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Article history:Received 29 September 2014Received in revised form 5 January 2015

rised data collected forit University Hospital

International Journal of Gynecology and Obstetrics xxx (2015) xxxxxx

IJG-08275; No of Pages 6

Contents lists available at ScienceDirect

International Journal of Gy

j ourna l homepage: www.erepeated doses for women still at risk of preterm delivery at least7 days after an initial course, quoting a reduced risk of adverse neonatal

Berlin, Germany, between January 1, 1996, and December 31, 2008(data stored in database KIM Argus, GMT GmbH, Frankfurt, Germany).imental evidence showing that surfactant production and lung matura-tion in fetal sheep is maximized after serial doses of glucocorticoidsadministered over a period of weeks [3]. Although there is evidenceagainst weekly glucocorticoid injections [4], others support the use of

2. Materials and methods

The present retrospective cohort study comp44 039 deliveries at the Clinic of Obstetrics, Char1. Introduction

Prenatal administration of synthetic glucocorticoids is a powerful in-tervention to reduce the frequency of respiratory distress syndrome,and neonatal morbidity andmortality amongwomen at risk of pretermbirth [1]. Until the late 1990s, repeated maternal glucocorticoid treat-ment was common practice for women who did not deliver within7 days of the initial course [2]. This practice wasmainly based on exper-

treatment interval, and whether repeated doses of glucocorticoids arebenecial [710]. Differences in effects between the sexes, wherebymale fetuses benet less than do female fetuses, have also been sug-gested in animal and human studies [11].

The aim of the present study was to determine the effects of mater-nal betamethasone treatment in initially normally grown fetuses onfetal growth, neonatal outcome, and placental weights.outcome [5,6]. Discussion is ongoing about t

Corresponding author at: Universittsmedizin BerCharit Campus Virchow, Augustenburger Platz 1, 1333045066439; fax: +49 30450564901.

E-mail address: [email protected] (T. Braun).

http://dx.doi.org/10.1016/j.ijgo.2015.01.0130020-7292/ 2015 International Federation of Gynecology

Please cite this article as: Braun T, et al, Fetal aJ Gynecol Obstet (2015), http://dx.doi.org/10dose-dependent manner without improving neonatal morbidity or mortality.2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.Accepted 18 March 2015

Keywords:BetamethasoneBirth weightDoseSexGlucocorticoid

symptomatic contractions, cervical insufciency, preterm premature rupture of membranes, or vaginal bleeding.Women in the control group were matched for gestational age at time of delivery and had not receivedbetamethasone. Fetal growth changes and neonatal anthropometry were compared. Results: Among 1799 new-borns in the betamethasone group and 42 240 in the control group, betamethasone was associated with signif-icantly lower birth weight (154 g lower on average) after adjusting for confounders (e.g. hypertension, smoking,and maternal weight), sex, and gestational age at delivery (P b 0.05). The higher the dose, the greater the differ-ence inmean birthweight versus controls in births before 34+0weeks (16mg444 g; 24mg523 g;N24mg811 g),without a detectable improvement inneonatalmorbidity ormortality. Therewas a dose-dependent de-cline in expected fetal weight gain as estimated by serial ultrasonography examinations 68 weeks afterbetamethasone administration (P b 0.05). Conclusion: Betamethasone exposure reduces fetal weight gain in aObjective: To determine the effects of betamethasone on fetal growth and neonatal outcomes.Methods: A retro-spective cohort study was performed of deliveries that occurred at Charit University Hospital Berlin, Germany,between January 1996 and December 2008. The betamethasone group included womenwith preterm labor anda b s t r a c ta r t i c l e i n f oCLINICAL ARTICLE

Fetal and neonatal outcomes after term anbetamethasone administration

Thorsten Braun a,, Deborah M. Sloboda b, Boris TutschJoachim W. Dudenhausen a, Andreas Plagemann a, Woa Departments of Obstetrics and Division of Experimental Obstetrics, Study Group Perinatal Prob Departments of Biochemistry and Biomedical Sciences, Obstetrics and Gynecology and Pediac Medical Faculty Heinrich Heine University, Dsseldorf, Germanyd Department of Physiology, Obstetrics and Gynecology, University of Toronto, Toronto, ON, Cae Faculty of Health Sciences, Simon Fraser University, Vancouver, BC, Canadaf Departments of Obstetrics and Gynecology, University of Western Australia, Perth, WA, Austrhe dose, type of steroid,

lin, Department of Obstetrics,53 Berlin, Germany. Tel.: +49

and Obstetrics. Published by Elsevier I

nd neonatal outcomes after te.1016/j.ijgo.2015.01.013preterm delivery following

c, Thomas Harder a, John R.G. Challis d,e,f,ang Henrich a

ming, Charit Campus Virchow, Berlin, GermanyMcMaster University, Hamilton, ON, Canada

necology and Obstetrics

l sev ie r .com/ locate / i jgoThe Charit University Hospital ethics review committee approved theretrospective, observational, and anonymized analysis, and deemedthat no formal ethical review or written consent from individual pa-tients was needed.

