Mwansa Kambafwile 2010 Antenatal Steroids i

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Antenatal steroids in preterm labour forthe prevention of neonatal deaths due tocomplications of preterm birthJudith Mwansa-Kambafwile,1,2 Simon Cousens,3 Thomas Hansen4,5 and Joy E Lawn1,6

1Saving Newborn Lives/Save the Children-USA, 11 South Way, Pinelands, Cape Town 7405, South Africa, 2Department of Public

Health, Faculty of Health Sciences, University of Cape Town, South Africa, 3Infectious Diseases Epidemiology Unit, London School

of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK, 4CEO, Seattle Childrens Hospital, Seattle, Washington,

USA, 5Department of Pediatrics, University of Washington School of medicine, Seattle, USA and 6Health Systems Strengthening

Unit, Medical research Council, Cape Town, South Africa.

Corresponding author. Saving Newborn Lives/Save the Children-USA, 11 South Way, Pinelands, Cape Town 7405, South Africa.

E-mail: [email protected]

Background In high-income countries, administration of antenatal steroids isstandard care for women with anticipated preterm labour.However, although 41 million deaths due to preterm birth occurannually, antenatal steroids are not routine practice in low-incomecountries where most of these deaths occur.

Objectives To review the evidence for and estimate the effect on cause-specificneonatal mortality of administration of antenatal steroids to womenwith anticipated preterm labour, with additional analysis for theeffect in low- and middle-income countries.

Methods We conducted systematic reviews using standardized abstraction

forms. Quality of evidence was assessed using an adapted GRADEapproach. Existing meta-analyses were reviewed for relevance tolow/middle-income countries, and new meta-analysis wasperformed.

Results We identified 44 studies, including 18 randomised control trials(RCTs) (14 in high-income countries) in a Cochrane meta-analysis,which suggested that antenatal steroids decrease neonatal mortalityamong preterm infants (


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scaled up, this intervention could save up to 500 000 neonatal livesannually.

Keywords Neonatal mortality, newborn care, preterm births, prematurity, lowbirth weight, antenatal steroids, respiratory distress syndrome,bethamethasone, dexamethasone

BackgroundEvery year, $4 million newborns die, and the leadingcause of death is direct preterm complicationsaccounting for 41 million deaths.1 The mostcommon cause of deaths among preterm babies isrespiratory distress syndrome (RDS), an acute lungdisease related to immaturity of the lungs and, spe-cifically, surfactant deficiency.2 The incidence andseverity of RDS show an inverse relationship withgestational age.36 In high-income countries, mostbabies 425 weeks gestation now survive.

7 In manylow-income countries, even moderately pretermbabies have high mortality ratesfor example, in ahospital in Dhaka, capital of Bangladesh, babiesborn under 32 weeks of gestation had a 79% mortalityrate.8 We use the World Bank definition of high-,low- and middle-income countries.9

Antenatal steroid treatment for women who are atrisk of preterm delivery has emerged as the mosteffective intervention for the prevention of RDS, redu-cing early neonatal mortality and morbidity.10 Mostglucocorticoid hormones, natural and artificial, arecapable of crossing the placenta and trigger thematurational process that leads to the productionand release of surfactant into the alveoli of the

foetal lung.

1113

In 1969, Liggins

14

employedb-methasone in the first clinical trial.Given the evidence of benefit, antenatal steroid

treatment is now considered standard practice, andin high-income countries, litigation is likely if antena-tal steroids are not given when indicated.15 Inhigh-income countries, coverage remained low for adecade or so after clear evidence of effectiveness wasavailable, but following the NIH Consensus Statementin 1994,15 there has been almost universal uptakein North America and Western Europe. As a result,the profile of RDS incidence and severity inhigh-income countries has altered allowing wideruse of non-invasive ventilation and continuous

airway pressure ventilation, reducing damage to thelungs.16

Antenatal steroid administration has been identifiedas an essential and feasible intervention that couldbeof enormous public health benefit in low/middle-income countries where preterm birth is morecommon, yet adequate neonatal care is often unavail-able. For over half of the worlds births,ventilator sup-port for RDS is very unlikely. To date, no systematicreviews have focused on the potential benefit of ante-natal steroid therapy in these settings.

Objective

The objective of the present study was to review theevidence globally for and estimate the effect on neo-natal mortality due to preterm birth complications ofantenatal steroid administration to women beforeanticipated preterm labour, compared with placeboor no treatment, with specific focus on variation onthe effect size in low- and middle-income countries.

