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CHIEF EDITORS NOTE: This article is part of a series of continuing education activities in this Journal through which a totalof 36 AMA/PRA category 1 credit hours can be earned in 0. Instructions for how CME credits can be earned appear on the

last page of the Table of Contents.

An Evidence-Based Approach to theEvaluation and Treatment of Premature

Rupture of Membranes: Part IITimothy P. Canavan, MD, FACOG,* Hyagriv N. Simhan MD, MSCR, and

Steve Caritis, MD*Fellow, MaternalFetal Medicine, Assistant Professor, and Director of MaternalFetal Medicine, Magee

Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania

Preterm premature rupture of membranes (PPROM) occurs in 3% of pregnancies and is respon-

sible for one third of all preterm births. In part I of this series, the definition, pathophysiology, and

diagnosis of PPROM was reviewed. In this part, treatment is discussed. Adjunctive antibiotic and

corticosteroid therapy has the strongest evidence for improving neonatal outcome. Treatment is

gestational age-dependent and will be influenced by local neonatal intensive-care unit (NICU)

survival statistics. This review presents the available evidence and grades it according to the U.S.

Preventative Task Force recommendations.

Target Audience: Obstetricians & Gynecologists, Family Physicians

Learning Objectives: After completion of this article, the reader should be able to summarize the data

on the use of labor inhibition in the setting of PPROM, list potential antibiotics regimens that arerecommended for prophylaxis in patients with PPROM, to describe the benefits of corticosteroid admin-

istration in patients with PPROM, and to outline potential management strategies for patients with PPROM

based on gestational age.

The perinatal complications of preterm prematurerupture of membranes (PPROM) change with gesta-tional age at rupture requiring a gestational age ap-proach to treatment. There is little maternal benefit toconservative management, but there can be signifi-cant neonatal benefit, especially in the late second

and early third trimester. The benefits of conserva-tive management are mainly in pregnancy prolonga-tion that has the potential to decrease gestational

age-related morbidity from prematurity. This must bebalanced with the risks of conservative management,which include cord prolapse, abruptio placentae,perinatal infection, emergent delivery for a nonreas-suring fetal status, and fetal death.

LABOR INHIBITION

Labor-inhibiting agents have been evaluated in theconservative management of PPROM and found tohave limited value. Two studies evaluated the bene-fits of ritodrine. Christensen and associates per-formed a randomized double-blind study amongwomen with PPROM between 28 and 36 weeks.Ritodrine was compared with placebo, and althoughpregnancy was prolonged for 24 hours longer withritodrine than with placebo, there was no obvious

Reprint requests to: Timothy P. Canavan, MD, FACOG, Magee

Womens Hospital, Department of Obstetrics, Gynecology & Re-

productive Sciences, 300 Halket Street, Pittsburgh, PA 15213.

E-mail: [email protected]

The authors have disclosed no significant financial or other

relationship with any commercial entity.

The authors have disclosed that Betamethasone, Dexametha-

sone, Magnesium sulfate, and Terbutaline are not approved by the

FDA for use during pregnancy.

CME REVIEWARTICLEVolume 59, Number 9

OBSTETRICAL AND GYNECOLOGICAL SURVEY

Copyright 2004

by Lippincott Williams & Wilkins27

678


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clinical benefit (duration of pregnancy after 24 hoursfrom PPROM, Apgar scores, birth weight, and respi-ratory distress syndrome) (1). Levy and Warsof per-formed a prospective, randomized trial comparingritodrine with no tocolysis in patients at 25 to 34weeks with PPROM without any evidence of laborand found an increase in latency (10 vs. 3.5 days,P 0.033) with 47.6% of the treated patients versus14.2% of those untreated having a latent period ofmore than 1 week (2). They did not evaluate neonataloutcome and had no evidence that the increasedlatency had any clinical benefit (neonatal or mater-nal). Weiner and associates evaluated the cost-effec-tiveness of tocolysis with ritodrine, terbutaline, ormagnesium sulfate in patients with PPROM at lessthan 34 weeks and reported a nonsignificant prolon-

gation of pregnancy (105.2

157 vs. 62.1

77hours, P 0.06), but there was no significant reduc-tion in cost or improvement in perinatal outcome (3).A prospective, randomized trial comparing magne-sium sulfate tocolysis with no tocolysis in patientswith PPROM between 24 and 34 weeks by How andassociates (4) found no significant improvement inperinatal outcomes. In this study, both groups re-ceived corticosteroids and antibiotics (4). Thus, la-bor-inhibiting agents can prolong pregnancy inwomen with PPROM, but there are no data to indi-cate that this prolongation has any benefit in terms of

perinatal outcome. This lack of evidence is in part theresult of limited sample size because most studieswere not powered to address this assertion.

