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Review Articles

Medical Progress

P

REVENTION

OF

P

REMATURE

B

IRTH

R

OBERT

L. G

OLDENBERG

, M.D.,

AND

D

WIGHT

J. R

OUSE

, M.D.

From the Department of Obstetrics and Gynecology, University of Ala-bama at Birmingham, 618 S. 20th St., OHB 560, Birmingham, AL 35294-7333, where reprint requests should be addressed to Dr. Goldenberg.

1998, Massachusetts Medical Society.

RETERM birth, which occurs in 11 percentof all pregnancies, is responsible for the major-ity of neonatal deaths and nearly one half of

all cases of congenital neurologic disability, includ-

ing cerebral palsy.

1

Although all births before 37weeks of gestation are considered premature, birthsbefore 32 weeks gestation (2 percent of all births)account for most neonatal deaths and disorders.

2

State and national vital statistics indicate that the in-cidence of preterm birth has risen over the past 15

years (Fig. 1), and it remains twice as high amongblack women as among white women.

3-5

Pretermbirth is commonly categorized as birth occurring af-ter spontaneous premature labor (in approximately50 percent of cases) or spontaneous rupture of themembranes (in approximately 30 percent) or deliv-ery of a premature infant as indicated for the benefitof either the infant or the mother (in approximately

20 percent).

6

Prevention of preterm birth is not an end in itself.Preterm birth is consequential only because it resultsin morbidity or death in some infants. If an infantdoes not die or have any disorders and does not havea prolonged hospitalization, preterm birth is of littleconsequence. Moreover, a full-term infant may dieor have neurologic damage as a result of a problemlate in the pregnancy. Thus, although delaying birthuntil term is desirable in most circumstances, in cer-tain cases, preterm birth may be the lesser of twoevils.

There are two categories of strategies used to re-duce adverse outcomes associated with prematurity:those intended to prevent or delay preterm birth, andthose intended to reduce prematurity-associated mor-bidity and mortality.

6

In this article, we do not review

P

in detail the many interventions that ameliorate pre-

maturity-associated morbidity and mortality. Amongthem, however, the most successful is regionalizationof perinatal care, which ensures that most preterm in-fants are delivered at a newborn intensive care unit

with appropriate facilities and trained personnel. Effec-tive neonatal interventions include improved methodsof mechanical ventilation, exogenous-surfactant thera-py, liberal antibiotic treatment, and appropriate fluidand electrolyte management. Effective obstetrical in-terventions include the use of prenatal corticosteroidsfor fetal maturation and intrapartum antibiotics to re-duce neonatal sepsis, as well as prevention and prompttreatment of fetal hypoxia.

7-10

Because of these inter-ventions, among infants with a birth weight of 1000

to 1500 g, mortality has decreased from about 50 per-cent in 1960 to about 5 percent today, and amongthose with a birth weight of 500 to 1000 g, mortalityhas decreased from about 95 percent in 1960 to about20 percent today.

11

Despite these dramatically lowermortality rates, approximately 50 to 60 percent of allneonatal deaths occur in those few infants (1 percent)

who weigh less than 1000 g at birth.

12

Moreover, theimprovement in survival has not been accompanied bya substantial reduction, if any, in the risk of prematu-rity-associated neurologic handicaps.

SPONTANEOUS PRETERM BIRTH

Our definition of spontaneous preterm birth in-cludes births that follow both spontaneous laborand spontaneous rupture of the membranes. Al-though these events are often thought of as distinct,there is considerable evidence that the risk factorsfor them are similar and that the distinction is largelyartificial.

13

Many interventions target both conditions.Although there are many ways of characterizing theinterventions aimed at reducing spontaneous pre-term birth, perhaps the most straightforward way isto distinguish between the strategies used before la-bor and those designed to treat preterm labor onceit has become clinically manifest. The strategies dis-cussed in this article are listed in Table 1.

Prenatal Care

Liberal provision of prenatal care is often advocat-ed as an effective means of reducing preterm births.Support for this approach comes from the observa-tion that preterm birth is less likely among women

who seek prenatal care early or have more prenatalvisits than among those who seek care later or havefewer visits. However, causality cannot be inferredfrom this association. First, women at lower risk availthemselves of prenatal care more often than those at

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Copyright 1998 Massachusetts Medical Society. All rights reserved.

