Effect of antenatal betamethasone administration on placental vascular resistance

EARLY REPORT

Early report

Effect of antenatal betamethasone administration on placental vascular resistance Euan M Wallace, Lesleigh S Baker

Summary Background High placental vascular resistance is an important cause of fetal growth restriction and subsequent perinatal mortality. Identification of affected pregnancies allows appropriate fetal surveillance and delivery, but there are no known therapeutic strategies to decrease resistance and improve blood flow. However, placental corticotropin-releasing hormone (CRH) is thought to be a potent fetoplacental vasodilator, and exogenous corticosteroids can increase placental CRH secretion. Therefore, we examined whether corticosteroids could improve fetoplacental blood flow in pregnancies with increased vascular resistance. Methods A retrospective review of umbilical-artery flowvelocity waveforms (FVWs) before and after betamethasone administration was undertaken in pregnancies with increased placental vascular resistance, as shown by umbilical-artery absent end-diastolic flow (AEDF). FVWs were obtained by pulsed-wave doppler ultrasonography. We studied all 28 pregnancies monitored at the maternal-fetal medicine unit of a university teaching hospital since 1995. Findings The median duration of gestation at presentation with AEDF was 27 weeks (range 23–33). In 19 (68% [95% CI 49–86]) pregnancies, umbilical-artery diastolic flow returned within 24 h after betamethasone administration, consistent with decreased resistance. The median duration of this effect was 3 days (range 2–7). There were no differences in duration of gestation at diagnosis or delivery, or in birthweight between fetuses showing a return of flow after betamethasone and those not showing a return of flow. Interpretation In pregnancies with umbilical-artery AEDF, betamethasone treatment is associated with decreased placental vascular resistance, possibly induced via increased placental CRH secretion. This study does not provide insights into whether this effect would be beneficial or harmful to the fetus. Lancet 1999; 353: 1404–07

Department of Obstetrics and Gynaecology, Monash University (E M Wallace MD); and Maternal-Fetal Medicine Unit, Monash Medical Centre (L S Baker RM), 246 Clayton Road, Clayton, Victoria 3168, Australia Correspondence to: Dr Euan M Wallace (e-mail: [email protected])

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Introduction Roughly 0·3% of all pregnancies and 5% of high-risk pregnancies are complicated by increased placental vascular resistance as shown by absent end-diastolic flow (AEDF) in the umbilical artery.1,2 This abnormal flow-velocity waveform (FVW), detected by doppler ultrasonography of the umbilical artery, is associated with impaired oxygen and substrate availability, fetal growth restriction, and high perinatal mortality.1,3 Although no therapeutic intervention capable of mitigating these risks has been described, the identification, by doppler ultrasonography of FVWs, of high-risk pregnancies with umbilical-artery AEDF provides an opportunity to apply intensive fetal surveillance, resulting in an almost 30% reduction in perinatal mortality.4 Placental corticotropin-releasing hormone (CRH), which is a potent vasodilator of the fetoplacental circulation,5 may be involved in the local regulation of antenatal placental blood flow.6 Furthermore, administration of corticosteroids, given to accelerate the development of fetal maturity and improve perinatal outcome in pregnancies at risk of preterm delivery, has been shown to upregulate placental expression and secretion of CRH,7 offering the possibility that corticosteroid treatment may alter placental blood flow. We sought to examine whether betamethasone might lower fetoplacental vascular resistance in pregnancies complicated with increased resistance shown by umbilical-artery AEDF by serially measuring umbilicalartery FVWs before and after betamethasone administration in 28 women with umbilical-artery AEDF.

Methods At our institution, the management of pregnancies with umbilical-artery AEDF involves inpatient admission on diagnosis, betamethasone administration (in anticipation of delivery), and daily surveillance of fetal wellbeing by biophysical profile. Our practice of routinely recording the umbilical-artery FVW at the time of the biophysical profile has given us an opportunity to review the case records of all women with umbilical-artery AEDF attending our unit over the past 3·5 years, and to explore possible effects of betamethasone on placental vascular resistance. All monitoring was done with the women’s oral informed consent, according to routine clinical practice. The corticosteroid regimen used involved two 11·4 mg intramusacular doses of betamethasone (Celestone Chronodose, Schering-Plough, Baulkham Hills, NSW, Australia), administered 24 h apart. Ultrasonographic and doppler FVW studies were done with pulsed-wave doppler and real-time colour flow localisation of the umbilical vessels with either an ATL HDI Ultramark 9 (January, 1995–August, 1997; Advanced Technology Laboratories, Dee Why, NSW,

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Women with Women with All altered FVW after unchanged FVW women betamethasone after betamethasone (n=28) (n=19) (n=9) Pregnancy hypertension Isolated fetal growth restriction Twins

14 (74%) 2 (10%) 3 (16%)

7 (78%) 2 (22%) 0

21 (75%) 4 (14%) 3 (11%)

Table 1: Principal diagnoses in 28 pregnancies with umbilicalartery AEDF Australia) or an ATL HDI 3000 (September, 1997–May, 1998) with a 3·5 MHz or 4·0 MHz curvilinear probe and with the high-pass filter set at low. For each FVW recording and analysis, the lowest resistance signal in any recording was taken, and both fetal apnoea, confirmed by a steady signal visualised separately in the umbilical-venous channel, and absence of fetal activity was ensured to avoid artefactual AEDF.