The deliverieswere divided on the basis of whether themothers hadreceived prenatal treatment with betamethasone. Women in the

reland Ltd. All rights reserved.

rmand pretermdelivery following betamethasone administration, Int

betamethasone grouphadbeendiagnosedwithpreterm labor and symp-tomatic contractions, cervical insufciency, pretermpremature rupture ofmembranes, or vaginal bleeding, and received betamethasone (Celestan,MSDGmbH, Haar, Germany) between 23weeks plus 5 days of pregnancy(23+5 weeks) and 33+6 weeks. Controls were women with gestational-age-matched pregnancies (on the basis of time of delivery) who did notreceive betamethasone treatment. The exclusion criteria were multiplegestations, major malformations, pregnancies with incomplete datasetsfor all variables under investigation, and pregnancies inwhich a glucocor-ticoid other than betamethasone was administered.

For women diagnosed with preterm labor, several dose regimensand intervals of betamethasone treatment were used. These regi-mens varied between two 8-mg doses (16 mg) or two 12-mgdoses (24 mg) given once during pregnancy, and repetitive dosesof betamethasone (8 mg weekly, or two 12-mg doses every secondweek) when the diagnosis of preterm labor still persisted (collec-tively grouped as N24 mg). For the present study, the effects ofbetamethasone dosage on neonatal outcomes were comparedamong three different total dosages: 16 mg or less, 24 mg, andmore than 24 mg. A time variable (year of delivery) was introducedin the multivariate analyses to adjust for secular trends.

betamethasone-associated changes were controlled for possibleconfounders.

Considering the periods in pregnancy clinically relevant for neonataloutcome, groups were divided by gestational age: very early preterm(group I: 25+027+6 weeks; group II: 28+030+6 weeks), early pre-term (31+033+6 weeks), late preterm (31+036+6 weeks), term(37+039+6 weeks), and post-term (40 weeks).

Effects of betamethasone treatment on neonatal body measure-ments, placental weight, ponderal index, umbilical cord blood gases,neonatal mortality and morbidity, and Apgar scores were analyzedusing the MannWhitney U test. Sex-specic statistical analyses wereperformed in the whole cohort. Betamethasone effects were analyzedamong three different dosages (16 mg, 24 mg, and N24 mg) usingthe MannWhitney U test. By multivariate analyses of variance,betamethasone-associated birth weight changes were controlled forpossible confounders.

Data are presented as mean standard error. Analyses were per-formed by using SPSS version 20 (IBM, Armonk, NY, USA). The odds ra-tios (ORs) with 95% condence intervals (CIs) for a birth weight in the10th centile or less and Apgar scores of less than 7 were calculated bybinary logistic regression using a birth weight reduction equal to or

0)

amsthema

2 T. Braun et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxxxxxThe estimated date of delivery was corrected by early prenatalultrasonography when the difference between the due date by the lastmenstrual period and that by early sonography was more than 7 days.Fetal weight before betamethasone treatment and during follow-up ul-trasonography was calculated by using the Hadlock formula. Fetuseswith an estimated fetal weight (EFW) below the 10th centile at thetime of the initial treatment were dened as small for gestational ageand excluded from the study.

The effects of betamethasone on neonatal anthropometrics(birth weight, head circumference, body length), placental weight,ponderal index, umbilical cord blood gases (umbilical artery bloodpH and umbilical vein blood pH), base excess, Apgar scores (1-, 5-,10-minute), and neonatal mortality were analyzed separately for bothsexes. Neonatal morbidity included respiratory distress syndrome orasphyxia, hypoglycemia (newborn plasma concentration b1.7 mmol/Lwithin 24 hours of delivery), and neonatal infections requiring antibiotictreatment.