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The New England Journal of Medicine

higher risk. Furthermore, women who deliver earlyoften have fewer prenatal visits, simply because rou-tine prenatal visits are scheduled at shorter intervalsin late pregnancy.

Interventions designed to reduce preterm birthsinclude the introduction of standard prenatal care inan area where there was previously little or no careand the use of enhanced rather than routine prenatalcare. Our review of the literature and reviews byothers suggest that making prenatal care available tomore women or making more visits available to thesame number of women has generally not reducedpreterm births.

14-17

Enhancing prenatal care by addingcombinations of patient education, case management,home visiting, and nutrition counseling appeared to

be effective in reducing preterm births in a few ran-domized trials but not in most.

18-23

An example of a study of enhanced prenatal careis the March of Dimes multicenter trial.

24

In thisstudy, women considered to be at high risk for pre-term birth were randomly assigned to either stand-

ard or enhanced prenatal care. Enhanced care in-cluded patient education, weekly evaluation for signsof preterm labor, and earlier use of tocolytic (labor-inhibiting) therapy. Despite evidence from an obser-

vational study that this intervention held promise, itwas not effective in this or other randomized tri-als.

24,25

Overall, because the enhancements to prena-tal care have varied from study to study and becausethe associated reductions in preterm birth have beeninconsistent, it is not clear which specific additionsto prenatal care, if any, are likely to result in a reduc-tion in preterm births.

Risk scoring, with the use of a standardized ques-tionnaire to gauge the intensity of prenatal care, has

been a component of several prematurity-preventionstrategies.

26-29

In general, each of these scoring sys-tems has been able to identify women with a risk ofpreterm birth that was twice the normal risk, pre-dominantly on the basis of a prior preterm birth.However, the use of these scoring systems has result-ed not in significant reductions in preterm births butrather in an increased use of interventions with un-proved effectiveness.

29

An incompetent, or structurally weak, cervix isdiagnosed in 1 in 200 to 1 in 1000 pregnant womenon the basis of a history of spontaneous second-tri-mester preterm birth in the absence of recognizableuterine contractions. The traditional treatment has

been the placement of one or several circumferentialstitches (cerclage) in the cervix. Whether women

with histories of second-trimester birth in the absenceof recognizable contractions benefit from cerclagehas not been tested prospectively, but comparisons

with historical controls suggest a benefit. However,most women with suspected incompetent cervix havehistories that make it difficult to differentiate be-tween an incompetent cervix and unrecognized pre-term labor. In a randomized study involving women

with such histories, cerclage resulted in a statisticallysignificant reduction in the rate of preterm birthbefore 33 weeks, but cerclage was required in 25

women to prevent 1 preterm birth.

30,31

Studies in animals and some studies in humansprovide evidence that maternal progesterone con-centrations decline before labor. Therefore, severalrandomized studies have evaluated the effect of sup-plementation with a progestin, including weekly in-

jections of hydroxyprogesterone caproate, in womenat risk for preterm birth.

32,33

A meta-analysis sug-gests that progestin supplementation is associated

with a significant reduction in the rate of prematurebirth.

34

Nevertheless, because the most widely studied

Figure 1.

Preterm Births in the United States, 1981 through1994.

Data are from the National Center for Health Statistics.

3

0123456789

101112

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

Year

Pre

termB

irths

(%o

flivebirths)

T

ABLE

1.

I

NTERVENTIONS

TO

P

REVENT

P

REMATURE

B

IRTH

.

Prenatal care (routine or enhanced)Risk-scoring systemsCervical cerclageProgestin supplementationPrograms for cessation of tobacco, drug, and alcohol

usePsychological supportNutritional interventions

CounselingCaloric supplementationProtein supplementation

Vitamin or mineral supplementationPatient education (to detect signs of preterm labor)Home uterine-activity monitoringFrequent contact with a nurseTocolytic therapyBed rest

HydrationScreening for and treatment of infection (urinary

tract infection or bacterial vaginosis)Antibiotics for preterm labor or premature rupture

of membranesLow-dose aspirinCalcium supplementation



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regimen required weekly injections and the improve-ments, although significant, were at times not sub-stantial, treatment with progestins is now rarelyused. Since the previous studies were relatively smalland had dissimilar designs, the Maternal Fetal Med-icine Units Network of the National Institute of

Child Health and Human Development has initiateda prospective, randomized trial of this intervention.