Results Between January, 1995 and May, 1998, 28 women who had umbilical-artery AEDF and who had been administered betamethasone were available for study. These women were representative of all such women in our unit during the study. The median (range) duration of gestation was 27 weeks (23–33) at diagnosis of AEDF and was 29 weeks (25–33) at delivery. Table 1 shows the principal diagnoses for the 28 women. All 21 women with hypertension received antihypertensive medication before delivery. In 12 women, labetalol alone was used, in four labetalol and nifedipine, in three nifedipine and methyl-dopa, and in two methyl-dopa alone. For the 25 singleton pregnancies, the median birthweight was 946 g (459–1354). Nine (36%) of the singleton neonates had birthweights below the third percentile, 12 (48%) below the fifth percentile, and 18 (72%) below the tenth percentile for gestation, as defined in a normal Australian population.8 No neonate had a birthweight above the 50th percentile. 19 women (68% [95% CI 49–86]) showed alteration in umbilical-artery FVW after administration of betamethasone. The figure shows this effect in one of the women. There was no association between the principal diagnosis and the return of diastolic flow in the umbilical artery after corticosteroid administration (table 1). Furthermore, there were no differences in duration of gestation at diagnosis or delivery or birthweight between fetuses showing a return of flow after betamethasone and those not showing a return of flow (table 2). The median time from diagnosis of umbilical-artery AEDF to delivery in the two groups was 5 days (range 1–23) for those with a return of diastolic flow after steroids and 4 days (1–12) for fetuses with unchanged umbilical-artery FVW (p=0·48, MannWhitney U test). Significant systemic disease before pregnancy was slightly less common in women who showed improved umbilical-artery FVW after betamethasone (two [10%]: one systemic lupus Women with altered FVW after betamethasone (n=19) Gestation at diagnosis (weeks) Gestation at delivery (weeks) Birthweight (g)

28 (22–33) 29 (25–33) 980 (459–1354)

Women with unchanged FVW after betamethasone (n=9) 27 (24–30) 28 (25–30) 804 (562–1224)

p*

Daily serial umbilical-artery doppler FVWs before and for 7 days after betamethasone in a pregnancy with AEDF before treatment 0·55 0·38 0·45

*Mann-Whitney U test.

Table 2: Outcome data for 19 pregnancies showing a return of end-diastolic flow and nine pregnancies with persistent AEDF

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erythematosis, one diabetic nephropathy) than in those who did not (five [56%]: one renal transplant, four nephropathy; p=0·02, Fisher’s exact test). In the 19 women in whom umbilical-artery diastolic flow returned after betamethasone, the change was 1405

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apparent on the day after the first dose of betamethasone, before the second dose. 12 (63%) women showed recurrence of AEDF before delivery with a median time to recurrence of 3 days (range 2–7). In the remaining seven women, delivery occurred before the recurrence of AEDF. The median time to delivery in these seven women was 2 days (1–5). In four of the 19 women, two courses of corticosteroids were given before delivery. In these four women, umbilical-artery AEDF was evident at the time of administration of each course. A return of diastolic flow was seen after both courses in three women, whereas only the first course induced a return in the other woman. In all 28 women, delivery was initiated because of deteriorating fetal condition, as shown by intensive fetal surveillance.

Discussion Of the factors that influence the FVW recorded from a vessel,9 the main determinants of impedance in the fetoplacental vasculature are the intermediate and terminal placental villi capillaries.10 Therefore, decreased flow or AEDF in the umbilical artery is believed to reflect increased resistance in the placental vascular bed.10 Placentas from pregnancies with umbilical-artery AEDF have fewer tertiary villus arterioles than do placentas from pregnancies with normal umbilical-artery FVWs,11–13 and in sheep, progressive in-vivo embolisation of the terminal vessels in the placenta induces increased resistance and AEDF.14 As expected from the nature of the underlying vascular lesions, impaired flow or AEDF is an irreversible and progressive process. The clinical importance of AEDF in the umbilical artery is conferred by the association between abnormal umbilical-artery FVWs and fetal hypoxaemia and acidaemia,15 fetal growth restriction, and substantially increased perinatal mortality,2,3 requiring intensive fetal surveillance. Indeed, in randomised controlled trials, the use of doppler ultrasonography to detect umbilical-artery AEDF in high-risk pregnancies significantly improved perinatal outcome by identifying the at-risk pregnancies and thereby allowing targeted fetal surveillance and appropriate timing of delivery.4 Umbilical-artery FVWs recorded after the administration of corticosteroids should be interpreted with caution. In the majority of pregnancies with umbilical-artery AEDF, flow will return for the first few days after betamethasone administration. False reassurance may be afforded by essentially normal FVWs if the doppler observations are made for the first time after corticosteroid administration. We therefore recommend that full fetal assessment is made before corticosteroid therapy, wherever possible, or that serial doppler assessments are made if there are other clinical features of concern. Our findings suggest that clinicians may be able to modulate fetoplacental vascular resistance by the maternal administration of corticosteroids. We cannot yet say whether such haemodynamic changes would benefit the fetus in any way or indeed whether the changes may even be detrimental. However, another possibility is that the improved umbilical-artery FVWs observed after betamethasone administration might be accompanied by improvements in fetal oxygenation and acid-base balance15 and therefore in fetal wellbeing. If the changes in fetoplacental blood flow are shown in 1406