Methods

SearchesSystematic searches of electronic databases wereundertaken including Cochrane Libraries, PubMed,LILACS, African Medicus, EMRO, all World HealthOrganization Regional Databases and publications inany language (Figure 1). Online searches of majorconference proceedings were also conducted in orderto identify unpublished literature. The key searchterms were Steroid antenatal, newborn steroids, RDS new-born steroids, Antenatal steroids, newborn steroids, RDS new-born steroids and prenatal steroids. The systematicsearches were for studies published between January1970 and September 2009. After initial screening oftitles and abstracts, we reviewed full-text publications

of possible studies.

Inclusion/exclusion criteria, abstraction

We applied the PICO format (Patient, Intervention,Comparison and Outcome) to define the studies tobe included as follows. The population of interest wasneonates, and the intervention being studied wasadministration of corticosteroids to women inpretem labour. We included randomized controlledtrials or observational studies, where antenatal ster-oids were given as therapy in premature labour and

where birth occurred between 24 h and 7 days aftertreatment. All included studies incorporated a placebo

or a suitable control group that was similar to theexperimental group except that it did not receiveantenatal steroids. Studies were included if antenatalsteroids were given alone or in combination with anti-biotics and surfactants. In trials including women

with multiple pregnancies, the number of babieswas used as the denominator for neonatal outcomes.We sought to identify randomized controlled trials,but due to lack of such studies, especially inlow-income settings, we also reviewed observationalstudies fitting the above criteria.

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The outcomes of interest were (i) neonatal mortalitydue to complications of preterm birth as used inInternational Classification of Disease (ICD) version 10and for global estimates for neonatal mortality; and(ii) serious neonatal morbidity related to prematurity(RDS and necrotizing enterocolitis). Preterm birth(


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Child Health Epidemiology Reference Group (CHERG)based on an adaptation of the GRADE approach.17

Analysis and summary measures

We planned a priori to conduct three meta-analyses,two for mortality outcomes (one with RCT as input

and one with observational studies) and one for mor-bidity outcomes (RCT only). We also planned toundertake additional sensitivity analysis to examinebias that may be introduced by excluding certainstudies not meeting our criteria. We conducted allmeta-analysis using STATA version 10.0 statisticalsoftware18 and report the MantelHaenszel pooled rel-ative risk and corresponding 95% confidence interval(CI). Heterogeneity between studies was summarizedusing the I2 statistic. If this statistic was


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neonatal mortality according to gestational age.Between 31 weeks and 36 weeks of gestational age,there is430% reduction in mortality. Before 30 weeks,the evidence for an effect is weaker and the benefitmay be smaller. After 36 weeks of gestation, there isno evidence of a mortality benefit. Hence, this inter-

vention has an effect only on preterm babies, is

mediated through a reduction in preterm specificrespiratory complications and can be assumed torelate to the category of direct preterm deaths usedin ICD and in LiST.

Treatment and doseDexamethasone is administered in four doses of 6 mgat 12-h intervals, whereas b-methasone is adminis-tered as two doses of 12 mg at 12-h interval.15 Mostof the RCTs (14 studies) involved the administrationof b-methasone. Six of the previous stud-ies21,23,30,31,33,34 used dexamethasone. According to aCochrane review, b-methasone resulted in a greater

reduction in RDS (RR 0.56; 95% CI 0.480.65; 14studies; 2563 infants) than dexamethasone treatment(RR 0.80; 95% CI 0.680.93; six studies; 1457infants).10 In addition, b-methasone did not increasepuerperal sepsis; whereas dexamethasone was asso-ciated with a significant increase (RR 1.74; 95% CI1.042.89; four studies; 536 women).10 However,another Cochrane review in the same year concludedthat dexamethasone was associated with not only ahigher rate of NICU admission but also a lower inci-dence of intraventricular haemorrhage compared withb-methasone (RR 0.44; 95% CI 0.210.92; four stu-dies; 549 infants).40 More trials of commonly usedcorticosteroids are required in order to make definitiverecommendations on the choice of steroid.

