www.elsevier.com/locate/ajog

American Journal of Obstetrics and Gynecology (2004) 190, 296e304

EDITOR’S CHOICE

The fetal cardiovascular response to antenatal steroidsin severe early-onset intrauterine growth restriction

Michal J. Simchen, MD,a,* Fawaz Alkazaleh, MD,a S. Lee Adamson, PhD,b

Rory Windrim, MSc, MD,a Joyce Telford, RDM,a Joseph Beyene, PhD,c

John Kingdom, MDa,b

Division of Maternal-Fetal Medicinea and Samuel Lunenfeld Research Institute,b Mount Sinai Hospital, and theDepartment of Health Policy, Management and Education,c University of Toronto, Toronto, Ontario, Canada

Received for publication August 27, 2002; revised November 20, 2002; accepted August 7, 2003

Presented at the Twenty-Second Annual Meeting of the Society for

Maternal-Fetal Medicine, New Orleans, La, January 2002, and at the

meeting of the International Society for Study of Hypertension in

Pregnancy, Toronto, Ontario, Canada, June 2002.

*Reprint requests: Michal J. Simchen, MD, Department of

Obstetrics and Gynaecology, Sheba Medical Center, Tel Hashomer,

Ramat-Gan 52621, Israel.

E-mail: michal_simchen@sheba.health.gov.il

0002-9378/$ - see front matter � 200

doi:10.1016/j.ajog.2003.08.011

––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––Objective: Our aim was to study the hemodynamic effects of betamethasone on fetuses with in-

trauterine growth restriction (IUGR) with absent or reversed end-diastolic (ARED) umbilical ar-tery flow.Study design: Color/pulsed Doppler waveforms were obtained before and after intramuscular in-

jections of betamethasone in 19 consecutive fetuses with IUGR/ARED and 6 control fetuses.Peak velocities and pulsatility index (PI) values were obtained from the umbilical (UA) and mid-dle cerebral (MCA) arteries and intrahepatic umbilical vein (UV).

Results: Ten ARED fetuses developed transient positive umbilical end-diastolic flow aftersteroids, whereas nine fetuses showed persistent ARED. The persistent ARED subgroup dem-onstrated increased UA and UV peak velocities after steroids, which may indicate fetal hyperten-sion. Fetal death (n=2) and severe acidosis (n=2) were confined to the subgroup with persistent

ARED.Conclusion: Preterm IUGR/ARED fetuses exhibit divergent cardiovascular responses to prenatalsteroids. Intensive Doppler-based fetal monitoring may identify a subset of fetuses prone to de-

compensation after maternal steroid administration.� 2004 Elsevier Inc. All rights reserved.

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KEY WORDSBetamethasoneSteroids

Intrauterine growthrestriction

Fetal Doppler

Perinatal outcome

Antenatal administration of glucocorticoids has be-come widely accepted in clinical practice because of itsdocumented effect in promoting fetal lung maturation

4 Elsevier Inc. All rights reserved.

in the preterm fetus.1 However, several recent clinicalstudies have demonstrated transient detrimental effectsof prenatally administered glucocorticoids on fetal heartrate tracing and behavior. These include decreased fetalheart rate variability, decreased fetal body movementsand breathing,2-5 all of which are used clinically asmarkers of fetal well-being. Invasive monitoring of thehealthy term sheep fetus demonstrated that doses of be-tamethasone equivalent to those used in clinical practiceinduced fetal hypertension with increased vascular resis-tance,6 reduced cerebral blood flow with decreased

Simchen et al 297

oxygen delivery,7 and a 2-fold increase in fetal lactatelevels.8 Recently published data from invasive monitor-ing of preterm baboons again demonstrated increasedfetal blood pressure in response to maternally adminis-tered betamethasone.9

Pregnancies with early-onset intrauterine growth re-striction (IUGR) typically present before 32 weeks ofgestation with a small fetus, reduced amniotic fluidvolume, and reduced diastolic velocities in the umbilicalarteries, suggestive of increased impedance in the feto-placental circulation.10 In its most severe form, thisincreased resistance to flow presents as absent orreversed end-diastolic (ARED) flow velocities. Reducedoxygen transfer leads to chronic fetal hypoxia, predis-posing the fetus to lactic acidosis and impaired myocar-dial function.11-13