Programs for cessation of tobacco, drug, and al-cohol use have been recommended as part of a strat-egy to reduce spontaneous preterm births. The useof these substances, however, is more closely linkedto restricted fetal growth than to preterm birth.

35,36

Moreover, these programs all achieve, at best, rela-tively low rates of cessation. For these reasons, suchprograms have limited potential to reduce the over-all rate of preterm birth.

Data on the association between various maternalpsychological characteristics (including stress, anxi-ety, and depression) and spontaneous preterm birth

are inconsistent,

36,37

and when an association hasbeen observed, the relative risk of premature birthamong women with specific psychological character-istics has usually not been substantially increased.

38

The few randomized studies in which psychosocialsupport or counseling was provided did not demon-strate that the intervention reduced preterm births,although it may have had other benefits for pregnant

women.

39,40

Nutritional Interventions

In developed countries, women who are under-weight before pregnancy and those who gain littleweight during pregnancy are at increased risk for

preterm birth.

41

Whether these associations suggestcausality is unknown, because the mediators havenot been elucidated. For example, low weight gainduring pregnancy may reflect limited expansion ofblood and amniotic fluid volume or suboptimal fetalgrowth, as well as inadequate nutritional intake.

41

Four types of nutritional interventions have beenstudied: counseling, protein supplementation, caloricsupplementation, and vitamin or mineral supplemen-tation. There is little evidence that nutritional coun-seling changes the eating habits of pregnant women,let alone the outcome of pregnancy.

42

Interestingly,the provision of protein supplementation has consis-tently been associated with adverse outcomes.

43

TheSpecial Supplementation Program for Women, In-fants, and Children, which provides a calorically en-riched diet to low-income pregnant women, hasbeen in operation in the United States for more than20 years. Studies of this and other caloric-supple-mentation programs in developed countries suggestthat they result in small increases in birth weight.

42,44

However, in areas of relative famine, much greater in-creases in birth weight have been achieved with caloricsupplementation.

45

In all likelihood, much of the in-

crease in birth weight is attributable to improved fetalgrowth rather than the prolongation of pregnancy.

42

Thus, those studies do not provide compelling evi-dence that caloric supplementation is associated witha reduction in preterm births.

The relation between maternal vitamin or mineral

status and prematurity is complicated. For example,many studies suggest that women with anemia are atincreased risk for preterm birth.

46

However, becauseof unequal rates of expansion of plasma volume andred-cell mass during pregnancy, women in the sec-ond or early third trimester routinely have lowerhematocrits than those at term. Failure to correct forgestational age has therefore resulted in a misleadingassociation between anemia and prematurity. Moreappropriate studies, which controlled for gestationalage, showed little correlation between anemia andpreterm birth.

47,48

Interventional studies have dem-onstrated that iron supplementation raises the hema-tocrit; however, there is no consistent evidence that

the rate of preterm birth is reduced with iron sup-plementation, and it may even be increased.

49-51

Low maternal zinc levels have been associatedwith an increased risk of restricted fetal growth andpossibly preterm birth.

52

Several, but not most, trialsof zinc supplementation have shown an increase inbirth weight, and some, including our recent study,

53

suggested that zinc supplementation may reduce therate of preterm birth, especially among thin women.

We studied a low-income minority population ofwomen with moderately low serum zinc values. Incontrast, a study of middle-class Scandinavian womenshowed no effect of zinc supplementation on theoutcome of pregnancy.

54

Studies of folate supple-

mentation to reduce the rate of preterm birth havelikewise had conflicting results.

The efficacy of combined vitamin and mineral sup-plementation, used in many Western countries, inlowering the risk of premature birth has not been rig-orously evaluated. A recent study of an inner-citypopulation found that women who used a vitaminmineral supplement had significantly fewer pretermbirths than those who did not.

