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HIGH-RISK PREGNANCY SERIES: AN EXPERTS VIEW

We have invited select authorities to present background information on challenging clinical problems andpractical information on diagnosis and treatment for use by practitioners.

The Management of Preterm Labor

Robert L. Goldenberg, MD

Preterm birth is the leading cause of neonatal mortalityand a substantial portion of all birth-related short- andlong-term morbidity. Spontaneous preterm labor is re-sponsible for more than half of preterm births. Its manage-ment is the topic of this review. Although there are many

maternal characteristics associated with preterm birth, theetiology in most cases is not clear, although, for the earliestcases, the role of intrauterine infection is assuming greaterimportance. Most efforts to prevent preterm labor have notproven to be effective, and equally frustrating, most effortsat arresting preterm labor once started have failed. Themost important components of management, therefore,are aimed at preventing neonatal complications throughthe use of corticosteroids and antibiotics to prevent group Bstreptococcal neonatal sepsis, and avoiding traumatic de-liveries. Delivery in a medical center with an experiencedresuscitation team and the availability of a newborn inten-sive care unit will ensure the best possible neonatal out-

comes. Obstetric practices for which there is little evidenceof effectiveness in preventing or treating preterm laborinclude the following: bed rest, hydration, sedation, homeuterine activity monitoring, oral terbutaline after success-ful intravenous tocolysis, and tocolysis without the concom-itant use of corticosteroids. (Obstet Gynecol 2002;100:102037. 2002 by The American College of Obstetri-cians and Gynecologists.)

PREMATURITY

A preterm delivery, as defined by the World HealthOrganization, is one that occurs at less than 37 and more

than 20 weeks gestational age. In the United States, the

preterm delivery rate is approximately 11%, whereas in

Europe it varies between 5% and 7%. In spite of ad-

vances in obstetric care, the rate of prematurity has not

decreased over the past 40 years. In fact, in most indus-trialized countries it has increased slightly (Figure 1).

Prematurity remains a leading cause of neonatal morbid-

ity and mortality in developed countries, accounting for

6080% of deaths of infants without congenital anoma-

lies. As the risk of neonatal morbidity and mortality nearterm is low, greater attention is now being focused on

early preterm birth (32 weeks gestation). Although

births in this gestational age group represent 1% to 2% of

all deliveries, they account for nearly 50% of all long-

term neurological morbidity and about 60% of perinatal

mortality.Neonatal mortality rates have declined in recent years

largely because of improved neonatal intensive care and

better access to these services. With appropriate medicalcare, neonatal survival dramatically improves as gesta-

tional age progresses, with over 50% of neonates surviv-

ing at 25 weeks gestation, and over 90% surviving by 28

to 29 weeks gestation (Table 1). In the United States,

survival rates of 2030% have been reported in neonatesdelivered at 22 to 23 weeks gestation; however, these

premature infants are often left with long-term neurolog-

ical impairment.1

Because of the rapid improvement in both survival and freedom from major handicap as

delivery gestational age increases from 22 to 28 weeks,the major benefits from delaying delivery are seen in thistime. Short-term morbidities associated with pretermdelivery include respiratory distress syndrome, intraven-tricular hemorrhage, periventricular leukomalacia, ne-crotizing enterocolitis, bronchopulmonary dysplasia,sepsis, and patent ductus arteriosus. Long-term morbid-

From the Department of Obstetrics and Gynecology, University of Alabama atBirmingham, Birmingham, Alabama.

This work is based in part on a literature review performed by Patrick Ramsey,MD, and his contribution is acknowledged.

We would like to thank thefollowing individuals who, in addition to members of ourEditorial Board, will serve as referees for this series: Dwight P. Cruikshank, MD,Ronald S. Gibbs, MD, Gary D. V. Hankins, MD, Philip B. Mead, MD,Kenneth L. Noller, MD, Catherine Y. Spong, MD, and Edward E. Wallach,

MD.

1020 VOL. 100, NO. 5, PART 1, NOVEMBER 2002 0029-7844/00/$22.00

2002 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc. PII S0029-7844(02)02212-3

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ities include cerebral palsy, mental retardation, and reti-nopathy of prematurity. The risk for these morbidities isdirectly related to the gestational age and birth weight.For example, cerebral palsy, defined as a nonprogressivemotor dysfunction with origin around the time of birth,complicates approximately two per 1000 of all livebirths. The relative risk for a preterm infant developing

cerebral palsy is nearly 40 times that for term infants.

Approximately 810% of surviving newborns weighingless than 1000 g at birth will develop cerebral palsy. These infants also have substantially higher rates ofmental retardation and visual disabilities, as well asneurobehavioral dysfunction and poor school perfor-mance.2

PRETERM LABOR

Preterm labor is usually defined as regular contractionsaccompanied by cervical change occurring at less than 37weeks gestation. Spontaneous preterm labor accountsfor 40 50% of all preterm deliveries, with the remainderresulting from preterm premature rupture of membranes(PROM) (2540%) and obstetrically indicated pretermdelivery (2025%).3 In this article I will deal only withthe management of preterm labor.

The pathogenesis of preterm labor is not well under-stood, and it is often not clear whether preterm labor

represents early idiopathic activation of the normal laborprocess or results from a pathologic mechanism. Severaltheories exist regarding the initiation of labor, including1) progesterone withdrawal, 2) oxytocin initiation, and3) premature decidual activation. The progesteronewithdrawal theory stems from the large body of workpreviously done with sheep. As parturition nears, thefetal-adrenal axis becomes more sensitive to adrenocor-ticotropic hormone, increasing the secretion of cortisol.Fetal cortisol then stimulates trophoblast 17-hydroxy-

Figure 1. Incidence of preterm birth in the United States, 19811999. Source of data: National Center for HealthStatistics.97

Goldenberg. Management of Preterm Labor. Obstet Gynecol 2002.

Table 1. Neonatal Survival by Gestational Age and Im-provement in Survival by Week

Gestationalage (wk)

Approximatesurvival (%)

Approximateimprovement

in survivalper week (%)

21 0 22 Rare 23 25 2524 50 2525 70 2026 80 1027 86 628 91 529 94 330 95 131 96 132 97 133 98 134 99 135 99 136 99 1

1021VOL. 100, NO. 5, PART 1, NOVEMBER 2002 Goldenberg Management of Preterm Labor

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lase activity, which decreases progesterone secretion andleads to a subsequent increase in estrogen production.This reversal in the estrogen/progesterone ratio results

in increased prostaglandin formation, initiating a cascadeof events that culminate in labor and subsequent deliv-ery. Although this mechanism is well established insheep, its role in humans has not been confirmed.

The second parturition theory involves oxytocin as aninitiator of labor. Because intravenously administeredoxytocin increases the frequency and intensity of uterinecontractions, it is natural to assume that oxytocin playsan important role in the initiation of labor. Acceptingoxytocin as the initiating agent for the onset of labor,

however, is difficult for two reasons: blood levels ofoxytocin do not rise before labor, and the clearance ofoxytocin remains constant during pregnancy. Thus,

though oxytocin likely plays a role in the support oflabor, its role in the initiation of labor, either at term orpreterm, is not established. The most likely pathway tothe initiation of preterm labor probably involves prema-ture decidual activation. Although decidual activationmay be mediated in part by the fetal-decidual paracrinesystem, and potentially by intrauterine bleeding, inmany cases, especially those involving early pretermlabor, it appears that this activation occurs in the contextof an occult upper genital tract infection (Figure 2).

Figure 2. Pathways leading from choriodecidual bacterial colonization to preterm labor and delivery. (Reprinted with

permission from Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm birth. N Engl J Med

2000;342:1500 7. Copyright 2000 Massachusetts Medical Society. All rights reserved.)

Goldenberg. Management of Preterm Labor. Obstet Gynecol 2002.