Standard curves for fetal weight in the control population weregenerated using LMS ChartMaker (Medical Research Council,Cambridge, UK); centiles and Z scores for anthropometric datawere calculated with LMS Growth (Medical Research Council,Cambridge, UK). To analyze the effects of betamethasone on fetalgrowth, initial and follow-up EFW Z scores were calculated and

Table 1Maternal characteristics of the study group.a

Maternal characteristics Female newborns

Control group (n = 20 467) BMS group (n = 82

Age at delivery, y 28.8 0.0 29.3 0.2Weight before pregnancy, kg 64.8 0.1 63.8 0.5Weight at delivery, kg 77.9 0.1 73.7 0.6Weight gain, kg 13.2 0.0 10.1 0.3Height, cm 164.1 0.1 163.6 0.6BMI before pregnancy 23.7 0.0 23.4 0.2BMI at delivery 28.5 0.0 27.1 0.2BMI gain 4.9 0.0 3.8 0.1DiseaseDiabetes 510 (2.5) 45 (5.5)Hypertensive disordersc 391 (1.9) 90 (11.0)

Country of originGermany 11053 (54.0) 547 (66.7)Turkey 4132 (20.2) 96 (11.7)Other 5282 (25.8) 177 (21.6)

Abbreviations: BMS, betamethasone; BMI, body mass index (calculated as weight in kilogra Values are given as mean standard error or number (percentage), unless indicated ob Calculated by MannWhitney U test for maternal parameters, and Fisher exact test forc Hypertension and pre-eclampsia.

Please cite this article as: Braun T, et al, Fetal and neonatal outcomes after teJ Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.01.013less than the 10th centile and/or an Apgar score of less than 7 as depen-dent variables and betamethasone dose as covariates. P b 0.05 was con-sidered signicant.

3. Results

The betamethasone group included 1799 newborns (979 male and820 female) and the control group included 42 240 newborns (21 773male and 20 467 female). The overall number of women treated withbetamethasone per year was 63 (4.0%; range 4286 [2.5%6.0%])among pregnancies with female fetuses and 75 (4.6%; range 45115[2.7%7.6%]) among those with male fetuses. Regarding pregnancyprolongation after betamethasone exposure, 558 (68.0%) womencarrying female fetuses and 734 (75.0%) women carrying malefetuses remained pregnant for longer than 7 days after treatment;369 (45.0%) and 480 (49.0%) women, respectively, delivered after34+0weeks, and 213 (26.0%) and 274 (28.0%)women, respectively, de-livered after 37+0 weeks. Maternal characteristics are shown in Table 1.None of thematernal variables examined accounted for anthropometricchanges after treatment in multivariate analyses (SupplementaryMaterial S1).

Standard curves for fetal weight in the control populationwere gen-erated (Supplementary Material S2) and the newborns (EFW 10

Male newborns

P valueb Control group (n = 21 773) BMS group (n = 979) P valueb

0.029 28.8 0.0 29.0 0.2 0.3220.001 64.9 0.1 63.7 0.5 b0.001

b0.001 78.4 0.1 74.1 0.5 b0.001b0.001 13.5 0.4 10.5 0.2 b0.0010.818 163.8 0.1 164.0 0.4 0.1670.001 23.8 0.0 23.3 0.2 b0.001

b0.001 28.7 0.0 27.2 0.2 b0.001b0.001 4.9 0.0 3.9 0.1 b0.001

b0.001 573 (2.6) 71 (7.2) b0.001b0.001 421 (1.9) 71 (7.2) b0.001

b0.001 11 706 (53.8) 593 (60.6) b0.001b0.001 4406 (20.2) 138 (14.1) b0.0010.004 5661 (26.0) 248 (25.3) 0.334

divided by the square of height in meters).rwise.ternal complications and country of origin.rmand pretermdelivery following betamethasone administration, Int

3T. Braun et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxxxxxcentile) of mothers who were exposed to betamethasone andwere born late preterm, at term, and post-term had signicantlylower birth weights (on average 154 g) than did age-matchedcontrols (Fig. 1A, Table 2). When analyzing by sex, the reduction inbirth weight after betamethasone treatment was signicant for femaleneonates born after 31+0 weeks (Fig. 1B) and for male neonatesborn between 34+0 weeks and 39+6 weeks (Fig. 1C, SupplementaryMaterial S3).

The birth weight of neonates exposed to betamethasone and bornlate preterm or at term was signicantly lower than that of controlsfor all three dosage regimens analyzed (Supplementary Material S4).The difference in mean birth weight versus controls increased withbetamethasone dose (Table 3). Neonates exposed to a higher dosewere more likely to be on or below the 10th centile for birth weight(16 mg vs 24 mg: OR 1.84 [95% CI 1.013.35] for early preterm; OR2.55 [95% CI 1.275.09] for late preterm; 16 mg vs N24 mg: OR 4.15

Fig. 1.Mean birth weight in the control and BMS groups. Error bars show standard errors.Asterisks indicate signicant differences (P b 0.05). Abbreviation: BMS, betamethasone.