A recent study observed that prenatally admininsteredglucocorticoids can induce a transient appearance of end-diastolic flow velocities in pregnancies with IUGR andabsent end-diastolic flow in the umbilical arteries.14 Theauthors suggested these findings were beneficial, repre-senting vasodilation in the fetoplacental circulation andimproved fetoplacental vascular resistance. However, inview of animal data suggesting that steroids induce tran-sient fetal acidosis, our aim in this study was to evaluatewhether steroids could be associated with fetal deteriora-tion in IUGR fetuses with ARED by exacerbating anypreexisting metabolic acidosis.

Methods

We conducted a prospective longitudinal study during2001 with local research ethics board approval. Inclu-sion criteria included a singleton structurally and chro-mosomally normal fetus at 24 to 34 weeks’ gestationwith ARED flow velocities in each umbilical artery, to-gether with supportive evidence of IUGR caused byuteroplacental vascular insufficiency (assymmetricallysmall, with estimated fetal weight less than the 10th per-centile and reduced amniotic fluid volume). Subjectswere enrolled in the study when a clinical decision wastaken to offer antenatal glucocorticoid administrationfor fetal lung maturation enhancement before antici-pated delivery. Exclusion criteria included severe pre-eclampsia necessitating immediate delivery on maternalgrounds, nonreassuring fetal heart rate tracings (whichwould have prompted immediate delivery), previousglucocorticoid treatment before the baseline Dopplerevaluation, and chromosomal and/or structural abnor-malities of the fetus. Women carrying singleton fetuseswith normal umbilical artery flow velocities, receivingsteroids for other risk factors for preterm birth (prema-ture contractions and/or shortened cervix) were re-cruited to serve as controls.

After informed consent, color/pulsed Doppler studieswere performed with an Advanced Technology Labora-

tories HDI 5000 ultrasound machine (Seattle, Wash).Doppler studies were performed before first glucocor-ticoid administration, and repeated 24, 48, and 72 hoursafter the initial betamethasone dose. Two doses of 12 mgbetamethasone were given intramuscularly 24 hoursapart, in accordance with our divisional guideline toaccelerate fetal lung maturation in pregnancies judgedto be at risk of preterm delivery (whether spontaneousor indicated) before 34 weeks.

Doppler studies included descriptive waveform anal-ysis of both umbilical arteries (reversed, absent, orpositive end-diastolic flow [EDF]), as well as angle-corrected peak velocities and pulsatility index (PI). Mag-nified images in color flow were used to insonate the um-bilical arteries individually in the vertical plane of thespiral and measurements were repeated for at least threeseparate cardiac cycles. Similar observations were alsomade in the fetal middle cerebral artery (MCA). Assess-ment of fetal venous return included description ofintrahepatic umbilical vein flow (pulsations present orabsent) and angle-corrected maxminal velocity. All an-gles of insonation were as close to 0 degrees as possible,and always less than 30 degrees. For clinical purposes,final decisions regarding delivery were made accordingto maternal condition, description of the umbilical ar-tery Doppler waveform and fetal heart rate tracings bythe attending physicians. With the exception of floridumbilical vein pulsations, study data were not used bythe attending physicians to dictate timing of delivery.All neonates were born at Mount Sinai Hospital and ad-mitted to the neonatal intensive care unit. Clinical out-comes, including cord blood gases, were correlatedwith study observations.

Statistical analysis

Continuous variables were described using medians andinterquartile range (IRQ), and categorical variables weresummarized using frequencies and percentages. Quanti-tative outcome variables that were measured seriallywere analyzed with use of a two-way repeated measuresanalysis of variance model. Student paired t test wasused for within-group comparisons. Changes from base-line were compared between groups with a two-sidedindependent-sample t test. Associations between preg-nancy-related categorical outcome measures and tran-sient EDF/persistent ARED status were assessed witheither c2 analysis or Fisher exact test, and the magnitudeof the effect was expressed with use of a risk differencealong with a 95% CI. Within-group median imputationtechnique was used to replace missing values for some ofthe outcome measures. Results of statistical tests weredeemed significant if P!.05 and data were analyzedwith the SAS statistical software, version 8.02 (SAS In-stitute, Cary, NC).