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INFECTION AND PRETERM BIRTH

There is a growing body of evidence that infection of thedecidua, fetal membranes, and amniotic fluid is associ-ated with preterm delivery.4 Clinical chorioamnionitiscomplicates 15% of term pregnancies, but nearly 25%of preterm deliveries. In a study by Guzick and Winn,5

histological chorioamnionitis was more common in pre-

term deliveries than in term ones (32.8% versus 10%).Watts et al6 investigated patients in preterm labor anddemonstrated that positive amniotic fluid cultures werepresent in 19% of women with intact membranes with noclinical evidence of intrauterine infection. In women withspontaneous preterm labor, an inverse relationship ex-ists between colonization of the chorioamnion and am-niotic fluid and gestational age at delivery. In one study,chorioamnion colonization was associated with 83% ofthe very early spontaneous preterm births, but played amuch less important role in the initiation of parturition ator near term.4 Organisms that have been associated with

histological chorioamnionitis include Ureaplasma urealyti-cum, Mycoplasma hominis, Gardnerella vaginalis, peptostrep-tococci, and Bacteroidesspecies.4

RISK FACTORS

In the United States, race is a significant risk factor forpreterm delivery. Black women have a prematurity rateof about 1618%, compared to 79% for white women.Women younger than 17 and older than 35 carry ahigher risk of preterm delivery. Less education andlower socioeconomic status are also risk factors, al-

though they probably are not independent of one other. The relative contribution of various causes of pretermbirth differs by ethnic group. For example, preterm labormore commonly leads to preterm birth in white women,whereas preterm PROM is more common in black wom-en.7 Various behavioral factors also increase the risk forpreterm delivery. Both poor and excessive weight gainare associated with an increase in preterm birth, whereaswomen with a low body mass index (less than 19.8kg/m2) are at higher risk for preterm delivery.8 Smokingplays a more significant role in fetal growth restrictionthan it does in preterm delivery. However, women who

smoke still have about a 2030% increase in pretermbirth.9 In the United States about 20% of pregnantwomen smoke, and 1015% of all preterm births can beattributed to maternal smoking. A history of a pretermdelivery is one of the most significant risk factors. Therecurrence risk of preterm birth in women with a historyof preterm delivery ranges from 17% to 40%, and ap-pears to depend on the number of prior preterm deliver-ies. Mercer et al10 recently reported that women whohad a prior preterm delivery had a 2.5-fold increased risk

of spontaneous preterm delivery with their next preg-nancy. The earlier the gestational age of the prior pre-term delivery, the greater the risk for a subsequent earlyspontaneous preterm delivery.

Multiple gestations carry one of the highest risks ofpreterm delivery. Approximately 50% of twin andnearly all higher multiple gestations end before 37 com-

pleted weeks. The average length of gestation is signifi-cantly shorter for twins (36 weeks), triplets (33 weeks),and quadruplets (31 weeks) than it is for singletons (39weeks).11 Vaginal bleeding caused by placenta previa ormarginal placental separation is associated with almostas high a risk of preterm delivery as multiple gestation. Additionally, second-trimester bleeding not associatedwith either placenta previa or separation has also beensignificantly associated with preterm birth.

In addition to the risk factors discussed above, avariety of other factors have been associated with anincreased risk for preterm labor. Extremes in the volume

of amniotic fluid, such as hydramnios or oligohydram-nios, have been associated with an increased risk forpreterm labor. Maternal abdominal surgery in the latesecond and third trimesters can cause an increase inuterine activity that may culminate in preterm delivery.Maternal medical conditions, such as gestational or pre-existing diabetes and hypertension (essential or preg-nancy induced), are associated with a higher rate ofpreterm delivery; however, these preterm births areoften indicated preterm deliveries due to maternal com-plications rather than the result of spontaneous pretermlabor. Asymptomatic bacteriuria is associated with an

increased rate of prematurity.12

Systemic infections, suchas bacterial pneumonia, pyelonephritis, and acute appen-dicitis, often lead to increased uterine activity, potentiallyleading to premature delivery.

Another potentially important clinical risk factor is thepresence of uterine contractions. In a study involvingapproximately 2500 patients, in which multiple gesta-tions, vaginal bleeding, preterm PROM, and hydram-nios were excluded, Nageotte et al13 evaluated uterineactivity in patients with preterm, term, and posttermdeliveries. The authors demonstrated an increase inuterine activity beginning 6 weeks before delivery, re-

gardless of gestational age at birth. A surge in uterineactivity occurred within 72 hours of delivery in all threegroups. Unfortunately, these patients depended on toco-dynamometry to determine this increase in frequency.When patients are instructed to self-detect an increase inuterine activity, they can identify only 15% of the con-tractions noted by tocodynamometry. Copper et al14

evaluated the use of tocodynamometry and cervicalexamination at 28 weeks gestation in 589 nulliparouswomen to determine whether patients at risk for preterm


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delivery could be identified. The investigators noted thatthe best predictor of spontaneous preterm birth was thepresence of a soft or medium consistency cervix. In thisstudy, the risk for spontaneous preterm delivery in-creased from 4.2% for those women with no contractionsdetected to 18.2% for those patients having four or morecontractions in 30 minutes. In a recent study from the

National Institute of Child Health and Human Develop-ment Maternal-Fetal Medicine Units Network, Iams etal15 again found an association between the presence ofcontractions and preterm delivery. However, because ofthe large overlap in contraction frequency between thosewho delivered at term and those who delivered preterm,monitoring contraction frequency was not found to beuseful in defining a population at especially high risk forspontaneous preterm birth. For this, among other rea-sons, the use of home uterine activity monitoring has notgenerally resulted in a reduction of preterm births.

Biochemical and Ultrasound PredictorsAs stated above, the biochemical processes leading to theinitiation of either term or preterm labor have not beenwell established in humans. Recently, however, impor-tant insights into the pathophysiology of spontaneouspreterm labor have helped to identify various biochem-ical markers that may predict preterm delivery. Themost powerful biochemical marker identified to date isfetal fibronectin. Fetal fibronectin is a glycoprotein foundin the extracellular matrix and, when found in the vaginaor cervix, appears to be a marker of choriodecidualdisruption. Typically, fetal fibronectin is absent from

cervicovaginal secretions from around the 20th week ofgestation until near term. In women undergoing routinescreening during prenatal care or when tested with adiagnosis of potential preterm labor, detection of ele-vated cervicovaginal levels of fetal fibronectin has beenshown to be strongly associated with an increased riskfor preterm delivery.16,17 For clinical care, the mostimportant characteristic of the fetal fibronectin test is itsnegative predictive value. In women in questionablepreterm labor, if the test is negative, less than 1% ofwomen will deliver in the next week or two. If the test ispositive, the risk of subsequent preterm delivery in the

next week or two is higherapproximately 20%. As labor approaches, the cervix tends to shorten,

soften, rotate anteriorly, and then dilate. These changestend to begin weeks before delivery, regardless of gesta-tional age. Digital examination is the traditional methodused to detect cervical maturation, but quantifying thesechanges is often difficult. For example, if the externalportion of the cervix is closed, it is impossible to evaluatethe internal os by digital examination. Vaginal ultra-sonography allows a more objective approach to exam-

ination of the cervix. In asymptomatic women, cervicalchanges described by ultrasound, including shorteningand funneling, appear to have high predictive value forsubsequent preterm birth. Okitsu et al18 noted that alter-ations in length begin to occur approximately 10 weeksbefore delivery. Digital examination changes, however,tend to occur only 3 to 4 weeks before delivery.