55

Since this was not arandomized trial, factors other than supplementation,such as self-selection, may have accounted for theobserved differences in the outcome of pregnancy.

In summary, women with an adequate nutritionalstatus and a normal body-mass index have betterpregnancy outcomes than other women. Despite thelarge number of studies that have been performedand the variations in institutional practices, it remainsunclear whether any nutritional intervention is asso-ciated with a reduction in the rate of preterm birth.

42

Early Identification of Preterm Labor

On the premise that labor-inhibiting drugs are ef-fective only if administered before preterm labor hasbeen fully established, a number of strategies have



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evolved to identify women in early preterm labor.Typically, pregnant women receive instruction in de-tecting contractions or other signs of labor, such aspelvic pressure, vaginal discharge, and back pain.

56

The March of Dimes prematurity-prevention pro-gram, which included instruction in uterine self-

palpation and detection of signs of labor, did not resultin a reduction in preterm births when tested pro-spectively in a number of settings.

24,25

One method of detecting uterine contractions be-fore the onset of active preterm labor is home uterine-activity monitoring, in which a contraction monitorrecords data on uterine activity and transfers the in-formation electronically to a central site for analy-sis.

57

The monitor was approved by the Food andDrug Administration primarily because it can detectcontractions, the data can be transmitted to a centrallocation, and contractions are associated with an in-creased risk of preterm birth. In most randomizedtrials, however, this approach has failed to prevent

preterm births.

58-61

In the most recent study, homemonitoring not only failed to reduce preterm births,but its use was also associated with an increasednumber of unscheduled hospital visits and increaseduse of tocolytic drugs.

61

Strategies using home uter-ine-activity monitoring have often included dailycontact with a nurse, and several authors have sug-gested that this interaction may result in a reducedrate of preterm birth. The data are, at best, conflict-ing, and there is little evidence that daily contact

with a nurse, as compared with routine prenatal care,reduces preterm births.

60-62

Tocolytic Drugs

Tocolytic drugs interrupt or stop uterine contrac-tions. Some of these drugs, such as beta-mimeticagents, have been thoroughly evaluated, whereas oth-ers, including magnesium sulfate, calcium-channelblockers, oxytocin antagonists, and nonsteroidal anti-inflammatory agents, have not. In general, data fromrandomized trials suggest that tocolytic drugs prolongpregnancy for up to 48 hours.

63-65

However, if a ben-efit is defined as a reduction in preterm delivery oreven a delay in delivery for more than a week, theeffect of tocolytic therapy appears to be minimal. Fur-thermore, the use of tocolytic agents alone has notbeen associated with a reduction in neonatal mortalityor the respiratory distress syndrome, which is the mostcommon neonatal disorder. In addition, use of beta-mimetic agents has been associated with an increasedrisk of neonatal intraventricular hemorrhage.

66,67

Nevertheless, the delay in delivery afforded bytocolytic drugs may have a substantial benefit. Ante-natal administration of corticosteroid drugs for asfew as 12 to 24 hours before delivery is associated

with significant reductions in neonatal respiratorydistress syndrome, intraventricular hemorrhage, andmortality.

8

Since the apparent benefit of tocolytic

drugs is to delay delivery for 48 hours, the combineduse of tocolytic drugs and corticosteroids has become

widespread. Even though this approach has not beenadequately tested in randomized studies, severalretrospective studies suggest that it improves theoutcome.

68

Bed Rest and Hydration

Although bed rest and hydration are widely usedin women in preterm labor, there is no convincingevidence of a reduction in preterm delivery witheither approach.

69,70

In fact, in two randomized trialsinvolving twins, hospitalization with bed rest wasassociated with increased rates of preterm birth.

69

Inaddition, there are other possible adverse outcomesassociated with these interventions, including venousthrombosis and pulmonary edema.

71

Treatment of Infection

In recent years, substantial progress has been made

in understanding the relation between maternal in-fection and preterm birth. Up to 80 percent of earlypreterm births are associated with an intrauterine in-fection that precedes the rupture of membranes.

72,73

There have been many trials of antibiotic therapy inwomen with preterm labor, most of which havefound that such therapy does not prevent prematurebirth.