298 Simchen et al

Table I Baseline characteristics of ARED group and control group*

ARED group (n = 19) Control group (n = 6)

Maternal age (y), median (IQR) 32 (29.5-36) 30.5 (25.25-35.75)Gestational age at betamethasone administration, (median [IQR]) 27.4 (26.2-29.3) 24.5 (24.2-28.6)Primiparous (%) 11/19 (57.9) 5/6 (83.3)Ethnicity: nonwhite (%) 12/19 (63.2) 3/6 (50)PET (%) 9/19 (47.4) 2/6 (33.3)Severe PET (%) 6/19 (31.6) 0/6 (0)EFW (g), median (IQR) 670 (593-1001) 791 (771-1161)

IQR - 1st and 3rd quartiles. PET, preeclampsia; EFW, estimated fetal weight (ultrasound assessment).

* There were no statistically significant differences between study and control groups.

Results

Nineteen women met our inclusion criteria and were in-cluded in the study group. Six women served as controls.Baseline demographic data are presented in Table Idemonstrating that the two groups were similar in termsof maternal age, gestational age at glucocorticoid ad-ministration, ethnicity, preeclampsia at presentation,and parity.

Umbilical artery Doppler responses to steroids

ARED fetuses demonstrated divergent changes in um-bilical artery waveform to steroid administration, as 10fetuses regained end-diastolic flow at 24 hours, returningto baseline ARED waveforms in the following 3 days(‘‘transient EDF’’ subgroup), whereas the remaining 9did not regain end-diastolic umbilical artery flow (‘‘per-sistent ARED’’ subgroup). There was no significantchange from baseline in umbilical artery PI values orin peak systolic velocities after steroid administrationfor either ARED fetuses or controls, although by defini-tion, all ARED fetuses had significantly higher baselinePI values. Umbilical artery PI values were highest at alltime point measurements in the persistent ARED sub-group, followed by the transient EDF subgroup, whichin turn was higher than the control group (statisticallysignificant main-group effect, F [2,22]=33.5, P!.001)(Figure 1, A). There was no significant group by time in-teraction.

Both the controls and the transient EDF subgroupdemonstrated stable maximal flow velocities in the um-bilical arteries, whereas the persistent ARED subgroupwas significantly different (P=.03). Maximal umbilicalartery flow velocities were significantly increased in thepersistent ARED subgroup at the 24-hour mark com-pared with baseline values (34-62 cm/s, P!.002),whereas in the transient EDF subgroup and the controlgroup values remained stable (56-49 cm/s and 58-62 cm/s,respectively). Maximal velocities then gradually de-creased toward baseline values (Figure 1, B).

MCA Doppler responses to steroids

MCA PI values were significantly lower in ARED fe-tuses at all time points compared with controls, consis-tent with the expected redistribution of fetal cardiacoutput to sustain cerebral oxygenation in the face ofprogressive arterial hypoxemia. MCA PI values weresignificantly lower than controls for both transientEDF and persistent ARED subgroups (statistically sig-nificant group main effect, F[2,22]=9.72, P!.001), ascan be seen in Figure 2, A. There was no difference be-tween maximal blood velocities in the MCA betweenstudy and control groups and between transient EDFand persistent ARED subgroups after steroid adminis-tration (Figure 2, B).

Venous Doppler responses to steroids

ARED and control fetuses exhibited similar maximalumbilical vein velocities throughout the study period.Subgroup analysis revealed no significant difference be-tween the two groups regarding the presence or new ap-pearance of umbilical vein pulsations.

There was no significant difference between transientEDF fetuses and persistent ARED fetuses in the changein maximal blood flow velocity over time. However, al-though umbilical venous flow velocity in transient EDFfetuses appeared relatively stable after glucocorticoidadministration (mean umbilical venous flow velocity23 cm/s at baseline to 22 cm/s 24 hours later), as in con-trol fetuses (20 cm/s to 22 cm/s), the persistent AREDsubgroup demonstrated a significant 44% increase inumbilical vein maximal flow velocity from baseline today 1 after glucocorticoids, 18 to 26 cm/s (P=.01) (Fig-ure 3). By day 2, umbilical vein velocities gradually de-creased in both groups.