One of the most difficult decisions an obstetrician hasto make is determining whether a woman presentingwith symptoms of preterm labor, such as contractionsand a small amount of cervical effacement or dilatation,is in preterm labor. Numerous studies confirm that be-tween 50% and 75% of women who fit this descriptionwill, without treatment, go on to deliver at term. For thisreason, traditionally, patients are observed for severalhours or more to await additional cervical change beforea decision is made to initiate tocolytic treatment, givecorticosteroids, or discharge home. In many cases, adecision regarding true or false labor cannot be made

with assurance even then. In recent years it has becomeapparent that, in some women, the presence of cervicalor vaginal fetal fibronectin, and perhaps a short cervix asdetermined by ultrasound, can separate those womennot in labor from those who carry a more significant riskof early delivery. Therefore, for women in whom thediagnosis of preterm labor is uncertain, obtaining one ofthese tests is a reasonable strategy. For those womenwhose fetal fibronectin is negative, and perhaps for thosewith a cervical length of greater than 30 mm, the likeli-hood of delivering in the next week is less than 1%. Thusmost women with a negative test can safely be sent home

without treatment.

PREVENTION

Conceptually, prevention of preterm labor may be di-vided into two major areas. The first involves a reduc-tion in the presence of one or more of the specific riskfactors described above or, in a more general approach,an improvement in quality of life including income andnutritional enhancement, and a reduction in physicaland emotional stress. Although space does not permit athorough review of these attempts, suffice it to say that in

developed countries these approaches have not consis-tently been found to reduce the incidence of pretermlabor. Other programs attempting to decrease the rate ofpreterm delivery have focused on screening for detectionof preterm contractions or cervical change before theonset of true labor. These approaches include 1) patienteducation to recognize preterm contractions, 2) providersurveillance for cervical changes, and 3) home uterineactivity monitoring. Educational programs generallytrain women to recognize symptoms of preterm labor


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including contractions, pelvic pressure, and vaginal dis-charge. In addition, weekly vaginal examinations havebeen used in an attempt to detect early cervical changesbefore the onset of labor. Several explanations have beenadvanced as to why these interventions have generallyfailed to demonstrate significant reductions in the pre-term birth rate. For example, the level of education and

supervision may have been inadequate for the patientpopulation under evaluation. One of the more importantreasons, however, may be that early symptoms of pre-mature labor are often subtle and varied, and womenoften do not perceive contractions until labor is relativelyadvanced. In a study by Newman et al,19 women whohad been trained in self-palpation of uterine activityidentified only 15% of the contractions detected by amonitor, and as few as 11% could identify 50% of theircontractions. Home uterine activity monitoring was pro-posed as a potential solution to this problem. Althoughsome of the early, small trials with home uterine activity

monitoring demonstrated a significant decrease in pre-term births among enrolled subjects, subsequent largerstudies have not.20 Hence, it appears that home uterineactivity monitoring is of little or no benefit in reducingthe frequency of preterm birth. One potential reason forthis failure is that the interventions available to treatearly preterm labor once detected are, for the most part,not effective. Thus, overall, attempts at prevention andtreatment of preterm labor through risk reduction andearly detection, though conceptually appealing, have notgenerally led to reductions in preterm birth.

TREATMENT

The therapeutic interventions considered in the settingof preterm labor generally have the following goals: 1) toinhibit or reduce the strength and frequency of contrac-tions, thus delaying the time to delivery, and 2) tooptimize fetal status before preterm delivery. In thissection, many of the contemporary obstetric therapeuticstrategies proposed to achieve these goals are reviewed.

Bed Rest

Bed rest represents one of the most common interven-

tions used for the prevention and/or treatment of threat-ened preterm labor. In fact, it is recommended for a widerange of pregnancy-related conditions. One survey21

found that bed rest was prescribed for at least 1 week for20% of pregnancies in the United States. Unfortunately,there are no prospective randomized studies that haveindependently evaluated the effectiveness of bed rest forthe prevention of preterm labor or its treatment in sin-gleton pregnancies. In four randomized trials of hospital-ization and bed rest for the prevention and/or treatment

of preterm delivery in twin pregnancies, two studiesfound no benefit, and two showed an increase in pretermbirth. Therefore, although a reduction of physical activ-ity may seem appropriate for some women at risk ofpreterm birth, there is no evidence that this intervention,especially when extended to full bed rest, will result in areduction in preterm birth. In fact, in twins this interven-

tion may be harmful. Therefore, no evidence exists thatbed rest should be a standard component of preventionor treatment for preterm labor.

Hydration/Sedation

Another common practice used for the initial treatmentof preterm labor is oral or intravenous hydration. Somephysicians attempt to differentiate true preterm laborfrom false labor using this strategy. Several theories areoffered as to why hydration may be effective in treatingpreterm labor. First, at least in animals, hydration inhib-its the release of antidiuretic hormone through the Hen-

ry-Gauer reflex. Second, women in preterm labor mayhave plasma volumes below normal. Few studies haveevaluated the use of hydration in a prospective manner.Pircon et al22 conducted a prospective randomized studyof 48 women with preterm contractions and found nobenefit from hydration. Guinn et al,23 in a prospectiverandomized study of 179 women with preterm contrac-tions, reported similar findings. Patients in this investiga-tion were randomized to observation alone, intravenoushydration, or a single dose of subcutaneous terbutaline.No significant differences were noted between the threegroups in the mean days to delivery or the incidence of

preterm delivery. Hence, intravenous hydration doesnot appear to reduce preterm birth, and the routine useof hydration to treat preterm labor or to differentiate truefrom false labor cannot be recommended.

Sedation is also a commonly used strategy to differen-tiate true preterm labor from preterm contractions. Sim-ilar to hydration, there are limited data documenting theefficacy of sedation in this clinical setting. Helfgott et al24

performed a prospective comparative study of 119women with preterm labor who were randomly assignedto treatment with hydration and sedation or to treatmentwith bed rest alone. Women randomized to the hydra-

tion and/or sedation group received 500 mL of lactatedRingers solution intravenously over 30 minutes and812 mg of intramuscular morphine sulfate. There wasno significant difference between hydration and/or seda-tion and bed rest alone with regard to contraction cessa-tion and rates of preterm delivery. Therefore, the litera-ture does not support the use of hydration and/orsedation in the initial treatment of preterm labor. Inmany cases, initial hydration with intravenous infusionof fluid occurs before the start of intravenous infusion of


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a tocolytic agent. A large fluid bolus may increase therisk of fluid overload and subsequent development ofpulmonary edema.

Progesterone

Based on the progesterone withdrawal hypothesis oflabor initiation, over the years there has been interest inthe use of progesterone and other progestins for thetreatment and/or prevention of preterm labor. A meta-analysis of six randomized controlled trials of 17-hy-

droxyprogesterone caproate used prophylactically toprevent preterm labor revealed a significant decrease inpreterm birth (odds ratio 0.5; 95% confidence interval0.3, 0.85).25 However, the use of progestins, includinglarge doses of intramuscular progesterone or 6-methyl-17-acetoxyprogesterone, has not successfully inhibitedactive preterm labor.26,27

Tocolytics

-Sympathomimetic Agents. There are three knowntypes of-adrenergic receptors in humans: 1 receptorsoccur primarily in the heart, small intestine, and adipose

tissue; 2 receptors are found in the uterus, blood ves-sels, bronchioles, and liver; and 3 receptors are foundpredominantly on white and brown adipocytes. -sym-pathomimetic agents are structurally related to cat-echolamines and, when administered in vivo, stimulateall -receptors throughout the body. Stimulation of the2 receptors results in uterine smooth muscle relaxation. Although some -sympathomimetic agents have beenproposed as 2-selective agents, at the dosages usedpharmacologically, stimulation of all receptor types often

occurs. Such stimulation results in many of the sideeffects associated with the -sympathomimetic agents.Of the -sympathomimetic agents, the 2-selectiveagents (eg, ritodrine, terbutaline) (Table 2) have been theprimary drugs utilized for the treatment of preterm la-bor.