Please cite this article as: Braun T, et al, Fetal and neonatal outcomes after teJ Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.01.013[95% CI 1.2813.44] for term). The difference was signicant only inmales (Supplementary Material S5).

For 1216 fetuses, datawere available to analyze the rate of fetalweightgain at the time of rst exposure and 28 weeks after exposure. Fetalweight gain declined dose-dependently with the greatest reduction inEFW Z scores for fetuses treatedwithmore than 24mg of betamethasone(Fig. 2). The effects were independent of major confounders.

Head circumference was smaller among betamethasone-exposedfemales born after 34+0 weeks (mean0.6 cm) and males born latepreterm than among controls (mean 0.5 cm). Body length wassignicantly decreased among betamethasone-exposed females bornafter 37+0 weeks (mean1.0 cm) and males born after 34+0 weeks(mean0.8 cm). A signicant reduction in ponderal index after expo-sure was found among females born early preterm (SupplementaryMaterial S3). The betamethasone-associated reduction in head circum-ference and body length was independent of major confounders(Supplementary Material S1).

Overall, mean placental weight was signicantly lower in thebetamethasone group than in the control group (females 116 g,males 114 g) (Supplementary Material S3). Overall, Apgar scores werenot signicantly improved by betamethasone treatment (Table 2).Indeed, mean Apgar 1-, 5-, and 10-minute scores for the whole cohortwere signicantly lower in the betamethasone group than in the controlgroup (Supplementary Material S3). For betamethasone-exposed fe-males, no signicant improvement in Apgar scores were found as com-pared with controls (Supplementary Material S3). For males, however,Apgar scores at 1 and 5 minutes were signicantly higher in neonatesborn early preterm after betamethasone treatment, as were umbilical ar-tery pH, umbilical vein pH, and base excess (SupplementaryMaterial S3).By contrast, betamethasone-exposed males born late preterm hadsignicantly lower 1- and 5-minute Apgar scores, and those bornlate preterm or at term had signicantly lower 10-minute scores;betamethasone-exposed females had signicantly lower 5-minuteApgar scores when born post-term (Supplementary Material S3).

Higher betamethasone dosages did not improveApgar scores overall(Table 4). Among female neonates exposed to 24mg of betamethasone,1-minute Apgar scores were signicantly higher among neonates bornbetween 28+0 weeks and 30+6 weeks (group II very early preterm)than among controls (meandifference 0.9; P=0.048). Females exposedto more than 24 mg betamethasone and born late preterm haddecreased Apgar scores (1-, 5-, 10-minute scores:0.8,0.5,0.3,respectively; P b 0.05). Apgar scores were signicantly increased withbetamethasone doses of 24 mg among male neonates born between28+0 weeks and 33+6 weeks (1-, 5-, 10-minute scores: 1.0, 0.7, 0.4, re-spectively; P b 0.05) and among those who received up to 16 mg andwere born late preterm (1- and 5-minute scores: 1.0, 0.6, respectively;P b 0.05). However, among males born late preterm, Apgar scoreswere signicantly lower in betamethasone-exposed cases, independentof the betamethasone dose (1-, 5-, 10-minute scores: 16 mg0.3,0.3, 0.2, respectively; 24 mg, 0.3, 0.3, 0.2, respectively;N24 mg,0.8 [1-minute score]; P b 0.05 for all).

Treatment with betamethasone signicantly reduced the ratesof breathing problems for neonates of both sexes born preterm(females: 51/1352 [3.6%] vs 5/601 [0.8%], P b 0.001; males: 71/1624[4.2%] vs 12/697 [1.7%], P = 0.001). No signicant differences wererecorded in the rates of hypoglycemia (females: 9/1394 [0.6%] vs10/606 [0.6%], P N 0.05; males: 17/1678 [1.0%] vs 4/705 (0.6%),P N 0.05) or infection (females: 35/1368 [2.5%] vs 11/595 [1.8%],P N 0.05; males: 50/1645 [2.9%] vs 14/695 [2.0%], P N 0.05).Betamethasone doses of more than 24 mg did not improve neonatalmorbidity: the rates of breathing problems, neonatal hypoglycemia,and neonatal infections were similar to those of controls for the pop-ulation as a whole (Table 4).

The proportion of neonates who died was higher in thebetamethasone group than in the control group for neonates of both

sexes born before 37 weeks (females: 12/1391 [0.9%] vs 19/587 [3.1%].