Pregnancy outcome

Table II describes indications for delivery and outcomedata. Median gestational age at delivery was 27.6 weeks(IRQ 26.8-30.6) in the 19 ARED study patients and 36.3

Simchen et al 299

Figure 1 Changes in umbilical artery flow/velocity patterns. A, Changes in PI values from baseline to 24, 48, and 72 hours after initialbetamethasone dose. B, Changes in maximal umbilical artery flow velocities. All values are in centimeters per second and are

presented as mean G SE. (Control cases are depicted in filled circles, the transient EDF subgroup as filled squares, and persistentARED subgroup cases as open squares).

weeks (IRQ 33.5-39) in the 6 control patients. Because ofthis difference in gestational age at delivery, as well as thenature of the study group, there was also a significant dif-ference in median birth weight (720 vs 2932.5 g, respec-tively, P!.001). In the control group, two women(33%) gave birth by cesarean section, of which one was

due to acute fetal heart rate decelerations. Control groupinfants were born between 31 and 40 weeks’ gestation,and there were no cases of fetal death or severe acidosis.

In the study group of 19 ARED fetuses, there were nosignificant differences between gestational age at deliv-ery or birth weight in the persistent ARED compared

300 Simchen et al

Figure 2 Changes in middle cerebral artery flow/velocity patterns. A, Changes in PI values from baseline to 24, 48, and 72 hours afterinitial betamethasone dose. B, Changes in maximal umbilical artery flow velocity values. All values are in centimeters per second andare presented as mean G SE. (Control cases are depicted in filled circles, the transient EDF subgroup as filled squares, and persistentARED subgroup cases as open squares).

with the transient EDF subgroups. All live-born studygroup fetuses were delivered by cesarean section. Twofetuses died in utero (both in the persistent ARED sub-group) and in those cases labor was induced with miso-prostol. Indications for delivery in the study groupincluded: acute deterioration of fetal condition

(n=10), severe preeclampsiaGHELLP syndrome(n=5), gradual deterioration at gestational age morethan 32 weeks (n=4), and intrauterine death (n=2).Some women had more than one indication for delivery.

Eight of 9 (89%) patients in the persistent AREDsubgroup suffered acute fetal deterioration or intrauter-

Simchen et al 301

Figure 3 Changes in intrahepatic umbilical vein flow velocity frequencies. All values are in centimeters per second, and presented as mean

G SE. (Control cases are depicted in filled circles, the transient EDF subgroup as filled squares, and persistent ARED subgroup casesas open squares).

Table II Perinatal outcome at delivery

Persistent AREDsubgroup (n = 9)

Transient EDFsubgroup (n = 10)

All ARED studypatients (n = 19)

Controlgroup (n = 6)

Gestational age at delivery (median [IQR]) 27.6 (26.8-30.6) 29 (27.2-32.8) 27.6 (27-31.6) 36.3 (33.5-39)Days from steroids to delivery (median [IQR]) 4 (1-10) 5 (2-16.5) 4 (2-11.5) 83.5 (27.5-104.25)Birth weight (g) (median [IQR]) 650 (585-970) 860 (602.5-1244) 720 (582-1212) 2932.5 (1681.2-3295)Cesarean delivery (%) 7/9 (78)

(2 IUFD fetusesborn vaginally)

10/10 (100) 17/19 (89) 2/6 (33)

Delivery!28 wk (%) 5/9 (56) 5/10 (50) 10/19 (53) 0/6 (0)Birth weight !1000 g (%) 7/9 (78) 5/10 (50) 12/19 (63) 0/6 (0)Severe acidosis at birth (cord pH!7.10 [%]) 2/9 (22) 0/10 (0) 2/19 (10.5) 0/6 (0)Intrauterine fetal death (%) 2/9 (22) 0/10 (0) 2/19 (10.5) 0/6 (0)Severe acidosis and/or fetal death (%) 4/9 (44) 0/10 (0) 4/19 (21) 0/6 (0)

IQR - 1st and 3rd quartiles. IUFD, Intrauterine fetal death.

ine demise, whereas only 4 of 10 (40%) in the transientEDF subgroup suffered acute fetal deterioration, nec-cessitating emergency deliveries (risk difference 49%,95% CI 12%-85%). A summary of the indications fordelivery is presented in Table III.