Timing of dosesAntenatal steroids administration appears to beeffective when there is birth within 24 or 48h oftreatment, if there is birth in 47 days after treatment(RR 1.45; 95% CI 0.752.8; 561 babies). This mayreflect the increasing maturity of such babies.26

Number of dosesIn 18 RCTs examined, eight had a protocol for arepeated course of treatment each week until

birth. In their study, comparing repeated steroiddoses to women at risk of preterm labour, Crowtheret al.41 found that babies born to women who hadreceived repeat corticosteroids were less likely tohave respiratory problems after birth. In addition,babies that did develop respiratory problems hadless severe episodes and lower requirement for venti-lation.41 However, the benefit of a single and/orincomplete dose of antenatal corticosteroids on mor-tality and morbidity related to preterm infants isclear.42,43

Effects of the intervention on neonataldeaths due to direct complications ofpreterm birth

In the Cochrane review, 18 studies with mortality out-comes involving 3956 infants were included.10

Antenatal steroid treatment was associated withreductions in neonatal mortality in very preterm

babies (RR 0.69; 95% CI 0.580.81; 18 studies;3956 babies) and morbidity (RDS) (RR0.66; 95%CI 0.590.73; 21 studies; 4038 babies). No evidenceof effects on maternal mortality or stillbirths wereidentified.10 No long-term complications wereobserved for surviving childrenindeed there werenon-significant trends towards reduced cerebralpalsy and visual impairment following treatment

with antenatal steroids. A sensitivity meta-analysisof the Cochrane review, but with two excluded stu-dies,36,37 also showed an association between antena-tal steroid treatment and a reduction in neonatalmortality among very preterm babies (RR 0.66;95% CI 0.560.78; 20 studies; 4143 babies).

Of the 18 studies with mortality outcomes, 14 arefrom HICs with current neonatal mortality rates(NMR) of less than 5 per 1000 and universal coverageof intensive care with ventilation for all babies andsurfactant for all babies since mid-1990s. In contrast,in sub-Saharan Africa, the average NMR is 30 per1000. Hence, the generalizability of these results tolow- and middle-income countries is unclear. Themortality effect estimated by the Cochrane reviewmight substantially underestimate the effect thatcould be expected in a setting in which preterm new-borns currently receive little or no basic neonatalmedical care, let alone intensive care.

Variation of mortality effect size in the pre-surfactantera and during testing and post-surfactant eraWe, therefore, hypothesized that earlier studies, in

which the control groups received no surfactant andless complex intensive care and thus more closelyresemble current conditions in low- andmiddle-income countries, might report larger effectsthan more recent studies. Reordering the 18 studiesin the Cochrane review by date, instead of authornames in alphabetical order, does not reveal a cleartrend, with relatively large effects seen in the fourmost recent studies (Figure 3). However, the lastfour studies were from middle-income countries and

so may confound any time trend in high-incomecountries. After excluding these four studies, there

was no evidence of a time trend in the effect of ster-oids (P 0.9). We undertook sub-analyses to see ifearlier studies in the pre-surfactant era, and whenintensive care was less complex, would indicate agreater effect size that may be more applicable forcurrent low-income country settings (meta-analysisnot shown). As the first surfactant trial was inJapan in 1980,44,45 we defined the pre-surfactant eraas pre-1980 (RR 0.71; 95% CI 0.540.93; five

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studies; 1615 babies), the surfactant testing era from1980 to 1990 (RR 0.94; 95% CI 0.661.33; five stu-dies; 1245 babies) and the post-surfactant era after

1991, excluding MICs (RR

0.80; 95% CI 0.481.35;four studies; 425 babies). There is no evidence thatthe mortality effect varied across these three periods(P 0.50). It is interesting to note that new studies

were not instituted in HICs after the NIH Consensusstatement on antenatal steroid use.15

Variation of mortality effect size in low- andmiddle-income countriesWe then performed a separate meta-analysisrestricted to four RCTs from middle-income countries(Table 1). There is evidence (P 0.008) of a largerreduction in neonatal mortality in middle-income set-

tings (Figure 4a; RR 0.47; 95% CI 0.350.64; fourstudies; 672 babies) than in high-income settings(Figure 5; RR 0.79; 95% CI 0.650.96; 14 studies;3284 babies).10A meta-analysis (Figure 4b) of mor-bidity (RDS) in middle-income countries producesan effect estimate (RR 0.63; 95% CI 0.490.81;four studies; 668 babies) similar to the effect estimatereported by the Cochrane review (RR 0.66; 95% CI0.590.73; 21 studies; 4038 babies).