Table 2Difference in neonatal parameters between control and betamethasone groups independent o

Fetal/neonataloutcome

Very early preterm,group Ib

Very early preterm,group IIb

Early preter

Differencebetweengroupsc

P valued Differencebetweengroupsc


Birth weight, g 0.672 0.158 Head circumference, cm 0.463 0.998 Body length, cm 0.407 0.803 Ponderal indexe 0.395 0.419 Apgar score1 min 0.392 0.054 5 min 0.769 0.096 10 min 0.451 0.096

UApH 0.869 0.265 0.03UVpH 0.613 0.134 0.03Base excess 0.100 0.085 1.31Placenta weight, g 0.383 0.079

Abbreviations: UApH, umbilical artery blood pH; UVpH, umbilical vein blood pH.a Only signicant differences after controlling for possible confounders by multivariate analb Across the six gestational age groups, the number of control/betamethasone neonates wasc Negative values indicate a reduction in the betamethasone group; positive values indicate

4 T. Braun et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxxxxxP b 0.001; males: 17/1678 [2.0%] vs 14/695 [1.0%], P = 0.046) andfor females born after 37 weeks (7/19 057 [0.9%] vs 2/212 [b0.1%],P=0.004). The overall increase in neonatal mortality was independentof betamethasone dosage (Table 4).

4. Discussion

In the present study, maternal betamethasone treatment wasassociated with lower birth weight, head circumference, and bodylength for bothmale and female neonates as compared with gestationalage-matched controls, independent of major confounders, sex, or timeof treatment in pregnancy. Higher betamethasone dosage regimens re-sulted in the greatest reduction in fetal growth without further im-provement in neonatal morbidity or mortality. Fetal weight gaindecreased in a dose-dependent manner in the 68 weeks followingthe initial exposure. Umbilical cord blood gas parameters were general-ly unchanged after betamethasone. Only among early preterm

d Calculated by MannWhitney U test.e 100 birth weight (g)/body length (cm3).males were Apgar scores improved after betamethasone treatment.For late preterm and term pregnancies, betamethasone exposurewas accompanied by signicantly lower Apgar scores for both sexes.

Table 3Effect of betamethasone dose on birth weight.a

Dose Difference in birth weight, g

0 mg (controls) 16 mg 24 mg

b34+0 wk16 mg 444 24 mg 523 N24 mg 811 367 288

34+036+6 wk16 mg 167 24 mg 249 N24 mg 293

37+039+6 wk16 mg 132 24 mg 119 N24 mg 464 332 344

40+0 wk16 mg 139 24 mg N24 mg

a Mean differences in birth weight (both females and males) are shown by gestationalage at delivery and dose (betamethasone vs control, higher vs lower dose). Only datawithsignicant differences (P b 0.05) are presented.

Please cite this article as: Braun T, et al, Fetal and neonatal outcomes after teJ Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.01.013Nearly half the fetuses exposed to betamethasone treatment wereborn after 34+0 weeks, and approximately one-third were born after37+0 weeks.

Birth weight is subject to a degree of constraint by the maternal in-trauterine environment and a strong determinant of perinatal survival.In the present study, betamethasone treatment was accompanied bysignicantly lower birth weight as compared with age-matched con-trols, independent of major confounders. The betamethasone-inducedreduction in birthweight, head circumference, and body lengthwere in-dependent of the duration of pregnancy after treatment. The follow-upEFW of fetuses that were initially growing normally showed that thereduction in fetal weight gain was directly related to the dose ofbetamethasone.

Large studies [12,13] have demonstrated that decreased birthweight, used as a surrogate marker of fetal growth and development,is associated with increased risk of adult disease. A small head circum-ference is strongly associated with learning difculties among school-

f sex.a

mb Late pretermb Termb Post-termb




P valued

0.233 197 b0.001 141 b0.001 142 0.0170.071 0.7 b0.001 0.4 b0.001 0.3 0.0180.181 1.0 b0.001 0.7 b0.001 0.8 b0.0010.201 0.348 0.505 0.197

0.054 0.110 0.054 0.8670.176 0.2 0.041 0.2 0.003 0.1660.159 0.063 0.1 0.005 0.606b0.001 0.252 0.050 0.614b0.001 0.709 0.666 0.465b0.001 0.251 0.471 0.3130.301 0.060 0.218 0.527

yses of variance are shown; full data are provided in Supplementary Material S3.121/233, 132/265, 305/449, 2540/368, 20 043/358, and 19 099/126, respectively.an increase in the betamethasone group.aged children [14]. Although the reduction in head circumference wassmall, the relationship between head circumference and intracranialvolume is dened by a cubic function. Therefore, small reductions inhead circumference are associated with a considerable decrease in in-tracranial volume; in the present study, the 4% decrease in head circum-ference observed would be associated with an 11% reduction inintracranial volume [15].