Ritodrine is the only medication approved by theUnited States Food and Drug Administration for thetreatment of preterm labor. This approval resultedlargely from studies done by Barden et al28 and Merkatzet al29 demonstrating efficacy similar to that of othertocolytic agents but with fewer side effects. The initialreports also suggested an increase in pregnancy durationwith a reduction in neonatal morbidity and mortality.Subsequent reports have not been as positive. The Ca-nadian Preterm Labor Investigators Group30 conducteda large multicenter clinical trial comparing ritodrine witha placebo. They concluded that ritodrine treatment sig-nificantly delayed delivery for 24 hours, but that it didnot significantly improve other perinatal outcomes. Kinget al31 conducted a meta-analysis involving 16 clinical

trials with a total of 890 women and demonstrated thatwomen treated with ritodrine had significantly fewerdeliveries within 24 and 48 hours of the start of therapy.However, no statistically significant decrease in the inci-dence of respiratory distress syndrome, birth weight lessthan 2500 g, or perinatal death was demonstrated. Thesestudies were completed before the use of antenatal ste-roid therapy became widespread.

Although ritodrine can be administered either intrave-nously or orally, treatment usually begins with intrave-

Table 2. Some Currently Used Tocolytics

Generic nameBrandname

Mechanismof action Usual dosing Major side effects Comments

Magnesiumsulfate

Calciumantagonist

4-g loading dose IV,then 13 g/h

Respiratory arrest;cardiac arrest

Monitor deep tendonreflexes and serummagnesium levels

Ritodrine Utopar 2 activator Start at 50 g/min IV,increasing to amaximum of 350g/min

Cardiac arrhythmias;pulmonary edema;myocardial ischemia

Monitor cardiacrhythm and fluidand electrolytestatus

Terbutaline Brethine 2 activator 510 g/min IV,increasing to amaximum of 80g/min

Cardiac arrhythmias;pulmonary edema;myocardial ischemia

Monitor cardiacrhythm and fluidand electrolytestatus

Nifedipine Procardia Calcium channelblocker

20 mg orally followedby 1020 mg orallyevery 68 h

Maternal hypotension Monitor bloodpressure

Indomethacin Indocin Prostaglandinsynthetaseinhibitor

50-mg loading dosePO, PV, or PR,followed by 2550 mg every 6 h

Maternal gastrointestinaldisturbance;oligohydraminios;ductal constriction

Not usually usedafter 32 wk;careful monitoringrequired 48 h

IV intravenously; PO orally; PV per vagina; PR per rectum.


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nous infusion. The initial recommended infusion ratewas 100g per minute. However, more recently, Caritiset al32 suggested an initial infusion of 50 g per minutewith a maximal rate of 350 g per minute. With cessa-tion of uterine activity the infusion rate should be re-duced. The patient should be closely monitored for fluidbalance, cardiac status, and electrolytes, including potas-

sium and glucose. Relative contraindications to any typeof-mimetic therapy include diabetes mellitus, underly-ing cardiac disease, use of digitalis, hyperthyroidism,severe anemia, and hypertension.

Many of the maternal side effects are due to stimula-tion of-receptors throughout the body. Serious mater-nal cardiopulmonary side effects include pulmonaryedema, myocardial ischemia, arrhythmia, and even ma-ternal death. Pulmonary edema may occur in about 4%of patients receiving parenteral ritodrine. Predisposingfactors associated with this complication include a mul-tiple gestation, positive fluid balance, blood transfusion,

anemia, infection, polyhydramnios, and underlying car-diac disease. The associated use of corticosteroids hasalso been implicated in the development of pulmonaryedema. However, because the two most commonly usedantepartum steroids, betamethasone and dexametha-sone, have minimal mineralocorticoid activity, it is un-likely that these drugs contribute significantly to thiscomplication. The maternal mortality that has been re-ported with intravenous ritodrine therapy is generallyassociated with pulmonary edema or cardiac arrhyth-mia. For those reasons pulse, blood pressure, and respi-ratory status should be closely monitored and discontin-

uation of therapy be strongly considered with anyrespiratory distress or a heart rate greater than 130 beatsper minute. Metabolic effects of ritodrine include hypo-kalemia resulting from an increase in insulin and glucoseconcentrations, which drives potassium intracellularly.This condition generally resolves within 612 hours ofdiscontinuing therapy.

A wide range of fetal cardiac complications has beendescribed, including rhythm disturbances such as su-praventricular tachycardia and atrial flutter. These usu-ally resolve within a few days to 2 weeks after cessationof therapy. Fetal cardiac septal hypertrophy has been

described with maternal ritodrine treatment. The degreeof hypertrophy correlates with the duration of therapyand usually resolves within 3 months of age. Other,more serious fetal complications have included hydrops,pulmonary edema, and cardiac failure. Fetal and neona-tal death, with histological evidence of myocardial isch-emia, have also been reported. Neonatal hypoglycemia isanother potential complication with -sympathomimet-ics and usually develops when delivery occurs within 2days of treatment. The hypoglycemia is transient and

results in medication-induced hyperinsulinemia. Neona-tal periventricular-intraventricular hemorrhage may beincreased with -sympathomimetic therapy. In a retro-spective study of 2827 women delivering preterm, therewas a two-fold increase in intraventricular hemorrhagein neonates whose mothers received -mimetics, but thisfinding has not been consistently demonstrated in other

studies.33

Studies evaluating long-term exposure to-sympathomimetics demonstrate no differences in Ap-gar scores, head circumference, or neurological status.Largely as a result of potential complications, as well asthe limited evidence for improvements in importantperinatal outcomes associated with its use, and perhapsbecause of its cost relative to magnesium sulfate, rito-drine has fallen out of favor as a tocolytic agent in theUnited States.

Terbutaline is now the most commonly used 2-selec-tive -mimetic agent in pregnancy and can be adminis-tered via oral, subcutaneous, or intravenous routes. It

was initially studied by Ingemarsson,34

who randomlyassigned 30 patients with preterm labor to intravenousterbutaline therapy and demonstrated an 80% successrate, in comparison with 20% for the placebo. Unfortu-nately, as with other tocolytic agents, subsequent studieshave not reported similar success rates. Similar to rito-drine, terbutaline has been effective in temporarily ar-resting premature labor, but not reducing the rate ofpreterm birth. The initial infusion is 510g per minute,with the rate increased when necessary every 1015minutes to a maximum of 80g per minute. Terbutalinemay be administered subcutaneously in 0.25-mg doses

every 2030 minutes (four to six doses) as the first-linetocolytic agent for preterm labor. Lam et al35 comparedthe use of the terbutaline pump with oral terbutalinetherapy, and Guinn et al36 conducted a prospectivedouble-blind randomized clinical trial comparing terbutaline pump maintenance therapy with a placebo. These investigators demonstrated no significant de-creases in the preterm delivery rate or improvement inneonatal outcomes with use of the terbutaline pump.Orally administered terbutaline has mostly been used toprevent recurrence of already inhibited contractions.The usual oral dosages range from 2.5 to 5 mg every

46 hours, titrated by patient response and maternalpulse. Most studies of oral terbutaline have not shown areduction in preterm birth. Maternal and neonatal sideeffects and complications are generally similar to thosestated for ritodrine.Magnesium Sulfate. The use of magnesium sulfate as atocolytic agent was first described by Steer and Petrie ina randomized study of 71 women with preterm labor.37

Patients were allocated to intravenous infusion of mag-nesium, ethanol, or dextrose in water. The magnesium


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group received a 4-g bolus followed by a maintenanceinfusion of 2 g per hour. The success rate, defined by theabsence of contractions for 24 hours, was 77% for themagnesium group, versus 45% for ethanol and 44% forthe placebo. Miller et al38 conducted a randomized com-parison of magnesium and terbutaline and demonstratedthat magnesium had efficacy similar to and fewer side

effects than terbutaline. Orally administered magnesiumhas not been shown to be effective in reversing pretermlabor or preventing its recurrence.3941

Magnesium sulfate is usually administered intrave-nously as an initial bolus of 46 g over 30 minutes,followed by a maintenance infusion of 13 g per hour.Serum magnesium levels of 58 mg/dL are consideredtherapeutic for inhibiting myometrial activity. Once ces-sation of uterine activity is achieved, the patient is gen-erally maintained at the lowest effective infusion rate for1224 hours and then weaned. Maternal side effectssecondary to magnesium sulfate are typically dose re-

lated. Common side effects noted with the use of mag-nesium sulfate include flushing, nausea, headache,drowsiness, and blurry vision. Diminishment of deeptendon reflexes occurs when serum magnesium levelsexceed 12 mg/dL (10 mEq/L). Significant respiratorydepression can occur as serum levels reach 1418 mg/dL(1214 mEq/L), and cardiac arrest may occur with levelsgreater than 18 mg/dL (15 mEq/L). In general, respira-tory depression does not occur before loss of deep ten-don reflexes. The toxic effects of high magnesium levelscan be rapidly reversed with the infusion of 1 g ofcalcium gluconate.