Finally, we undertook a meta-analysis of the twoidentified observational studies from middle-income

countries, which gave a summary risk ratio of 0.55(95% CI 0.400.76) for mortality (Figure 6).

Overview of the findings and the qualityof evidence

In summary, there is high-quality evidence of a sub-stantial mortality effect of antenatal steroids, and thiseffect is greater in MICs than in high-income settings(Table 2). However, there is a dearth of data fromlow-income countries (Box 1).

DiscussionPreterm birth is the leading cause of neonatal mortal-ity and morbidity in both high- and low-incomecountries. The recent Cochrane review shows very

substantial benefit of antenatal steroid therapy onpreterm neonatal mortality (31%) and morbidity out-comes (34% reduction in RDS). Our meta-analysis,restricted to four RCTs from middle-income countries,suggests an even larger effect: namely a halving ofdeaths due to complications of preterm birth (53%reduction with a CI of 3665%). Given that thereare 41 million preterm deaths each year,1 most of

whom do not currently benefit from antenatal ster-oids, this intervention has the potential to prevent upto 500 000 neonatal deaths each year.

Risk ratio.1 1 10

Study% Weight

Risk ratio

(95% CI)

0.87 (0.63,1.19)Liggins 1972 24.3

0.19 (0.02,1.54)Block 1977 1.8

1.02 (0.43,2.41)Taeusch 1979 3.0

0.27 (0.09,0.81)Doran 1980 4.3

0.23 (0.07,0.79)Schutte 1980 4.21.06 (0.67,1.68)Collaborative 1981 10.9

1.00 (0.07,15.00)Nelson 1985 0.3

0.32 (0.01,7.45)Parsons 1988 0.5

0.84 (0.43,1.63)Gamsu 1989 5.8

0.78 (0.30,2.06)Morales 1989 2.9

0.99 (0.47,2.10)Garite 1992 3.4

0.64 (0.19,2.21)Kari 1994 2.1

1.03 (0.07,15.82)Lewis 1996 0.3

0.68 (0.27,1.73)Silver 1995 3.1

0.50 (0.28,0.89)Amorim 1999 9.6

0.48 (0.15,1.55)Dexiprom 1999 2.8

0.45 (0.29,0.70)Qublan 2001 13.8

0.46 (0.23,0.93)Fekih 2002 6.9

0.69 (0.58,0.81)Overall (95% CI)

Figure 3 A meta-analysis (fixed effects) of 18 RCTs comparing administration of antenatal steroids for preterm labour withplacebo and showing effect on preterm cause-specific mortality outcome. Total events491; heterogeneity 221.54(df17); P0.203; test of RR1; z4.50; P0.000. Fixed effect meta-analysis. Note: 18 RCTs the same inputs asCochrane review10 but meta-analysis revised to order by date of study instead of author alphabetical order

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Risk ratio.1 1 10

Study % Weight

Risk ratio

(95% CI)

0.50 (0.28,0.89)Amorium 1999 28.9

0.48 (0.15,1.55)Dexiprom 1999 8.4

0.45 (0.29,0.70)Qublan 2001 41.8

0.46 (0.23,0.93)Fekih 2002 20.9

0.47 (0.35,0.64)Overall (95% CI)

Risk ratio.1 1 10

Study % Weight

Risk ratio

(95% CI)

1.16 (0.75,1.79)Dexiprom 1999 24.0

0.53 (0.35,0.82)Amorium 1999 37.9

0.54 (0.31,0.95)Qublan 2001 21.9

0.17 (0.05,0.55)Fekih 2002 16.1

0.63 (0.49,0.81)Overall (95% CI)

(a)

(b)

Figure 4 Meta-analysis of four RCTs from middle-income countries comparing administration of antenatal steroids forpreterm labour with placebo: (a) effect size on preterm cause-specific mortality outcome [total events 142; heterogeneity20.08 (d.f.3); P0.994; test of RR1; z4.87; P0.000; fixed effect meta-analysis]; and (b) effect size on RDS

(severe morbidity outcome) [total events185; heterogeneity 213.40 (d.f.3); P0.004; test of RR1; z3.58;P0.000; random effects meta-analysis]

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Risk ratio.1 1 10

Study % Weight

Risk ratio

(95% CI)

0.61 (0.43,0.85)Meneguel 2003 76.0

0.39 (0.18,0.84)Nayeri 2005 24.0

0.55 (0.40,0.76)Overall (95% CI)