The clinically recommended dose of glucocorticoids was notempirically tested [16], and was later found to expose the fetus toconcentrations comparable to physiological stress levels of cortisolthat are normally present after birth [17]. The current recommendedpractice is one course of two 12-mg betamethasone doses for lungmaturation [18,19], but repeated maternal glucocorticoid treatmentwas common practice until at least the late 1990s [2]. In thepresent study, higher doses of betamethasone resulted in a greaterreduction in fetal weight gain and birth weight among bothfemales and males. The greatest reduction in birth weight of up to16% versus controls was observed among females who were bornat term, and whose mothers had received more than 24 mg ofbetamethasone.

Although betamethasone signicantly improved neonatal morbidityin neonates born before 37 weeks; no improvement was seen at higherdosages. In fact, mortality rates appeared to increase with higherbetamethasone dosages. Only males born early preterm benetedfrom betamethasone treatment, with higher Apgar scores. Althabe


et al. [20] recently investigated the feasibility, effectiveness, and safetyof corticosteroid treatment versus standard care for the reduction ofneonatal mortality due to preterm birth in low- and middle-income

countries. They raised questions regarding the uncritical use of gluco-corticoid treatment. The study found that glucocorticoid interventionnot only was ineffective for reducing neonatal mortality among fetuses

Table 4Effect of betamethasone treatment on neonatal Apgar scores, morbidity, and mortality.a,b

Neonatal parameters Control group Betamethasone 16 mg Betamethasone 24 mg Betamethasone N24 mg

Value P valuec Value P valuec Value P valuec

Both sexes 42 240 1177 474 148

0.000.000.00

Fig. 2. Dose-dependent estimated fetal weight before and after rst betamethasone treatment. t0, immediately before the rst betamethasone treatment; t1t4, follow-up ultrasonogra-phy at a mean of 18, 32, 45, and 55 days, respectively. When lower-case letters (16 mg), upper-case letters (24 mg), or numbers (N24 mg) are different, this indicates a signicant dif-ference between follow-up measurements (P b 0.05). Asterisks indicate a signicant difference between doses at follow-up measurements t1t3. Error bars show standard errors.

5T. Braun et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxxxxxApgar score1 min 8.7 0.0 7.2 0.1 b5 min 9.6 0.0 8.4 0.0 b10 min 9.8 0.0 9.0 0.0 b

dMorbidityBreathing problemse 797 (1.8) 18 (1.5) 0.269Hypoglycemiaf 285 (0.7) 4 (0.3) 0.105Infectionsg 460 (1.1) 24 (2.0) 0.004

Mortalityd 52 (0.1) 20 (1.7) b0.00Females 20 467 557Apgar score1 min 8.7 0.0 7.1 0.1 b0.005 min 9.6 0.0 8.3 0.1 b0.0010 min 9.8 0.0 8.9 0.1 b0.00

Morbidityd

Breathing problemse 301 (1.5) 4 (0.7) 0.091Hypoglycemiaf 119 (0.6) 1 (0.2) 0.052Infectionsg 180 (0.9) 13 (2.3) 0.002

Mortalityd 19 (0.1) 15 (2.7) b0.00Males 21 773 620Apgar score1 min 8.6 0.0 7.3 0.1 b0.005 min 9.6 0.0 8.5 0.1 b0.0010 min 9.8 0.0 9.1 0.0 b0.00

Morbidityd

Breathing problemse 466 (2.1) 14 (2.3) 0.460Hypoglycemiaf 119 (0.8) 4 (0.6) 0.491Infectionsg 280 (1.3) 11 (1.8) 0.186

Mortalityd 33 (0.2) 5 (0.8) 0.004

a Values are given as number, mean standard error, or number (percentage), unless indicb Data were adjusted for gestational age at delivery.c Versus the control group.d Morbidity and mortality rates are presented as a percentage of the total number of cases ie Breathing problems include respiratory distress syndrome and asphyxia.f Plasma glucose levels in the newborn of less than 1.7 mmol/L within 24 h of delivery.g Newborn infections that required antibiotic treatment.