formal prospective investigation to be beneficial, corticosteroids could be used to improve fetal condition immediately before delivery, in the expectation that neonatal survival would be better if the fetus was born with normal oxygenation and acid-base balance. The time course of any steroid-related blood-flow changes would therefore be important and remains to be precisely elucidated. Placental secretion of CRH, which may be the mechanism underlying the betamethasoneassociated vasodilation, increases within 3 h of steroid a d m i n i s t a t i o n . 16 We cannot provide direct evidence to explain the decreased placental vascular resistance after betamethasone administration, but we suggest that a possible mechanism is through increased placental secretion of CRH. Placental CRH is thought to be an important regulator of fetoplacental blood flow;5,6 invitro studies show that placental CRH is a potent vasodilator6 mediating its effect via nitric oxide.17 Maternal and fetal concentrations of CRH are higher than normal in pregnancies complicated by hypertension, 18 fetal growth restriction,19 and abnormal umbilical-artery FVWs,20 possibly reflecting an autoregulatory response of the fetoplacental unit to hypoxaemia. We were unable to measure maternal or fetal CRH concentrations. However, Giles and colleagues20 reported that baseline CRH concentrations were higher in pregnancies with AEDF than in normal controls matched for duration of gestation. Administration of exogenous corticosteroid suppresses CRH secretion from the hypothalamus but increases placental CRH expression and secretion both in vitro7 and in vivo.16,21 The betamethasone-associated umbilical-artery FVW changes we observed may therefore reflect steroid-induced increased CRH secretion and subsequent vasodilation via induction of nitric oxide synthase. Altered placental vascular resistance is not observed after the administration of corticosteroids in pregnancies with normal umbilicalartery FVWs.22 Insight into this apparent discrepancy may be gained from two studies of glyceryl trinitrate’s effects on the fetoplacental vasculature. Like betamethasone, glyceryl trinitrate reduces vascular resistance in pregnancies with AEDF,23 although the effect is more acute and of shorter duration, but it has no effect on umbilical-artery FVW in pregnancies with normal vascular resistance.24 We believe that these findings are in keeping with a relative nitric oxide synthase deficiency in placentas with increased impedance.25 Furthermore, betamethasone stimulation of nitric oxide synthase, via CRH, would also be consistent with a vasodilatory effect in nitric-oxidedeficient vasculature and no effect on normal vasculature. Further studies are required to test this hypothesis of a placental corticosteroid-CRH-nitric oxide synthase pathway. Another possible mechanism for the observed changes in FVW may be an effect on fetal blood pressure. In sheep, direct administration of corticosteroids to the fetus increases its blood pressure acutely,26 and antenatal maternal administration of corticosteroids in women is associated with increased blood pressures in the preterm neonate for the first few days of life.27 Another possibility is that increased fetal blood pressure is a response to a decrease in total vascular resistance resulting from placental vasodilatation. THE LANCET • Vol 353 • April 24, 1999

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14 (74%) of the pregnancies with improved FVWs after betamethasone were complicated by severe preeclampsia requiring antihypertensive treatment; the altered FVWs may have been related to the antihypertensive therapy rather than to betamethasone. However, ten women received labetalol, an ␣,␤1,␤2antagonist that impairs rather than improves placental blood flow28 and vascular resistance decreased in all of them. The remaining women received either nifedipine or methyl-dopa, which may have reduced fetoplacental impedance. Nonetheless, in five pregnancies, altered FVWs were observed in the absence of any antihypertensive treatment (table 1), and in four pregnancies, FVW effects were studied over two separate courses of steroids 1 week apart. Improved FVWs were observed after both courses in three of these four pregnancies. We believe therefore that the FVW effects observed were indeed corticosteroid-related rather than coincidental or related to other therapy. The effect of betamethasone on placental vascular resistance in pregnancies with umbilical-artery AEDF has clear implications for the interpretation of umbilicalartery doppler studies following steroid administration, and may have implications for the future management of such high-risk pregnancies and for the use of corticosteroids in this clinical setting. Further elucidation of the mechanisms underlying this effect is expected to provide novel opportunities for the modulation of impaired placental blood flow and subsequent improvements in neonatal outcomes.

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Contributors Euan M Wallace made the original observations, performed the database analyses, developed the data-related hypotheses, and co-wrote the paper. Lesleigh S Baker performed the ultrasound examinations, compiled the database, and co-wrote the paper.

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References 1

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