Based on the evidence stated here and the evidenceforthcoming on corticosteroid therapy, patients withPPROM at 32 weeks or less could be offered initialacute labor inhibition to achieve 48 hours of cortico-steroid benefit. This should only be considered in theabsence of clinically apparent or subclinical amnioticfluid infection, abruptio placentae, nonreassuring fe-tal status, or other maternal/fetal contraindications tolabor inhibition. Figure 1 presents this option.

The literature currently does not support the use ofmaintenance or prophylactic labor-inhibiting agentsbeyond the initial 48 hours to provide corticosteroids.In the setting of recurrent labor in PPROM in theextremely preterm (less than or equal to 28 weeks)gestation, amniocentesis could be performed for thedetection of amniotic fluid infection in light of thehigh frequency of amniotic fluid infection amongwomen with PPROM (see part I of this review). Inthe absence of any evidence to the contrary, laborinhibition could be considered in this group in theabsence of subclinical amniotic fluid infection.

ANTIBIOTICS

The benefits of group B streptococcal (GBS) pro-phylaxis are well established (5,6). Intrapartum pro-phylaxis should be initiated in any patient with an

unknown GBS status or a history of a positive cultureduring the present pregnancy (treatment is not indi-cated if there was a negative anovaginal culture in thepast 2 weeks). Therapeutic options include a 5-mil-lion-unit bolus of intravenous penicillin followed by2.5 million units every 4 hours; or a 2-g bolus ofintravenous ampicillin followed by 1 g every 4 hours;or 500 mg intravenous erythromycin every 6 hours;or 900 mg intravenous clindamycin every 8 hours(penicillin allergy) (6). The Centers for Disease Con-trol and Prevention has recommended that a 2-gintravenous loading dose of cefazolin (Ancef; Smith-

Kline Beecham, Philadelphia, PA) followed by 1 gevery 8 hours be used in patients with an uncertainpenicillin allergy or with a minor allergic reaction(rash) (6).

Adjunctive antibiotic therapy has been recom-mended in the conservative management of PPROMwith the goal to prevent or treat ascending intrauter-ine infection thereby prolonging pregnancy and de-creasing maternal and neonatal infection. Numerousstudies have been performed to evaluate the benefitof antibiotics and have found significant evidencethat adjunctive antibiotics are beneficial in the con-servative management of PPROM. Table 1 providesa summary of those studies that were placebo-con-trolled.

Therapies have varied by antibiotic choice, route ofdelivery, and duration of treatment. The NationalInstitute of Child Health and Human DevelopmentMaternalFetal Medicine Unit Network (NICHDMFMU) study found that published evidence andexpert opinion supported starting with intravenoustherapy for 48 hours using ampicillin and erythromy-cin. This was followed by a limited course of oral

therapy of both drugs. This trial found that antibioticsimproved neonatal health by reducing the risk ofrespiratory distress syndrome (RDS), early sepsis,severe intraventricular hemorrhage (IVH), and se-vere necrotizing enterocolitis (NEC) (compositemorbidities down from 53% to 44%, P 0.04) (7).There was a decrease in amnionitis and an increase inthe likelihood of latency for longer than 1 week.

Several studies have evaluated ampicillinsulbac-tam followed by amoxicillinclavulanic acid, but Ke-nyon and associates (8) raised concern for this regi-men as a result of an increased risk of NEC in their

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Fig. 1. Algorithm for the management and treatment of PPROM. Abx antibiotics; Amnio amniocentesis; D&E dilatation and

evacuation; FLM fetal lung maturity testing; GBS group B streptococcus; GC gonorrhea; LEA leukocyte esterase; OCT

oxytocin challenge test; PPROM preterm premature rupture of membranes; WBC white blood cell count.

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TABLE1

Prospectiverandomized

placebo-controlledstudiesevaluating

adjunctiveantimicrobialtreatmentforPPROM

Authors

Sample

Size

GA

(wk)

Antibiotics

Outcomes

Kenyon20018

4826

37

EES250mg,

Co-amoxiclav,

both,placeboq6X10d

EESassocw2

neonataldeath,2

lungd

z,2

majorce-

rebralabnormalityonus.

Co-amoxicla

vsameaspla-

cebowith1

NEC.

Bothprolongedpregnancy.

Mercer19977

614

2432

Amp2gm

IV

EES250

mgq6hX48hthenamox250mg

po

EES33mgpoq

8hX5d

Abx:2

RDS,2

IVH,2

NEC,2

fetaldeath,2

fetalsepsis

(compositeoutcome44.1

%

vs.