Two fetuses in the persistent ARED subgroup were se-verely acidotic at delivery (umbilical artery pH !7.10),whereas none of the fetuses in the transient EDF sub-group had cord pH less than 7.10. As previously men-tioned, there were two cases of intrauterine death, bothin the persistent ARED subgroup. The incidence of se-vere acidosis or death in the persistent ARED subgroup

was 44% compared with 0% in the transient EDF sub-group (risk difference 44%, 95% CI 12%-77%). Com-parison of pregnancy outcome between transient EDFand persistent ARED subgroups is presented in Table II.

Comment

The practice of administering antenatal glucocorticoste-roids to mothers judged to be at risk of preterm deliveryis widespread in the developed world because of theeffective dissemination of evidence from randomized

302 Simchen et al

Table III Indications for delivery of ARED fetuses

Total AREDgroup (n = 19)

Persistent AREDsubgroup (n = 9)

Transient EDFsubgroup (n = 10)

Deteriorating maternal condition 3/19 (15.8%) 2/9 (22.2%) 1/10 (10%)Gestational age O32 wk 5/19 (26.3%) 1/9 (11.1%) 4/10 (40%)Intrauterine death 2/19 (10.5%) 2/9 (22.2%) 0/10 (0%)Spontaneous recurrent heart rate decelerations 7/19 (36.8%) 4/9 (44.4%) 3/10 (30%)Worsening Doppler parameters 9/19 (47.4%) 5/9 (55.6%) 4/10 (40%)Acute fetal deterioration or intrauterine death* 12/19 (63.1%) 8/9 (88.9%) 4/10 (40%)

Worsening Doppler parameters-new development of REDF; significant MCA redistribution; umbilical vein pulsations; increased resistence in ductus venous.

Some study patients presented more than 1 indication for delivery.

* Acute fetal deterioration or intrauterine demisedfetuses delivered for at least 1 of the following: fetal death, spontaneous heart rate decelerations,

or worsening Doppler (Risk difference 49%, 95% CI 12%-85%).

controlled trials showing that this treatment reduces therisk of death and handicap.1 However, the majority ofpregnancies in those studies, and at whom steroids arecurrently directed, are healthy appropriately grownfetuses rather than severely growth-restricted fetuses.Healthy fetuses are able to cope with the transient met-abolic demands of transplacental glucocorticosteroids,although this may not be the case in severe IUGR.The aim of our study was to investigate the fetal cardio-vascular response to steroids in the context of severepreterm IUGR, where absent/reversed EDF was notedin both umbilical arteries. Fetal blood sampling studiesin this setting11,12,15 clearly demonstrate that these fe-tuses are compromised, with many existing in a stateof chronic hypoxia and acidosis. Because invasive hemo-dynamic monitoring data in normal sheep8 as well asbaboons9 indicate transient acidosis after steroid admin-istration, we predicted that these IUGR fetuses wouldtolerate steroids poorly.

As in the study by Wallace and Baker,14 we were sur-prised but encouraged to demonstrate that more than50% of these fetuses tolerate steroids well, with umbilicalartery Doppler waveforms that demonstrate an apparentimprovement and persisted for several days. However,by using a prospective study design, and imaging the um-bilical and fetal vessels in a way that permitted analysisof peak systolic velocities, we have been able to definea subgroup of IUGR fetuses with ARED that demon-strated very different responses within 24 hours of ad-ministration, placing them at increased risk of fetalacidosis and perinatal death. These fetuses may havemore extensive placental damage and therefore be asicker subgroup to begin with, although they could notbe defined as such within the ARED group by their ul-trasound/Doppler findings at presentation. By analyz-ing absolute velocity measurements as well as PI values,we could track possible circulatory changes in these fe-tuses that may have remained undefined in studies look-ing at the PI as the main parameter.16

We observed a significant increase in absolute veloc-ities in both the umbilical artery and the umbilical vein

at 24 hours in persistent ARED fetuses, whereas thosefetuses with transient EDF reappearance demonstratedremarkably stable velocities, similar to the control groupof appropriately grown fetuses with normal umbilicalartery Doppler findings.

