nd 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?Observation

N=56

Hydration

N=62

Terbutaline x1, n=61

Mean time to discharge

5.2 5.1 hrs

6.0 5.7 hrs 4.1 5.1 hrs

Triage

< 4hrs

64% 57% 79%

PTB < 34 wks 5 (9%) 4 (6%) 4 (7%)

More tocolysis 10 (18%) 8 (13%) 8 (13%)

admitted 7 (13%) 8 (13%) 5 (8%)

Mean cost < 24 hours

$717 $966 $687

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 Agents for intrapartum prophylaxisprophylaxis

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

Agent Dose and Route Contra- indication

CCB

Nifedipine

30-40 mg load PO 10-20 q 4-6hrs

Maternal hypotension

Also using Magnesium

NSAID

Indomethacin

(<32 weeks)

50 rectal, 50-100 mg PO, then 25-50 orally q6 x 48 hrs

Renal failure, Active Ulcer

Coagulation disorders

NSAID asthma trigger

Mimetic

Terbutaline

0.25mg SQ q 20min-3hr

Hold if P>120

Uncontrolled thyroid or Diabetes

Cardiac arrhythmia

Mag Sulfate 4-6 gm IV bolus in 20 min, then 2-3gm/hr

Myasthenia gravis

Also using Calcium channel Blocker

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 2nd, 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

18th 2004 Crowther, C et al, Magnesium Sulfate for preventing preterm birth in

threatened preterm labor, Oct 21st 2002 King, J et al, Cyclo-oxygenase (COX) inhibitors for treating pretem

labour, Feb 2nd 2005 King, J et al, Calcium Channel Blockers for inhibiting Preterm Labor,

Jan 20th, 2003 Roberts D, Dalziel, S; Antenatal Steroids for accelerating fetal lung

maturation in women at risk of preterm birth, May 15th 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 5th 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 24th 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 15th, 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 16th 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 12th 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 25th 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 2nd, 357; p 462-9

Rouse, D et al, A Trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins, NEJM, 2007, Aug 2nd, 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%

Length Percentile

On Curve

24 weeks RR of PTB

28 weeks RR of PTB

13 mm 1% 14 24.9

22 mm 5% 9.5 13.9

26 mm 10% 6.7 9.5

40 mm 75% 1.0 1.0

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

Finding Sample OR

Perinatal Mortality

7 RTC

9%, 62/682 mimetic

8%, 48/604 placebo

OR 1.08

CI (0.72-1.62)

RDS 6 RTC

18%, 117/639 mimetic

25%, 140/565 placebo

OR 0.76

CI (0.57-1.01)

LBW < 2,500 gms

5 RTC

55%, 332/601 mimetic

65%, 332/525 placebo

OR 0.79

CI (0.61-1.01)

2004 Systematic Review