Please cite this article as: Braun T, et al, Fetal and neonatal outcomes after teJ Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.01.0131 7.1 0.1 b0.001 6.5 0.2 b0.0011 8.5 0.1 b0.001 8.1 0.1 b0.0011 9.0 0.1 b0.001 8.8 0.1 b0.0017 (1.5) 0.371 3 (2.0) 0.5052 (0.4) 0.381 1 (0.7) 0.3681 (0.2) 0.035 4 (2.7) 0.080

1 9 (1.9) b0.001 6 (4.1) b0.001209 54

1 7.0 0.1 b0.001 6.5 0.3 b0.0011 8.4 0.1 b0.001 8.3 0.2 b0.0011 9.0 0.1 b0.001 8.9 0.1 b0.001

2 (1.0) 0.406 2 (3.7) 0.1901 (0.5) 0.297 1 (1.9) 0.7331 (0.5) 0.159 1 (1.9) 0.381

1 3 (1.4) 0.001 3 (5.6) b0.001265 94

1 7.2 0.1 b0.001 6.4 0.3 b0.0011 8.5 0.1 b0.001 8.0 0.2 b0.0011 9.0 0.1 b0.001 8.7 0.2 b0.001

5 (1.9) 0.499 1 (1.1) 0.4002 (0.8) 0.671 1(1.1) 0.4881 (0.4) 0.146 3 (3.2) 0.1236 (2.3) b0.001 3 (3.2) b0.001

ated otherwise.

n each dose and treatment group.


below the fth centile, but also increased mortality among the overallpopulation, with an excess of perinatal deaths as compared with stan-dard care [20].

Sex-dependent responses to glucocorticoid treatment have beenpreviously found in animal and human studies with poorer outcomes

References

[1] Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturationfor women at risk of preterm birth. Cochrane Database Syst Rev 2006(3):CD004454.

[2] Brocklehurst P, Gates S, McKenzie-McHarg K, Alrevic Z, Chamberlain G. Are we pre-scribingmultiple courses of antenatal corticosteroids? A survey of practice in the UK.Br J Obstet Gynaecol 1999;106(9):9779.

[3] LoehleM, SchwabM, Kadner S, Maner KM, Gilbert JS, Brenna JT, et al. Doseresponseeffects of betamethasone onmaturation of the fetal sheep lung. Am J Obstet Gynecol2010;202(2):186.e17.

[4] Wapner RJ, Sorokin Y, Thom EA, Johnson F, Dudley DJ, Spong CY, et al. Single versusweekly courses of antenatal corticosteroids: evaluation of safety and efcacy. Am JObstet Gynecol 2006;195(3):63342.

[5] McKinlay CJ, Crowther CA, Middleton P, Harding JE. Repeat antenatal glucocorticoidsfor women at risk of preterm birth: a Cochrane Systematic Review. Am J ObstetGynecol 2012;206(3):18794.

6 T. Braun et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxxxxxmetabolizing enzymes (11- hydroxysteroid dehydrogenase type 2;11HSD-2), which protect the fetus from elevated levels of maternalcortisol, could contribute to sex-dependent responses to glucocorticoids.At term, placental 11HSD-2 activity is higher in females than in males[23], suggesting that the female fetus is exposed to lower levels of ma-ternally derived cortisol, which facilitates autonomous development offetal hypothalamic-pituitary-adrenal function, perhaps as an attemptto survive any further potential maternal insults [11].

The present study has some limitations. Retrospective studies areobservational in nature and thus do not provide the same level ofevidence as randomized controlled trials. Retrospective investigationsare inherently subject to data collection bias; however, selection biasis unlikely to account for the differences observed in the presentstudy. The healthcare workers who performed chart reviews and datacollectionweremasked to the present study objective. Although regres-sion analyses were used to control and adjust for possible confoundingvariables, including maternal parameters that did not account for theanthropometric changes after betamethasone treatment, unknown ad-ditional factors might have affected fetal weight gain and perinataloutcomes.

There are difculties in predicting whether preterm delivery willoccur within 7 days of betamethasone treatment, and further studiesare required to identify and optimize predictors limiting unnecessaryfetal exposure to betamethasone treatment. In the present study, 49%of males and 45% of females who had received betamethasone wereborn after 34+0 weeks. Furthermore, 28% of males and 26% of femalesexposed to betamethasone were born after 37+0 weeks and thereforemight have unnecessarily received treatment. For amore selective indi-cation, cervical lengthmeasurements on ultrasonography, vaginalbro-nectin tests, and/or individualized scores to evaluate the risk of pretermdelivery might become useful tools.

Although the present data provide insight into the fetal and neonataleffects of betamethasone in people, further studies are needed to deter-mine the clinical signicance of the ndings and the role of the placentain fetal growth and development after betamethasone treatment. Clini-cally, there should be a general awareness among practitioners for crit-ical judgment in identifying pregnancies truly at risk of pretermdelivery. The present results suggest that repetitive and high doses ofbetamethasone should be avoided. Sex- and gestational-age adaptedbetamethasone treatment for lung maturation might be considered inthe future.

Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.ijgo.2015.01.013.