Absolute contraindications to the use of magnesiumsulfate include myasthenia gravis and heart block. Rela-tive contraindications include underlying renal diseaseand recent myocardial infarction. Concurrent use ofcalcium channel blockers and magnesium sulfate cantheoretically result in profound hypotension and probably should be avoided, especially because there is noevidence of greater efficacy for combination treatmentrelative to either treatment used alone.42 Pulmonaryedema has been reported in approximately 1% of womentreated with magnesium sulfate, and the risk is increasedin patients with multifetal gestations and those receiving

combined tocolytic therapy. Because of the potential riskof fluid overload and the subsequent development ofpulmonary edema, periodic assessment of fluid intakeand output is essential.

Magnesium readily crosses the placenta, achievingfetal steady-state levels within hours of the start of treat-ment. No significant alterations in neurological states orApgar scores have been reported with umbilical cordconcentrations of 4 mg/dL or less. At cord concentra-tions between 4 and 11 mg/dL, respiratory depression

and motor depression have been seen. Serum calciumlevels in the fetus and newborn are unchanged or mini-mally reduced. Several observational reports have sug-gested that antenatal magnesium sulfate treatment forpreterm labor or preeclampsia is associated with a de-creased risk for cerebral palsy in very low birth weightinfants.43 A large prospective multicenter trial is now

ongoing to further explore the neonatal benefits of ante-natal magnesium sulfate therapy.

In summary, although both maternal and neonatalside effects occur with magnesium use, they appear to beless common as well as generally less severe when com-pared with those seen with -sympathomimetic therapy.If we are going to use tocolytic drugs, none of whichwork particularly well in reducing preterm birth or im-proving important neonatal outcomes, we ought to usethe safest one available, and for now, this seems to bemagnesium sulfate. It is for this reason that I and mostother practitioners now use magnesium sulfate as the

primary tocolytic agent.Prostaglandin Synthetase Inhibitors. Prostaglandinsare 20-carbon cyclopentane carboxylic acids derivedfrom membrane phospholipids (primarily arachadonicacid) via the enzymatic action of phospholipase A andcyclooxygenase (prostaglandin synthetase). Therefore,this pathway represents a key target for pharmacologicalintervention. A number of drugs that inhibit the action ofprostaglandin synthetase (eg, aspirin, ibuprofen, indo-methacin, sulindac) are available. Of these drugs, indo-methacin has been the most extensively studied.

Indomethacin was first used as a tocolytic agent by

Zuckerman et al,44

who administered it to 50 patientswith preterm labor. Tocolysis was achieved in 40 of the50 patients for at least 48 hours. The first prospective,randomized, double-blind, placebo control study wasperformed by Niebyl et al.45 In this study of 30 womenwith preterm labor, only one of 15 women in the indo-methacin group failed therapy after 24 hours, in compar-ison with nine of 15 women in the placebo group.Morales et al46 compared indomethacin with ritodrine ina randomized trial and found similar efficacy in delayingdeliveries 48 hours and 7 days. Maternal side effectscausing discontinuation of treatment were much more

common in the ritodrine group (24% versus 0%). Similarefficacy was noted by the same authors in a comparativetrial of indomethacin and magnesium sulfate.47

Indomethacin is usually administered orally or rec-tally. A loading dose of 50100 mg is followed by a total24-hour dose not greater than 200 mg. Indomethacinblood concentrations usually peak 1 to 2 hours after oraladministration, whereas rectal administration is associ-ated with levels that peak slightly sooner. Most studieshave limited the use of indomethacin to 2448 hours


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duration because of concerns regarding the developmentof oligohydramnios and constriction of the ductus arte-riosus. Major maternal side effects are infrequent. Gas-trointestinal upset may occur but can usually be relievedby taking the medication with meals or using an antacid.Maternal contraindications to indomethacin use includepeptic ulcer disease; allergies to indomethacin or related

compounds; hematological, hepatic, or renal dysfunc-tion; or drug-induced asthma. Fetal contraindicationsinclude preexisting oligohydramnios and congenital fetalheart disease in which the fetal circulation is dependenton the ductus arteriosus.

Indomethacin readily crosses the placenta, with fetallevels equilibrating with maternal concentrations about 5hours after administration. Several fetal side effects havebeen reported with the use of indomethacin. Fetal urineoutput has been shown to decrease after administrationof indomethacin. Long-term therapy may result in thedevelopment of oligohydramnios, although the timing of

the onset is unpredictable. Therefore the amniotic fluidindex should be followed while the patient is receivinglong-term therapy, and if the amniotic fluid index fallsbelow 5 cm, therapy is usually discontinued. Resolutionof oligohydramnios usually occurs within 48 hours ofdiscontinuation of treatment. However, persistent an-uria, renal microcystic lesions, and neonatal death have been reported with prenatal indomethacin exposure.Most of these infants were exposed to doses greater than200 mg per day for more than 48 hours without ade-quate amniotic fluid assessment. Another important po-tential complication related to indomethacin use is the

development of ductal constriction or closure, whichleads to the diversion of right ventricular blood flow intothe pulmonary vasculature. With time, this causes pul-monary arterial hypertrophy. After birth, relative pul-monary hypertension can cause shunting of bloodthrough the foramen ovale and away from the lungs,resulting in persistent fetal circulation. This complicationhas been described with long-term indomethacin therapybut not in fetuses exposed to the drug for less than 48hours. For this reason, it has been recommended that,for longer term treatment, patency of the ductus arterio-sus be monitored and, if the pulsatility index is less than

2 cm per second, discontinuation of therapy be consid-ered. The effects on ductal constriction have been shownto increase with advancing gestational age. At 32 weeksgestational age, it is estimated that 50% of fetuses willdemonstrate ductal constriction. On the basis of thesedata, indomethacin therapy should be discontinued by32 weeks at the latest.

Another reported complication in fetuses exposed toindomethacin prenatally and delivered at less than 30weeks is an increased risk of necrotizing enterocolitis.

Norton et al48 performed a retrospective case-controlstudy of 57 fetuses delivered at less than 30 weeksgestation after recent exposure to indomethacin andcompared them with 57 matched control fetuses. Theincidence of necrotizing enterocolitis was 29% in theindomethacin group, versus 8% in the control group.Additionally, higher incidences of intraventricular hem-

orrhage and patent ductus arteriosus were noted in theindomethacin treatment group. The effect of the dura-tion of treatment and the timing of the exposure inrelation to delivery were not reported. Although theseresults are of concern, when used with appropriate cau-tion (less than 48 hours of therapy, less than 3032weeks gestation), indomethacin appears to be a rela-tively safe and effective tocolytic agent. I generally useindomethacin as a second-line tocolytic agent after fail-ure of magnesium sulfate in early gestational age pretermlabors.

