IJG-08401; No of Pages 4 International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx

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CLINICAL ARTICLE

Effect of prenatal betamethasone on fetal, uteroplacental, and maternal blood flow velocity in pregnancies complicated by fetal growth restriction Shirin Niroomanesh, Kobra Shojaei ⁎, Sahar F. Moghadam, Noshin Mohammadi, Zahra Rahimi, Khadija RezaeiKeyhanaei Department of Obstetrics and Gynecology, Women’s Hospital, Tehran University of Medical Sciences, Tehran, Iran

a r t i c l e

i n f o

Article history: Received 28 October 2014 Received in revised form 6 April 2015 Accepted 19 June 2015 Keywords: Betamethasone Corticosteroid Doppler Fetal growth restriction Ultrasonography

a b s t r a c t Objective: To assess Doppler flow velocity in fetal, uteroplacental, and maternal arteries before and after betamethasone therapy among singleton pregnancies complicated by fetal growth restriction (FGR). Methods: A prospective, longitudinal, multicenter study was conducted at three university-affiliated hospitals in Tehran, Iran, between January 1 and November 30, 2013. The inclusion criteria were FGR, a gestational age of 24–34 weeks, no fetal anomalies, and no previous betamethasone therapy. Doppler blood flow was measured in uterine, umbilical, and middle cerebral arteries before treatment, and 24 hours and 5 days after completion of betamethasone therapy (two 12-mg doses at a 24-hour interval). Results: Overall, 40 women were enrolled. Doppler blood flow through the uterine and umbilical arteries showed significant but transient changes across the three timepoints (P b 0.001), whereas the middle cerebral artery showed no changes. Conclusion: Prenatal betamethasone led to transient improvements in blood flow in the uterine and umbilical arteries among pregnancies affected by FGR. © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction Pregnancies with fetal growth restriction (FGR) are often affected by many serious complications—e.g. chronic fetal hypoxia, necrotizing enterocolitis, and respiratory distress syndrome—especially when the neonate is delivered prematurely [1,2]. If there is a likelihood of premature delivery among patients affected by FGR, it might be useful to prescribe a course of betamethasone between 24 and 34 weeks of pregnancy. The course of treatment depends on the severity of FGR, findings of Doppler ultrasonography, and other associated factors [3]. For more than 30 years, glucocorticoids have been used to increase the secretion of surfactant and to accelerate fetal lung maturity in premature neonates [4–6], but the benefits of betamethasone therapy among preterm neonates with growth restriction have been questioned [7]. Doppler ultrasonography is the recommended method for evaluation and monitoring of pregnancies with suspected FGR. Furthermore, changes in blood flow can be properly observed by Doppler flow velocimetry, which in turn helps to determine fetal outlook. Several studies have demonstrated that use of Doppler ultrasonography can

⁎ Corresponding author at: Department of Obstetrics and Gynecology, Women’s Hospital, Kharim Khan Zand Street, Ostad Nejatollahi Shomali Street, Tehran 151871–8311, Iran. Tel./fax: + 98 21 2401885. E-mail address: [email protected] (K. Shojaei).

reduce both fetal death rate and unnecessary induction of labor in pregnancies with FGR [3,8,9]. Previous studies [3,7] have shown that growth restriction might occur after multiple courses of prenatal corticosteroids, providing conflicting data on the impact of steroids on uteroplacental blood flow. As a result, the aim of the present study was to assess the Doppler flow velocity in fetal, uteroplacental, and maternal arteries among singleton pregnancies complicated by FGR at three timepoints during a course of betamethasone therapy. 2. Materials and methods The present prospective, longitudinal, multicenter study was conducted among women with pregnancies complicated by FGR who attended prenatal care clinics at three university-affiliated hospitals (Imam Khomeini Hospital, Women’s Hospital, and Shariati Hospital) in Tehran, Iran, between January 1 and November 30, 2013. The inclusion criteria were a singleton pregnancy complicated by FGR (estimated fetal weight [EFW] below the 10th percentile for gestational age or abdominal circumference below 10th percentile), a gestational age of 24–34 weeks, no fetal anomalies detected by ultrasonography, and no betamethasone therapy before enrollment in the study. Cases of structural or congenital anomalies and chromosomal disorders were excluded. Women with type 1 or type 2 diabetes were excluded. The Ethics Committee of the Department of Obstetrics and Gynecology at

http://dx.doi.org/10.1016/j.ijgo.2015.04.043 0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Please cite this article as: Niroomanesh S, et al, Effect of prenatal betamethasone on fetal, uteroplacental, and maternal blood flow velocity in pregnancies complicated by fetal growth restriction, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.04.043

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S. Niroomanesh et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx

Tehran University of Medical Sciences approved the study. All patients provided written informed consent for participation in the study. As part of routine care at the study’s prenatal care clinics, two separate doses of 12 mg of betamethasone (Betamethasone LA DP, 1-mL ampule; CT Pharma, Gilan, Iran) are given intramuscularly at a 24-hour interval to women at 24–34 weeks of pregnancy and a diagnosis of FGR. Therefore, this course of treatment was used as routine therapy for participants in the present study. Characteristics and clinical information were gathered from the study patients, including maternal age, length of pregnancy at study commencement, body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters), maternal blood pressure, presence of gestational diabetes or pre-eclampsia, and parity. Pre-eclampsia was defined as systolic blood pressure of 140 mm Hg or more or diastolic blood pressure of 90 mm Hg or more, and proteinuria of 300 mg/day or more after 20 weeks of pregnancy. Doppler measurements were recorded at three timepoints: before treatment, and 24 hours and 5 days after completing the course of betamethasone. An Acuson Antares ultrasonography instrument (Siemens, Berlin, Germany) was used to perform the Doppler studies. Doppler flow velocity waveforms were obtained from a maternal uterine artery (UA), fetal umbilical artery (UmA), and fetal middle cerebral artery (MCA), with subsequent calculation of the MCA/UmA systolic/ diastolic (S/D) ratio. To obtain steady signals in the venous and arterial channels, all waveforms were recorded when the fetus was not breathing or moving. The S/D ratio, resistance index (RI), and pulsatility index (PI) were determined from the waveforms. Both the value of indices and the flow velocity of arteries were automatically obtained by the ultrasonography instrument. In addition to Doppler flow velocity in fetal and maternal arteries, the patients were followed up until delivery. Events such as intrauterine fetal death or emergency termination of pregnancy were recorded. Women who had a stillbirth or an emergency delivery were excluded from analyses. The data were analyzed with SPSS version 17 (SPSS Inc, Chicago, IL, USA). Continuous variables are reported as mean ± SD, and categorical variables as number (percentage). Longitudinal changes in the Doppler velocity waveform patterns of the UA, UmA, MCA, and MCA/UmA, and their respective flow indices were assessed over the three timepoints by analysis of variance for repeated measures. Post hoc tests to compare subgroups were performed; the Scheffe test was used when equal variances were assumed. Indices of women with and without preeclampsia, and of women with and without gestational diabetes from each of the timepoints were compared with the t test. P b 0.05 was considered to be statistically significant. 3. Results In total, 40 pregnant women with FGR were enrolled. None of the participants experienced intrauterine fetal death or emergency delivery; thus, the analysis included all 40 women. The demographic and clinical characteristics of the study patients are summarized in Table 1. The average gestational age at delivery was 29.7 weeks and the mean newborn weight was 948.5 g, demonstrating that the pregnancies affected by FGR resulted in extremely premature neonates. There were transient changes in the flow velocity of different vessels and the respective indices across the three timepoints (Table 2, Fig. 1). In the repeated measures analysis of Doppler flow velocity in the different arteries, the UA PI, UmA S/D ratio, UmA PI, UmA RI, and MCA/UmA RI ratio showed significant changes among the three timepoints (all P b 0.001). By contrast, the MCA RI remained steady across the three timepoints (P = 0.5). Compared with before betamethasone therapy, the UmA S/D ratio, UmA RI, and MCA/UmA RI were significantly lower 24 hours after treatment than beforehand (P b 0.001 for all) (Table 3). Although significant differences in the UA PI were recorded between baseline and 24 hours

Table 1 Demographic and clinical characteristics.a Characteristic

Value (n = 40)

Maternal age, y Maternal BMI Maternal systolic blood pressure, mm Hg Maternal diastolic blood pressure, mm Hg Length of pregnancy, wk Estimated fetal weight, g Pre-eclampsia Gestational diabetes Nulliparous Multiparous

29.8 ± 7.7 26.2 ± 3.8 126.6 ± 22.8 78.8 ± 16.8 29.7 ± 2.8 948.5 ± 330 16 (40) 9 (23) 19 (48) 21 (53)

Abbreviation: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters). a Values are given as mean ± SD or number (percentage).

(P = 0.002) and between 24 hours and 5 days (P = 0.009), it seemed to return to its value before treatment at 5 days (P N 0.99) (Table 3). The UmA PI also differed significantly by time: the differences between before and 24 hours after therapy (P b 0.001), and that before and 5 days after therapy (P = 0.007) were significant, although that between 24 hours and 5 days was not (P = 0.27) (Table 3). Length of pregnancy at time of study participation is depicted in Fig. 2. There was a fairly even distribution across 24–34 weeks of pregnancy. There were no significant differences in Doppler flow velocity of the UA, UmA, and MCA between women with and without pre-eclampsia and between women with and without gestational diabetes (data not shown). 4. Discussion In the present study, Doppler blood flow was measured in the UA, UmA, and MCA for 40 singleton pregnancies complicated by FGR at three timepoints during betamethasone treatment: immediately before treatment, 1 day after treatment, and 5 days after treatment. In addition, the index values of flow in these blood vessels were calculated. The RI, PI, and S/D ratio of the UmA showed the same pattern of changes across the three timepoints: values had reduced by 24 hours after treatment, but had increased again by 5 days. Consistent with the present results, other studies have shown a transient improvement (for absent or reversed flow) in the flow velocity of the UmA in fetuses with FGR [10–12]. Wijnberger et al. [13] also showed a transient reduction in flow indices of the UmA. According to Nozaki et al. [10], betamethasone therapy led to a reduction in the UmA and ductus venosus PI after 24 hours; this reduction continued until 48 hours after treatment. By contrast, Urban et al. [14] found no significant changes in the UmA PI. In a study in Australia, Robertson et al. [11] observed that betamethasone therapy was associated with a transient reduction in the end-diastolic flow of the UmA for two-thirds of fetuses with FGR. They suggested that a subgroup of fetuses with persistent absent end-diastolic flow in the UmA have a higher prenatal risk.