52.9%

,P

.04).In

GBSnegativewomenpregnancyprolonged(6.1vs.

2.9

days,

P

.001)

OvalleSalas199732

88

2434

Clindamycin600mgIV

Gent4mg/kg/dX48hthen

Clindamycin300mgp

oq6h

Gent2mg/kg/dIM

q12h

X5d

1

latency(10.5vs.

4d,

P

.05);2

mate

rnalinfection

(4.8

%

vs.

28.9

%,

P

.01);2

RDS(9.5

%

vs30.2

%,

P

.05);2

NICUadmissions(54.8vs.

86%,

P

.01).Notocolyticsorsteroidsused

Lovett199733

112

2335

1.

Amp-sul1.5gm

IVq6hX72hthenamox-cla500mgpo

q8htodel;2.

Amp2g

m

IVq6hX72hthenamox500mg

poq8htodel3.placebo

Grp1vs.

Grp3:2

neonataldeath,sepsis

&RDS(26.3

vs.

48.6

%,

P

.05),1

MBW

(P

.02),1

latency

(13.1/-1.9vs.

6.8/-1.9

days,

P

.

025),1

Apgars

@1&5mingrp1&grp2,

P

.05,2

chorio(grp1:

10.5

%

vs.grp2:18.9

%

vs.grp3:32.4%

,P

0.0

5)

Lockwood34

75

2434

Piperacillin3gm

IVq6hX72h

Abx:1

latency(11vs.

6d,

P

.001)

Johnston199035

85

2034

MezlocillinIVX48hthen

amoxpountildel(dosesnot

given)vs.placebonosteroidsortocolytics

1

latency

7d(45vs.

18%,

P

.01);2

chorio(7vs.

35%,

P

.01);2

endo(12vs.

33%,P

.05);

1

MBW

(1897vs.

1587gm,

P

.05);

1

Apgar1min

(6.9vs.

5.4,

P

.05);2

sepsis,

IVH&

hospital

stay30d(P

.05)

Amp

ampicillin;Amox

amoxicillin;chorio

chorioamnionitis;cla

clav

ulanate;Co-amoxiclav

amoxicillin250

mg

clavulanicacid125mg;d

days

;del

delivery;

dz

disease;EES

erythromycin;endo

endometritis;Gent

gentamicin;GB

S

groupBstreptococcus;IVH

intraventricularhemorrhage;MBW

meanbirthweight;NEC

necrotizingenterocolitis;RDS

respiratorydistresssyndrome;sul

sulbacta

m;US

ultrasound.

Evaluation and Treatment of Premature Rupture of Membranes Y CME Review Article 681


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patients. Until this is substantiated or refuted in fu-

ture trials, these drugs should be avoided.Azithromycin can be considered as an alternative

to erythromycin in view of its improved patient tol-

erance (less gastrointestinal upset and vascular scle-rosis) and similar mechanisms of action. A reason-able dose equivalent would be 500 mg orally on day

1 followed by 250 mg daily for 6 days.

CORTICOSTEROIDS

The administration of antenatal corticosteroids to

patients at risk for delivery of a premature infant hasbeen clearly shown to reduce perinatal morbidity andmortality. The National Institute of Health consensus

conference of 1994 recommended corticosteroid ad-ministration in patients with PPROM before 30 to 32weeks using a single course of either betamethasone

(12 mg intramuscularly every 24 hours 2 doses) ordexamethasone (6 mg intramuscularly every 12hours 4) (9). The consensus found that corticoste-

roids reduced the incidence of RDS, IVH, and neo-natal mortality. There was some uncertainty regard-

ing a possible risk that corticosteroids could increasethe risk of neonatal infection, but 2 randomized,controlled trials (RCTs) have not found any associ-

ation. Lewis et al. (10) studied patients with PPROM

between 24 and 34 weeks who received antibioticsand corticosteroids and found a reduced risk of RDS

(18.4 vs. 43.6%, P 0.03) without evidence ofincreased neonatal infection (3% vs. 5%, P not

significant). A recent metaanalysis by Harding andassociates (11) found that corticosteroids adminis-tered to patients with PPROM reduced the risks of

NEC (relative risk [RR], .21; 95% confidence inter-val [CI], 0.05.82), IVH (RR, .47; 95% CI, 0.31.7),RDS (RR, .56; 95% CI, 0.46.7) without any signif-

icant increased risk in maternal infection (RR, .86;95% CI, 0.611.2) or neonatal infection (RR, 1.05;

95% CI, 0.661.68).This information supports the concept that a single

course of antenatal corticosteroid is highly advanta-

geous in PPROM before 32 weeks gestation. If thepatient has documentation of immaturity (negativefetal maturity testing of the vaginal pool) or there is

no fluid for testing, corticosteroids therapy could beconsidered in patients with PPROM from 32 to 34weeks. The balance of risks and benefits of repeated

corticosteroid courses has not been determined andtherefore repeated courses are not recommended.