Sulindac is another prostaglandin synthetase inhibi-

tor, closely related to indomethacin in structure, whichlikely has similar efficacy in inhibiting preterm labor.Initially, suldinac was reported to have fewer side effectsthan indomethacin when used for tocolysis. However,Kramer et al (Kramer W, Saade G, Belfort M, DormanK, Mayes M, Mose K. Randomized, double-blind studycomparing sulindac to terbutaline: Fetal renal and amni-otic fluid effects [abstract]. Am J Obstet Gynecol 1996;174:326) conducted a randomized double-blind study toevaluate the comparative effects of sulindac and terbutal-ine on fetal urine production and amniotic fluid volume.Sulindac administration resulted in a significant decrease

in fetal urine flow and amniotic fluid volume. Addition-ally, two fetuses developed severe ductal constriction. Thus, sulindac shares many of the fetal side effectsassociated with indomethacin, and its safety, relative toindomethacin, is unknown.Calcium Channel Blockers. Calcium channel block-ers are agents that reduce transmembrane calcium in-flux, thus controlling muscle contractility and pacemakeractivity in cardiac, vascular, and uterine tissue. To date,the majority of clinical investigations evaluating the useof calcium channel blockers for the treatment of pretermlabor have utilized nifedipine. Ulmsten et al49 first re-

ported the use of nifedipine for the treatment of pretermlabor in a study involving 10 patients, with resultantcessation of uterine activity for 3 days in all patientsundergoing treatment. In a subsequent randomizedstudy, Read and Wellby50 reported that the nifedipinegroup had a significantly longer time interval from pre-sentation to delivery than either a ritodrine or placebocontrol group. Ferguson et al51 demonstrated that nifed-ipine was as effective as ritodrine in prolonging preg-nancy, but had far fewer side effects leading to discon-


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tinuation of therapy. Several subsequent studies andmeta-analyses also suggest that nifedipine has a bettersafety profile than ritodrine and is at least equally effec-tive in delaying delivery.5254 Nifedipine is reported tobe as equally effective in delaying delivery as magnesiumsulfate.55,56 In women with a diagnosis of sucessfullytreated preterm labor, maintenance oral nifedipine did

not prolong pregnancy relative to a no-treatment orcontrol group.57

Nifedipine can be administered orally or in sublingualform. It is rapidly absorbed by the gastrointestinal tract,with detectable blood levels attained within 5 minutes ofsublingual administration. Nifedipine readily crosses theplacenta, and serum concentrations of the fetus and themother are comparable. An initial loading dose of 20 mgorally is typically given, followed by 1020 mg every6 8 hours. The sublingual form is not recommended fortreatment of preterm labor because it acts more rapidlythan the oral form and can cause acute hypotension.

Contraindications to the use of nifedipine, or any of thecalcium channel blockers, include hypotension, conges-tive heart failure, and aortic stenosis. As stated previ-ously, concurrent use of calcium channel blockers andmagnesium sulfate can theoretically result in profoundhypotension and should probably be avoided.42 Mater-nal side effects of orally administered nifedipine resultfrom the vasodilatory effects and include dizziness, light-headedness, flushing, headache, and peripheral edema.The incidence of these side effects is approximately 17%,with severe effects resulting in the discontinuation oftherapy in 25% of patients.

Studies evaluating the fetal effects of calcium channelblocker therapy have been limited to date. One concernis the potential adverse effect calcium channel blockersmay have on uteroplacental blood flow, as has beenreported in animal studies. However, several reportshave examined uteroplacental blood flow in patientsreceiving nifedipine and have demonstrated no signifi-cant adverse effects on fetal or uteroplacental blood flowduring treatment.58 As with many of the other tocolyticagents, additional studies are needed to more completelyevaluate the potential fetal effects of calcium channelblocker therapy and the overall role of calcium channel

blockers as a tocolytic agent for the treatment of pretermlabor. To date, the available literature provides littleevidence that calcium channel blockers have better effi-cacy in treating preterm labor than magnesium sulfate.Oxytocin Antagonists. Although oxytocin antagonistsare not available for use in the United States, becausethey are available elsewhere, their use to inhibit pretermlabor will be discussed. Oxytocin antagonists have beenshown to effectively inhibit oxytocin-induced uterinecontractions in both in vitro and in vivo animal models.

The initial human studies were performed in the late1980s. Akerlund et al59 reported 13 patients who re-ceived a short-term infusion of an oxytocin antagonistthat resulted in inhibition of premature labor in allpatients; however, ten of these patients subsequentlyrequired treatment with -agonists. Similarly, Andersenet al60 reported 12 patients who were treated with an

oxytocin receptor antagonist. Nine had arrest of contrac-tions. The most studied oxytocin antagonist is atosiban,which is a nonapeptide oxytocin analogue that competi-tively binds with the oxytocin-vasopressin receptor andis capable of inhibiting oxytocin-induced uterine contrac-tions. Atosiban is typically administered intravenously,beginning with a single bolus of 6.75 mg, followed by aninfusion at 300 g per minute for 3 hours, and then100 g per minute for up to 18 hours.

Several prospective randomized, blinded clinical trialshave demonstrated that atosiban is effective in diminish-ing uterine contractions in women with threatened pre-

term birth without causing significant maternal fetal orneonatal adverse effects. Goodwin et al61 demonstratedthat a 2-hour infusion of atosiban significantly decreasedcontraction frequency relative to placebo. Romero etal,62 in a prospective randomized, double-blind investi-gation of 501 women with preterm labor, demonstratedthat atosiban is significantly more effective than a pla-cebo in delaying delivery 24 hours, 48 hours, and 7 days.However, there was no improvement in perinatal out-comes. Moutquin et al63 compared atosiban with rito-drine for the treatment of preterm labor. In this random-ized controlled trial involving 212 women, the

investigators demonstrated that atosibans tocolytic effi-cacy was comparable to that of ritodrine therapy. How-ever, atosiban use was associated with fewer adverse sideeffects. No differences were noted between the groupswith respect to neonatal outcomes. In a recent interna-tional study of atosiban versus -mimetic agents,64 theefficacy of atosiban was similar to that of -mimetictherapy, but the maternal cardiovascular side effectswere considerably fewer in those women receiving atosi-ban. The potential use of atosiban for maintenance ther-apy in patients with arrested preterm labor has alsorecently been evaluated. Valenzuela et al65 reported

experience from a multicenter double-blind, placebo-controlled trial of 513 women with arrested pretermlabor. Median time from start of maintenance therapy tofirst recurrence of labor was significantly longer forwomen treated with atosiban (32.6 days) than for theplacebo-treated women (27.6 days). These data suggestthat atosiban may be useful in delaying delivery 24 48hours in the setting of preterm labor. However, thisdelay appears to have minimal impact on neonatal out-comes. Further studies are needed to more clearly eluci-


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date the role of the oxytocin antagonists for the treat-ment of preterm labor.Nitric Oxide Donors. Nitric oxide is a potent endoge-nous hormone that facilitates smooth muscle relaxationin the vasculature, the gut, and the uterus. The use ofnitric oxide donors (eg, nitroglycerin, glycerol trinitrate)for tocolytic therapy has been investigated. Lees et al66

compared transdermal glycerol trinitrate with ritodrinefor tocolysis in 245 women with documented pretermlabor between 24 and 36 weeks gestation. There wereno differences with respect to tocolytic effect and neona-tal outcomes. Clavin et al (Clavin DK, Bayhi DA, Nolan TE, Rigby FB, Cork RC, Miller JM. Comparison ofintravenous magnesium sulfate and nitroglycerin forpreterm labor [abstract]. Am J Obstet Gynecol 1996;174:307) randomized 34 women in preterm labor to eithertocolysis with intravenous nitroglycerin or magnesiumsulfate. No difference in the tocolytic efficacy was notedbetween the two treatments; However, three of the 15