73

Whether this failure is due to the selectionof inappropriate antibiotics, the initiation of treat-ment too late in the cascade of events leading tospontaneous preterm delivery, or other factors is un-known.

If treatment with antibiotics in women with estab-lished preterm labor is ineffective, it remains possible

that antibiotic therapy before labor in selected wom-en may prevent spontaneous preterm birth. In fact,in the 1970s, it was demonstrated that women ran-domly assigned to tetracycline treatment for asymp-tomatic urinary tract infections had fewer spontaneouspreterm deliveries than those assigned to a controlgroup. However, because tetracycline adversely af-fects the development of fetal teeth and bones, itsuse during pregnancy declined. More recently, bothsymptomatic and asymptomatic urinary tract infec-tions have been associated with an increased risk ofpreterm delivery, and several randomized trials haveprovided confirmation that treating asymptomaticbacteriuria not only reduces the risk of maternalpyelonephritis but may also reduce the risk of pre-term birth.

74

Identification of other infections that may have acausal role in spontaneous preterm birth is the focusof much of the current research. For example, nearlyevery sexually transmitted disease, including syphilis,gonorrhea, and infection with chlamydia, has beenassociated with increased preterm births.

75

However,women with sexually transmitted diseases often haveother risk factors for preterm birth, which have rarely



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been evaluated as confounding factors. Furthermore,because of the inconsistency of the association be-tween infection and preterm birth and the relativelylow prevalence of most infections, their eliminationin pregnant women, although otherwise beneficial,is not likely to have a major effect on the overall rate

of preterm birth.

75

We are therefore left with the question of how toprevent preterm birth associated with an intrauterineinfection. Bacterial vaginosis, a polymicrobial over-growth of predominantly anaerobic bacteria, hasbeen consistently associated with a risk of spontane-ous preterm birth that is increased by a factor of 1.5to 3.

76

Furthermore, in two randomized trials in-volving women at high risk for preterm birth (pre-dominantly because of prior preterm birth), treat-ment of bacterial vaginosis with metronidazoleeither alone or in combination with erythromycinresulted in substantial reductions in rates of sponta-neous preterm birth.

77,78

How generalizable these

findings are to women at lower risk remains to beestablished. However, since so many premature birthsare related to infection, antibiotic treatment hasgreat promise in reducing early spontaneous pre-term births, especially among black women, whohave significantly higher rates of bacterial vaginosisthan other women (30 percent vs. 10 percent).

79-81

PRETERM RUPTURE OF THE MEMBRANES

In the absence of intervention, the majority ofwomen with preterm rupture of the membranes havespontaneous labor and deliver within a week. Thus,most pregnancies complicated by preterm rupture ofthe membranes end in preterm birth. Interventions in

these pregnancies have generally not been intended toreduce the rate of preterm delivery but instead havehad more pragmatic goals, such as increasing the timefrom preterm rupture of the membranes to deliveryor reducing morbidity and mortality in mothers andinfants.

Because of concern about the increased risk ofmaternal and fetal infection associated with pretermrupture of the membranes, until two decades agopreterm rupture of the membranes was nearly alwaysconsidered an indication for expeditious delivery, re-gardless of gestational age. With the availability ofmore potent antibiotics and a better understandingof the risk of infection as compared with the risk ofcomplications of prematurity, management of pre-term rupture of the membranes at less than 32 or 34

weeks of gestation has evolved into a policy of watch-ful waiting, with delivery at any sign of infection. Thisstrategy appears to benefit the minority of infants

who are not delivered for a substantial period of time.Prophylactic antibiotic therapy has been found to

be effective in prolonging the period between pretermrupture of the membranes and delivery.

82,83

The largeststudy to date, as well as meta-analyses of studies, has

also demonstrated that antibiotic treatment reducesthe risks of maternal chorioamnionitis, neonatal res-piratory distress syndrome, and neonatal sepsis.

82,83

There is considerable controversy over the use of cor-ticosteroid treatment in women with preterm ruptureof the membranes. Meta-analyses have produced con-

flicting data on the efficacy of this approach.