Figure 6 Fixed effect meta-analysis of two observational studies from low/middle-income countries comparing adminis-tration of antenatal steroids for preterm labour with placebo showing effect size on neonatal mortality outcome. Totalevents135; fixed effect meta-analysis; heterogeneity 21.09 (df1); P0.297; test of RR1; z3.70; P0.000

Risk ratio

.1 1 10

Study % Weight

Risk ratio

(95% CI)

0.19 (0.02,1.54)Block 1977 2.6

1.06 (0.67,1.68)Collaborative 1981 16.3

0.27 (0.09,0.81)Doran 1980 6.4

0.84 (0.43,1.63)Gamsu 1989 8.6

0.99 (0.47,2.10)Garite 1992 5.1

0.64 (0.19,2.21)Kari 1994 3.1

1.03 (0.07,15.82)Lewis 1996 0.5

0.87 (0.63,1.19)Liggins 1972 36.3

0.78 (0.30,2.06)Morales 1989 4.3

1.00 (0.07,15.00)Nelson 1985 0.5

0.32 (0.01,7.45)Parsons 1988 0.8

0.23 (0.07,0.79)Schutte 1980 6.3

0.68 (0.27,1.73)Silver 1996 4.6

1.02 (0.43,2.41)Taeusch 1979 4.5

0.79 (0.65,0.96)Overall (95% CI)

Figure 5 Fixed effects meta-analysis of 14 RCTs from high-income countries comparing administration of antenatalsteroids for preterm labour with placebo showing effect size on neonatal mortality outcome. Total events 349; fixed effectmeta-analysis; heterogeneity 212.48 (df 13); P0.489; test of RR1; z2.33; P0.020

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Table2

Qualityassessment

gradetableoftheeffectofantenatalsteroidsforpreterm

labouronneona

talmortalityduetodirectcomplicatio

nsofpreterm

birth

Qualityassessment

Summaryoffindings

No.of

studies

Design

Limitations

Consiste

ncy

Directness

No.ofeventsintotal

RR(95%CI)

Generalizability

topopulation

ofinterest

Generalizability

tointerve

ntion

ofinterest

Intervention

Control

Cause-specificmortalitya

(evidenceGRADEhighquality)

Eighteeen

RCT

Noneorfew,e.g.

smallsamplesizes,

norandomization

methodandno

allocation

concealment

Yes

Mostlyhigh

income

Direct

200events

in1988

291event

s

in1968

0.6

9(0.5

80.8

1)

Four

RCT

Noneorfew,e.g.

smallsamplesizes,

norandomization

methodandno

allocation

concealment

Very

Allmiddleincome

Direct

46events

in338

96events

in334

0.4

7(0.3

50.6

4)

Twofrom

MICs

Observational

Neitherwasacohort

study,

therefore

temporalityanissue

Yes

Also14from

HIC

notabstracted

Direct

48events

in345

87events

in347

0.5

5(0.4

00.7

6)

Severemorbidity(evidenceG

RADEhigh-qualityevidence,

distalm

ortalityeffect)

Twenty-one

RCT

Noneorfew,e.g.

smallsamplesizes,

norandomization

methodandno

allocation

concealment

Yes

Low

asmostly

studiesfrom

HIC

Indirect

(severe

morbidity,

i.e.

RDS

)

351events

in2030

523event

s

in2008

0.6

6(0.5

90.7

3)

Four

RCT

Noneorfew,e.g.

smallsamplesize

andunclearalloca-

tionconcealment

Yes

Allmiddleincome

Indirect

(severe

morbidity,

i.e.

RDS

)

72events

in335

113event

s

in333

0.6

3(0.4

90.8

1)

aAllcauseneonatalmortalitybutnomortalityeffect436weeksgestationmaximum

at3132weeks,soeffectisonneonataldeathsduepreterm

birthdir

ectcomplication.

HIC,

high-incomecountry.

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The clearest evidence for an effect is for babies bornbetween 31 weeks and 36 weeks gestation but, sur-prisingly, there may be benefit at even lower gesta-tional ages, although it should be noted that in allthese studies mechanical ventilation was routinelyavailable in addition to antenatal steroids (Figure 1).Importantly, the trials from settings with neonatal

intensive care may underestimate the effect inlow-income countries where there is little or no carefor preterm neonates because neonatal intensive care

was standard practice for the control group in allthese trials (Box 1). Even if only one dose is given


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Mwansa Kambafwile 2010 Antenatal Steroids i