women who received nitroglycerin experienced severehypotension. Similarly, El-Sayed et al67 compared intra-venous nitroglycerin with magnesium sulfate in 31women studied before 35 weeks gestation. Tocolyticfailures (tocolysis 12 hours or longer) were significantlymore common in patients treated with nitroglycerin thanin the women treated with magnesium sulfate. Impor-tantly, 25% of the patients treated with nitroglycerinexperienced significant hypotension that required dis-continuation of treatment. Given the potential profoundhemodynamic effects of these nitric oxide donors on thecentral and peripheral circulation, these agents should be

used with caution in the pregnant patient. Clinical use ofthese agents for the treatment of preterm labor remainsexperimental.TocolyticsSummary. More than 20 years ago, in aneditorial,68 the British Medical Journal stated that, inwomen in preterm labor, the use of tocolytics was fre-quently unnecessary, often ineffective, and occasionallyharmful. Not much is different today. In many women,tocolytics seem to stop contractions temporarily, butrarely prevent preterm birth. Most importantly, usedalone, they appear to convey little or no benefit for anyfetal or neonatal outcome. For example, a recent meta-

analysis of tocolytic therapy69

concluded that althoughtocolytics may prolong pregnancy, they have not beenshown to improve perinatal outcomes, but do haveadverse health effects on women. However, in somewomen they do appear to delay delivery long enough forsuccessful administration of corticosteroids, one of thefew interventions of clear benefit. Therefore, as a generalrule, if tocolytics are given, they should be given con-comitantly with corticosteroids. The gestational agerange in which tocolytics should be used is open to

debate, but because corticosteroids are not generallyused at or after 34 weeks, and because the perinataloutcomes in later gestational age preterm infants aregenerally good, most authorities do not recommend useof tocolytics at or after 34 weeks gestational age. Thereis no consensus on a lower gestational age limit for theuse of tocolytic agents.

ANTIBIOTICS

Preterm labor, especially at less than 30 weeks gestation,has been associated with occult upper genital tract infec-tion (Figure 2). Many, if not all, of the bacterial speciesinvolved in this occult infection are capable of inciting aninflammatory response, which ultimately may culminatein preterm labor and delivery. Antibiotics therefore havethe potential to prevent and/or treat spontaneous pre-term labor. Elder et al70 were among the first investiga-tors to study the use of antibiotics to prevent preterm

birth, and demonstrated that treatment of nonbacteriuricasymptomatic pregnant patients with daily tetracyclinetherapy resulted in fewer preterm births. However, al-though the data are mixed, many subsequent prospec-tive trials of prenatal administration of antibiotics inwomen colonized with Chlamydia trachomatis, Ureaplasmaurealyticum, and group B streptococcus have not shown asignificant decrease in preterm birth. Recently, however,the association of bacterial vaginosis with preterm birthhas prompted renewed interest in the use of antibiotics toprevent preterm birth in asymptomatic women. Theresults of the trials have been mixed as well. Similarly,

the use of antibiotics for the treatment of documentedpreterm labor has also produced mixed results7187 (Ta-ble 3). A recent Cochrane meta-analysis71 summarizingeight of the randomized controlled clinical trials compar-ing antibiotic therapy (mostly penicillin derivatives) witha placebo for the treatment of documented preterm labordemonstrated no difference between the placebo andantibiotic treatment in pregnancy prolongation, pretermdelivery, respiratory distress syndrome, or neonatal sep-sis. Antibiotics were, however, associated with a signifi-cantly decreased risk for maternal infection and neonatalnecrotizing enterocolitis. Two randomized studies in

women in early preterm labor, one performed in SouthAfrica and one in Denmark, suggest that a combinationof metronidazole and ampicillin, given to women withpreterm labor for 68 days, may significantly delaydelivery, increase birth weight, and improve neonataloutcomes such as sepsis and necrotizing enterocoli-tis.81,85As a profession, we adopt many clinical practiceswithout such randomized trial evidence, and in specificcases, this intervention might be considered. Clearly,further studies are needed to evaluate various antibiotic


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regimens for the treatment of women with preterm laborwith intact membranes. However, in the interim period,treatment of women in preterm labor with antibiotics forthe sole purpose of preventing preterm delivery is not generallyrecommended.

GROUP B STREPTOCOCCUS

Group B streptococcus is an important cause of neonatalmorbidity and death, especially in premature infants, butits role in the initiation of preterm labor is uncertain. Approximately 1020% of US women are group Bstreptococcus positive during pregnancy. The risk ofpreterm birth appears to be greatest in women withgroup B streptococcus in the urine, perhaps indicating agreater degree of colonization; thus treatment of theurinary tract infection may result in a reduction in pre-term birth. As an example, in a randomized trial ofwomen who had a urine culture positive for group Bstreptococcus treated with antibiotics, Thomsen et al88

reported that the treated group had a lower incidence ofpremature delivery than the nontreated group (37.5%versus 5.4%). These studies may be interpreted as show-ing that asymptomatic bacteriuria with group B strepto-coccus (or in fact with any organism) is a risk factor forpreterm delivery and that eradication with antibioticsdecreases the risk. From a labor management perspec-tive, these and other data suggest that women in pretermlabor should be evaluated for bacteriuria and, if positive,treated. However, whether this strategy applied to labor-

ing patients will result in a significant reduction in pre-term birth is unknown.

Group B streptococcus can cause significant neonatalmorbidity and mortality. Usually acquired from thematernal genital tract after membrane rupture, the portof entry is generally the fetal lung. Sepsis often follows. In1996, the Centers for Disease Control and Prevention inconjunction with The American College of Obstetricians

and Gynecologists (ACOG) and the American Academyof Pediatrics set forth recommendations regarding twodifferent approaches to the prevention of early-onsetneonatal group B streptococcus disease.89 In the firststrategy, intrapartum antibiotic prophylaxis is offered towomen identified as being at high risk for having infantswho develop early-onset group B streptococcus sepsis.Unless shown to be group B streptococcus negative, allwomen in preterm labor are in this category. In thesecond strategy, prenatal screening cultures are collectedat 3537 weeks gestation, and women who are positiveare considered high risk. For intrapartum chemoprophy-

laxis, intravenous penicillin G (5 mU initially and then2.5 mU every 4 hours) until delivery is recommended.Intravenous ampicillin (2 g initially and then 1 g every 4hours until delivery) is an acceptable alternative to pen-icillin G. Clindamycin or erythromycin may be used forwomen allergic to penicillin, although the efficacy ofthese drugs for group B streptococcus disease preventionhas not been measured in controlled trials. It should beemphasized that the goal of this strategy is to preventtransmission of the group B streptococcus from the

Table 3. Randomized Controlled Trials of Antibiotics in Women in Preterm Labor With Intact Membranes

Author YearWeeks

gestation n Antibiotics (type)

Outcomes

Delayin

delivery

Decrease inpretermdelivery

Decrease inperinatal mortality

and morbidity

McGregor et al74 1986 34 17 Erythromycin Yes No NoMorales et al75 1988 2134 150 Erythromycin, ampicillin Yes Yes Not stated

Newton et al76

1989 2434 95 Ampicillin, erythromycin No No NoMcGregor et al77 1991 34 103 Clindamycin Yes No NoNewton et al78 1991 2433 86 Ampicillin, sulbactam No No NoMcCaul et al79 1992 1933 40 Ampicillin No No NoRomero et al80 1993 2434 277 Ampicillin, erythromycin,

amoxicillinNo No No

Norman et al81 1994 2634 81 Ampicillin, amoxicillin,metronidazole

Yes No Yes

Watts et al82 1994 34 56 Mezlocillin, erythromycin No No NoGordon et al83 1995 2435 95 CeftizoxineCox et al84 1996 2434 78 Ampicillin, sulbactam,

AugmentinNo No No

Svare et al85 1997 2634 110 Ampicillin, metronidazole Yes Yes NoOyarzun et al86 1998 2236 170 Amoxicillin, erythromycin No No NoKenyon et al87 2001 2433 6295 Erythromycin, amoxicillin,

clavulonic acidNo No No


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mother to the fetus and subsequent neonatal sepsis, andnot to prevent preterm birth. Therefore, unless provento be group B streptococcus negative, all women inpreterm labor should receive group B streptococcus pro-phylaxis.