8,84

Nev-ertheless, a National Institutes of Health consensusconference recommended the use of corticosteroidsin women with preterm rupture of the membranes atless than 30 to 32 weeks of gestation in order toreduce the risk of intraventricular hemorrhage.

85

Be-cause there were few randomized trials restricted to

women with preterm rupture of the membranes,however, the American College of Obstetrics andGynecology did not make a similar recommendation.The combined use of corticosteroids and antibioticshas been associated with a reduced risk of the respi-ratory distress syndrome, as compared with the use ofcorticosteroids alone.

86

Thus, antibiotics are benefi-

cial in prolonging the interval between preterm rup-ture of the membranes and delivery and in reducingneonatal morbidity. Corticosteroids may augmentthis benefit. Tocolytic drugs used independently or inconjunction with corticosteroids or antibiotics havenot consistently been shown to provide further im-provement in the outcome. No strategy has resultedin a reduction in preterm birth after preterm ruptureof the membranes.

CONDITIONS THAT REQUIRE

PREMATURE DELIVERY

Two conditions account for the majority of non-spontaneous preterm births: preeclampsia and pre-

sumed fetal growth restriction. In most cases, theinfant is delivered prematurely because of the pres-ence of preeclampsia and the judgment that eitherthe mother or the infant is at unacceptable risk shouldthe pregnancy continue.

6,87

Since the pathway leadingto preeclampsia involves a relative overproduction ofthromboxane, low-dose aspirin has been used toinhibit its production selectively, and early studiessuggested that aspirin reduced the risk of preeclamp-sia.

88

In recent years, however, several large, multi-center, randomized trials have shown that low-doseaspirin confers little, if any, protection against pre-eclampsia.

89-91

Like aspirin, calcium supplementa-tion, which lowers blood pressure, was associated

with a reduction in preeclampsia in several early tr i-als.

92,93

In the largest randomized, multicenter study,however, calcium supplementation did not reducethe risk of preeclampsia.

94

There are also no data insupport of the many other interventions, includingbed rest, use of antihypertensive medications, use ofdiuretics, and salt restriction, that have been used inthe hope of preventing preeclampsia.

Infants with presumed fetal growth restriction areoften delivered prematurely because of the physicians



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belief that they are at increased risk for stillbirth orneurologic impairment if left undelivered. Many strat-egies have evolved to reduce maternal risk factors as-sociated with fetal growth restriction or at least mit-igate its consequences. These include programs forsmoking, alcohol, and drug cessation, bed rest, ad-

ministration of oxygen, and nutritional supplementa-tion. These types of interventions may have a posi-tive, albeit marginal, effect on fetal growth, but theyhave not been associated with a reduction in prema-ture delivery.

42,69,95-97

Although the use of ultrasonog-raphy to determine gestational age and the use of var-ious amniotic fluid tests to assess fetal pulmonarymaturity have greatly reduced the number of iatro-genic preterm births associated with elective induc-tion of labor and cesarean delivery, there are no spe-cific interventions that reliably prevent the clinicalconditions that require indicated preterm delivery.

Therefore, the current strategy to reduce the riskof death or disability associated with preeclampsia

and fetal growth restriction is to identify at-risk fetusesthrough fetal-movement counting, fetal-heart-ratemonitoring, fetal ultrasonography, or Doppler blood-flow measurements.

98

If the fetus is considered to beat high risk for death or neurologic damage, an earlydelivery is effected. Although this approach does notprevent premature birth, the substantial reduction inthird-trimester stillbirths over the past two decadessuggests that it is effective in reducing the numberof stillbirths.

99

SUMMARY

The available data on the effectiveness of variousinterventions aimed at reducing premature births

provide an explanation for the epidemiologic obser-vation that the rate of preterm birth is not declining.Most interventions designed to prevent preterm birthdo not work, and the few that do, including treat-ment of urinary tract infection, cerclage, and treat-ment of bacterial vaginosis in high-risk women, arenot universally effective and are applicable to only asmall percentage of women at risk for preterm birth.

A more rational approach to intervention will requirea better understanding of the mechanisms leading topreterm birth. In the meantime, substantial reduc-tions in preterm delivery are unlikely to be achieved.

Supported in part by a contract with the Agency for Health Care Policy

and Research (290-92-0055).

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