Acknowledgments

The research, authorship, and publication of the studywere supportedby Deutsche Forschungsgemeinschaft (BR2925/3-1,3-2 and PL241/8-2).

Conict of interest

The authors have no conicts of interest.Please cite this article as: Braun T, et al, Fetal and neonatal outcomes after teJ Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.01.013[6] Crowther CA, McKinlay CJ, Middleton P, Harding JE. Repeat doses of prenatal cortico-steroids for women at risk of preterm birth for improving neonatal health outcomes.Cochrane Database Syst Rev 2011(6):CD003935.

[7] Brownfoot FC, Crowther CA, Middleton P. Different corticosteroids and regimens foraccelerating fetal lung maturation for women at risk of preterm birth. CochraneDatabase Syst Rev 2008(4):CD006764.

[8] Yinon Y, Haas J, Mazaki-Tovi S, Lapidot N, Mazkereth R, Hourvitz A, et al. Should pa-tients with documented fetal lung immaturity after 34 weeks of gestation be treatedwith steroids? Am J Obstet Gynecol 2012;207(3):222.e14.

[9] Khandelwal M, Chang E, Hansen C, Hunter K, Milcarek B. Betamethasone dosing in-terval: 12 or 24 hours apart? A randomized, noninferiority open trial. Am J ObstetGynecol 2012;206(3):201.e1201.e11.

[10] Caughey AB, Parer JT. Recommendations for repeat courses of antenatal corticoste-roids: a decision analysis. Am J Obstet Gynecol 2002;186(6):12219.

[11] Challis J, Newnham J, Petraglia F, Yeganegi M, Bocking A. Fetal sex and preterm birth.Placenta 2013;34(2):959.

[12] Barker DJ, Osmond C, Golding J, Kuh D,WadsworthME. Growth in utero, blood pres-sure in childhood and adult life, and mortality from cardiovascular disease. BMJ1989;298(6673):5647.

[13] Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancy anddeath from ischaemic heart disease. Lancet 1989;2(8663):57780.

[14] Stathis SL, OCallaghan M, Harvey J, Rogers Y. Head circumference in ELBW babies isassociated with learning difculties and cognition but not ADHD in the school-agedchild. Dev Med Child Neurol 1999;41(6):37580.

[15] French NP, Hagan R, Evans SF, Godfrey M, Newnham JP. Repeated antenatal cortico-steroids: size at birth and subsequent development. Am J Obstet Gynecol 1999;180(1 Pt 1):11421.

[16] Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment forprevention of the respiratory distress syndrome in premature infants. Pediatrics1972;50(4):51525.

[17] Ballard PL, Ballard RA. Scientic basis and therapeutic regimens for use of antenatalglucocorticoids. Am J Obstet Gynecol 1995;173(1):25462.

[18] American College of Obstetricians and Gynecologists Committee on Obstetric Prac-tice. ACOG Committee Opinion No. 402: Antenatal corticosteroid therapy for fetalmaturation. Obstet Gynecol 2008;111(3):8057.

[19] Royal College of Obstetricians and Gynaecologists. Antenatal Corticosteroids to Re-duce Neonatal Morbidity and Mortality: Green-Top Guidline No. 7. https://www.rcog.org.uk/globalassets/documents/guidelines/gtg_7.pdf. Published October 2010.Accessed December 10, 2014.

[20] Althabe F, Belizn JM, McClure EM, Hemingway-Foday J, Berrueta M, Mazzoni A,et al. A population-based, multifaceted strategy to implement antenatal corticoste-roid treatment versus standard care for the reduction of neonatal mortality due topreterm birth in low-income and middle-income countries: the ACT cluster-randomised trial. Lancet 2015;385(9968):62939.

[21] Eriksson JG, Kajantie E, Osmond C, Thornburg K, Barker DJ. Boys live dangerously inthe womb. Am J Hum Biol 2010;22(3):3305.

[22] Osei-Kumah A, Smith R, Jurisica I, Caniggia I, Clifton VL. Sex-specic differences inplacental global gene expression in pregnancies complicated by asthma. Placenta2011;32(8):5708.

[23] Murphy VE, Gibson PG, Giles WB, Zakar T, Smith R, Bisits AM, et al. Maternal asthmais associated with reduced female fetal growth. Am J Respir Crit Care Med 2003;168(11):131723.reported for males [11,21,22]. Differences in placental glucocorticoidrmand pretermdelivery following betamethasone administration, Int

Fetal and neonatal outcomes after term and preterm delivery following betamethasone administration1. Introduction2. Materials and methods3. Results4. DiscussionAcknowledgmentsReferences

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