CORTICOSTEROIDSThe use of antenatal corticosteroids for the prevention ofneonatal respiratory distress syndrome stems from theanimal work by Liggins and Howie in the late 1960s.90

They observed that gravid sheep, which had receivedglucocorticoids to induce preterm labor, gave birth tolambs that had accelerated fetal lung maturity and de-creased respiratory problems at birth. After this observa-tion, these investigators conducted the first trial of ante-natal glucocorticoid therapy in humans and found that12 mg of betamethasone on two occasions 24 hours apartresulted in a significant decrease in the incidence of

respiratory distress syndrome associated with a decreasein perinatal mortality in newborns born before 34 weeks.The beneficial effect was noted only if delivery occurredafter more than 24 hours had elapsed from the first doseand before 7 days.

Since then, 15 additional prospective randomized con-trolled trials have been performed. Crowley conducted ameta-analysis of these trials91 confirming that antenatalglucocorticoid therapy significantly decreased the inci-dence and severity of neonatal respiratory distress syn-drome. Neonatal mortality was also significantly re-duced, as was the incidence of intraventricular

hemorrhage and necrotizing enterocolitis. These benefitsappeared to be maximal if delivery occurred more than24 hours after start of treatment but within 7 days.

Despite these data, antenatal corticosteroids remainedunderused throughout the 1980s and early 1990s. Forthis reason, the National Institutes of Health convened aConsensus Development Conference on Antenatal Ste-roids in 1994 to review the potential risks and benefits ofantenatal corticosteroid therapy.92The panel concludedthat antenatally administered corticosteroids (beta-methasone or dexamethasone) significantly reduce therisk of respiratory distress syndrome, intraventricular

hemorrhage, and neonatal death. The panel recom-mended that all women between 24 and 34 weeksgestation at risk for preterm delivery should be consid-ered candidates for antenatal corticosteroid treatment.Additionally, given that treatment for less than 24 hourswas associated with a significantly decreased risk forrespiratory distress syndrome, intraventricular hemor-rhage, and mortality, the panel concluded that steroidsshould be administered unless delivery is imminent. Forpatients with preterm PROM, treatment was recom-

mended for patients at less than 30 32 weeks because ofthe high risk of intraventricular hemorrhage. Recentstudies suggesting worse outcomes in newborns whosemothers received multiple courses of corticosteroids, andone randomized trial showing no benefit, strongly sug-gest that the practice of giving repetitive weekly dosecourses until 34 weeks be discontinued, unless data from

ongoing randomized clinical trials demonstrate benefitfor this practice. Long-term follow-up of infants exposedin utero to a single course of antenatal corticosteroidtherapy has not demonstrated any adverse effect ongrowth, physical development, motor or cognitive skills,or school progress at 3 and 6 years. Hence, the use of asingle course of corticosteroids appears to be an effica-cious and safe treatment for improving neonatal out-comes in patients with preterm labor.

The commonly utilized steroids for the enhancementof fetal maturity are betamethasone (12 mg intramuscu-larly every 24 hours, two doses) and dexamethasone

(6 mg intravenously every 6 hours, four doses). Thesetwo glucocorticoids have been identified as the mostappropriate for antenatal use as they readily cross theplacenta and have long half-lives and limited mineralo-corticoid activity. One study,93 however, suggests thatbetamethasone is more effective in reducing intraventric-ular hemorrhage and periventricular leukomalacia thandexamethasone. Therefore, in the absence of other data,betamethasone given as a single course appears to be thebetter choice.

DELIVERYThe remarkable reduction in neonatal mortality that hasoccurred in the last several decades is mostly due to thewidespread use of newborn intensive care for pretermnewborns. Birth in close proximity to a newborn inten-sive care unit with an experienced resuscitation team inattendance is one of the best predictors of neonatalsurvival. Obstetricians and other delivery attendantsshould do all in their power to insure that each pretermnewborn can benefit from this technology.

Women in preterm labor are more likely to havefetuses in the breech presentation than those at term, and

the earlier the preterm labor, the more likely the breechfetus is to have a nonfrank presentation. Fetuses in the breech position, especially those less than 32 weeks,when delivered vaginally are prone to cord prolapse,muscle trauma, and head entrapment. They appear lesslikely to have traumatic and asphyxial injuries whendelivered by cesarean delivery. Vaginally delivered pre-term breech fetuses near term appear to have outcomesnearly comparable to those of vertex infants of the samegestational age, but few randomized trials exist to guide


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our choice of delivery method. Nevertheless, in mostinstitutions virtually all preterm breech infants are deliv-ered by cesarean delivery. Given the limited experienceof most obstetricians in conducting breech deliveries andthe reported increases in morbidity and mortality withvaginal delivery, this practice seems appropriate, and isconsistent with the ACOG position on breech delivery at

term.94

There is little or no evidence that routinelydelivering preterm vertex infants by cesarean deliveryimproves outcome. Therefore, in preterm vertex infants,cesarean delivery should generally be performed for thesame indications as in term infants. How to select theearliest gestational age for which cesarean deliveryshould be offered is a complicated issue. However, fac-tors considered should include the gestational agespe-cific survival and short- and long-term neonatal morbid-ity rates at the delivering institution. In specific cases,after appropriate counseling, the parents wishes shouldbe strongly considered as a guide to management. That

said, it is the practice in many institutions with a goodnewborn intensive care unit to offer cesarean deliverieswhen indicated at about 24 weeks, and to stronglyrecommend them when indicated beginning at 26 weeksgestational age.

Preterm infants, and especially very early preterminfants, are more vulnerable to trauma during deliverythan fetuses at term. They are far more likely to suffersoft tissue damage, neurological injury, and traumaticintracranial hemorrhage than term infants. For this rea-son, special care should be taken not to traumatize theseinfants, especially during cesarean delivery or when

using forceps. Vacuum extraction in preterm births mayadd extra risk and is considered to be contraindicated bysome authorities. Although there are no randomizedtrials to confirm it, there appears to be less labor anddelivery trauma when preterm labor is conducted withintact membranes. For this reason, especially for earlypreterm deliveries, artificial membrane rupture shouldbe performed only for a clear indication. For the veryearly preterm breech fetus of borderline viability forwhich a cesarean delivery will not be performed, an incaul delivery appears to result in the least trauma.95Thechoice of anesthesia should be based on similar consid-

erations for both term and preterm labors.

SUMMARY

The epidemiology, pathophysiology, and current thera-peutic strategies utilized in the setting of preterm laborhave been reviewed. Despite our best efforts, pretermdelivery remains a significant clinical problem, account-ing for a substantial component of all neonatal morbidityand mortality. Although we have gained important in-

sights into the pathophysiology of preterm labor over thepast several decades, effective therapeutic interventionsto decrease spontaneous preterm delivery have not beendiscovered.96 Therefore the successful management ofpreterm labor includes preventing neonatal diseasewhen possible, including the use of corticosteroids and,when appropriate, group B streptococcus prophylaxis,

and reducing trauma and asphyxia during delivery. Pre-term newborns should be delivered at a site that canperform expert resuscitation and provide intensive carewhen necessary. Clearly, additional research is neededto further explore the pathophysiology of spontaneouspreterm labor and potential therapeutic approaches todeal with this important clinical problem. In the mean-time, it seems important to practice evidence-based med-icine, doing the things that work, and to eliminate fromour practices those things for which there is no evidenceof efficacy. The latter practices include hydration, seda-tion, bed rest, home uterine activity monitoring, tocoly-

sis without the concomitant use of corticosteriods, andoral terbutaline after successful intravenous tocolysis.

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