ANTENATAL FETAL SURVEILLANCE

Antenatal fetal surveillance (AFS) is recommendedduring conservative management of PPROM. Regi-mens vary and are usually based on expert opinion.

The 2 most common testing modalities are the non-stress test (NST) and the biophysical profile (BPP).The goal of testing is to predict untoward fetal out-come from the 2 major sources of fetal compromise:umbilical cord compression (secondary to oligohy-dramnios or anhydramnios) and chorioamnionitis.

NONSTRESS TESTING

Moberg and associates (12) performed a studycomparing the fetal heart rate patterns of 267 patients

with PPROM between 28 and 35 weeks with 130patients with preterm labor and intact membranes.Preterm premature rupture of membranes increasedthe incidence of cesarean section for fetal distress(7.9 vs. 1.5%, P 0.05) with or without chorioam-nionitis and 76% of the fetuses with fetal distresshad patterns consistent with severe cord compres-sion. Harding and associates (13) followed 50 pa-tients with PPROM between 23 and 34 weeks withdaily NSTs and noted that variable decelerations andnonreactive NSTs predicted a significantly lower am-niotic fluid index (AFI). Hoskins and associates (14)

followed 3158 patients at34 weeks with NSTs andAFI measurements and found that fetuses with spon-taneous deceleration on their NSTs with an AFI lessthan 5 had an increased incidence of operative deliv-eries for fetal distress and increased incidence ofneonatal acidosis and low Apgar scores. These stud-ies suggest that the NST could be used to monitor forlow AFI and cord compression in patients withPPROM. There is no evidence to guide the frequencyof testing or the actual thresholds for delivery. Thenegative predictive value of the NST, as a means ofprimary fetal surveillance for stillbirth within 1 week

of a negative test, is 99.8% (1.9 per 1000) (15).Expert opinions recommend a range of frequency ofNSTs in women with PPROM, from daily to twiceweekly (13,17). Test frequency between daily totwice weekly would seem reasonable when lookingfor evidence of cord compression as a result of lowAFI.

Vintzileos and associates (16) reviewed the recordsof 127 patients with PROM from 25 to 41 weeksevaluating the NST findings with the outcome ofamnionitis and/or neonatal sepsis and found the sen-sitivity and specificity of the NST for predicting

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infection was 78.1% and 86.3%, respectively (seepart I of this review).

BIOPHYSICAL PROFILE

There are presently no data to determine the fre-quency of biophysical profile (BPP) testing inPPROM. A reasonable course of testing could be 1)BPP twice weekly for those patients whose AFI isgreater than or equal to 5 or 2) BPP daily for thosepatients whose AFI is less than 5 and continuedexpectant management as planned.

TIMING OF DELIVERY

Previable Preterm Premature Rupture of Mem-

branes (

24 weeks gestation)Previable PPROM presents many challenges. The

major issue concerns immediate delivery that can belethal or associated with a high risk of serious mor-bidity. Previable PPROM has been associated withincreased perinatal infection and is frequently asso-ciated with fetal pulmonary hypoplasia (17). Fetalrestriction deformities, as seen in Potters syndrome,are a risk with previable PPROM in the presence ofpersistent oligohydramnios or anhydramnios.

Studies (see Table 2) indicate that survival in-creases as the gestational age at PPROM increases

and as birth weight increases (18). This would indi-cate that latency is an important factor for neonatalsurvival in these patients. However, these patientsface several factors that lead to fetal morbidity andmortality. Amnionitis, advanced labor, and nonreas-suring fetal status usually force the clinician to affectdelivery despite fetal immaturity. As noted in Table2, 24% to 71% require delivery as a result of amnio-nitis and more than 50% of patients are delivered by1 week in most studies. Perinatal mortality is high(range, 3775%) especially among newborns in theless than 24-week groups and intact survival in-

creases as gestational age at PPROM increases.Patients with PPROM before 24 weeks should be

counseled carefully about the maternal and neonatalrisks and outcomes associated with PPROM beforeviability. Table 2 provides data on recent prospectiveand retrospective trials on outcomes that can be usedto guide patients in their decisions. Several studiesnoted maternal deaths in expectantly managed pa-tients and this should be included in counseling.Figure 1 gives guidelines for clinical management.

After 24 to 48 hours of observation and appropriatecounseling, patients can be monitored as outpatientsTA

BLE2

Outcomefrom

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