Ohlsson et al17 demonstrated an increase in mean ar-terial blood pressure after treatment with dexametha-sone in very-low-birth-weight infants in an intensivecare unit setting. Furthermore, glucocorticoids havebeen shown to increase fetal blood pressure in both an-imal models6,8 and in vitro preparations.18 Finally, in-creased blood pressure in response to betamethasonemay therefore explain the increased velocity of flowthrough both the umbilical artery and vein after steroidadministration. Interestingly, this potential hypertensivereaction was not demonstrable in the cerebral circula-tion, presumably because autoregulation ensures stablebrain perfusion.

Several investigators have studied Doppler flow ve-locity patterns in the human fetus after antenatal gluco-corticoid administration. No significant changes weredemonstrated in fetoplacental resistance as indicatedby umbilical artery PI values, whereas MCA PI valueswere either unchanged2,19 or transiently reduced.20,21

All these studies involved normally grown fetuses inwomen at risk of preterm delivery caused by preterm la-bor. As stated, Wallace et al14 retrospectively evaluatedwaveform changes in fetuses with absent umbilical ar-tery EDF and documented a transient return of end-diastolic umbilical flow in 19 of 28 fetuses. No fetalDoppler studies were reported in this series. Senatet al22 investigated uterine, umbilical, descending aortic,and MCA waveform PI changes in growth-restrictedfetuses after dexamethasone or betamethasone adminis-tration and reported no significant changes.

One interpretation of these findings is that glucocor-ticosteroids should not be given to mothers of severelygrowth-restricted fetuses with ARED in the umbilicalarteries. There is some evidence that such fetuses arealready exposed to more maternal steroids than theirappropriately grown counterparts because of the break-

Simchen et al 303

down of the 11B-hydroxysteroid dehydrogenase type IIenzyme that normally prevents maternal glucorticoidsfrom crossing the placenta.23,24 No subgroup analysisof the effect of steroids on perinatal outcome has beenperformed for this group of IUGR fetuses,1 althougha recent study in extremely preterm infants confirmsclinical benefit in very-low-birth-weight infants withgrowth restriction.25 For this reason we would con-tinue to advocate steroid administration in this set-ting, but believe our data support the need for dailyDoppler-based monitoring to define the fetal responseto this ‘‘steroid stress test.’’ One possible protocol forsuch monitoring is to perform a Doppler study on theday after steroid administration in fetuses with ARED.If positive umbilical artery EDF velocity is demon-strated, these fetuses are not likely to deteriorate acutelyand thus may need less intensive monitoring (eg, every2-3 days). However, if no positive EDF response is dem-onstrated, the fetal venous circulation should be evalu-ated by Doppler and if abnormal, serious considerationfor delivery should be given.

Although the number of fetuses in our study is small,we remain concerned that about 45% of unselectedIUGR fetuses with umbilical artery ARED toleratedsteroids poorly. Future studies are therefore planned todefine baseline characteristics that might predict a poorresponse to steroids, such as ultrasound evidence of ex-tensive placental damage, echogenic fetal bowel, and se-verity of and drug treatment for coexistent preeclampsia.At the present time we do not know which endpoints offetal compromise to use to time delivery and minimizethe morbidity of severe IUGR, and this dilemma hasbeen addressed in the GRIT trial as well.26 Should ran-domized controlled trials of intensive fetal monitoringrecommend earlier delivery for severe preterm IUGRwith ARED in the umbilical arteries, it may be safer todeliver this subset of preterm fetuses. We suggest thatARED fetuses with low umbilical arteries and umbilicalvein maximal velocities be examined by fetal Doppler im-aging and, where abnormal venous Doppler studies arefound, delivery may be more appropriate than steroids,given the risks of fetal deterioration or death.

Acknowledgment

We thank Dr Arne Ohlsson, from the Division of Neo-natology, Mount Sinai Hospital, and the Department ofHealth Policy, Management and Education from theUniversity of Toronto, Canada, for his constructivecomments on reviewing our manuscript.

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