Table 2 Repeated measure analysis of Doppler blood flow during betamethasone treatment.a Artery index

Before treatment

24 h after treatment

5 d after treatment

P value

UA PI UmA S/D UmA PI UmA RI MCA RI MCA/UmA RI

0.96 ± 0.35 3.57 ± 0.84 1.16 ± 0.16 0.68 ± 0.08 0.75 ± 0.10 1.13 ± 0.27

0.92 ± 0.33 3.13 ± 0.69 1.03 ± 0.16 0.62 ± 0.06 0.77 ± 0.11 1.25 ± 0.23

0.93 ± 0.33 3.31 ± 0.73 1.07 ± 0.17 0.66 ± 0.07 0.77 ± 0.10 1.18 ± 0.25

b0.001 b0.001 b0.001 b0.001 0.5 b0.001

Abbreviations: UA, uterine artery; PI, pulsatility index; UmA, umbilical artery; S/D, systolic/diastolic ratio; RI, resistance index; MCA, middle cerebral artery. a Values are given as mean ± SD unless indicated otherwise.

Please cite this article as: Niroomanesh S, et al, Effect of prenatal betamethasone on fetal, uteroplacental, and maternal blood flow velocity in pregnancies complicated by fetal growth restriction, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.04.043

a

0.96 0.93 0.9

3.8 3.6 3.4 3.2 3 2.8 Time 1

Time 1 Time 2 Time 3

1 0.9 Time 1

Time 2

0.78 Mean MCA RI

0.76

0.74 Time 2

Time 3

d

0.68

14 14 12

10

9 8

8 6 4

0

0.6

25–27

0.56 Time 1

Time 2

Time 3

28–30

31–32

33–34

Length of pregnancy, wk Fig. 2. Length of pregnancy at time of study participation.

1.3

f

1.2 1.1 1 Time 1

Time 3

9

2

0.64

Time 3

e

Time 1

Mean UmA RI

c

1.1

0.72

Mean MCA/UmA RI

Mean UmA PI

1.2

Time 2

3

16

b Number of participants

Mean UA PI

0.99

Mean UmA S/D

S. Niroomanesh et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx

Time 2

Time 3

Fig. 1. Mean values of the indices for Doppler flow velocity in maternal, placental, and fetal arteries before and after betamethasone treatment. (a) UA PI. (b) UmA S/D. (c) UmA PI. (d) UmA RI. (e) MCA RI. (f) MCA/UmA RI. Time 1, before treatment; Time 2, 24 hours after treatment; Time 3, 5 days after treatment. Abbreviations: UA, uterine artery; PI, pulsatility index; UmA, umbilical artery; S/D, systolic/diastolic ratio; RI, resistance index; MCA, middle cerebral artery.

This subgroup of fetuses was also more likely to need assisted ventilation after delivery [11]. The present series demonstrated significant changes across three timepoints for UA PI, but these changes were transient, with a significant reduction 24 hours after treatment, but returning to the baseline value after 5 days. By contrast, Thuring et al. [15], Cohlen et al. [16], and Piazze et al. [17] reported no transient or significant changes in the UA PI after betamethasone therapy. The MCA RI has not been extensively evaluated for pregnancies complicated by FGR and treated with betamethasone. In the present study, the MCA RI did not change significantly over the assessment period and betamethasone treatment had no effect on the Doppler flow velocity of the MCA. In agreement with these results, Nozaki et al. [10] and Urban et al. [14] found no significant changes in MCA indices. Severe adverse effects of betamethasone therapy for FGR cases during the second half of pregnancy do not seem to have been reported, although betamethasone has some adverse effects including reduced fetal activity and breathing, and beat-to-beat variability [18,19]. In addition, maternal betamethasone has been shown to improve end-diastolic flow in the UmA in FGR fetuses complicated by placental insufficiency [20,21]. Fetuses that do not respond to betamethasone exposure have a worse outlook. In the follow-up until time of delivery in the present

Table 3 Comparison of mean index scores between treatment timepoints for different arteries.a Artery index

Before vs 24 h after treatment

24 h vs 5 d after treatment

Before vs 5 d after treatment

UA PI UmA S/D UmA PI UmA RI MCA RI MCA/UmA RI

0.002 b0.001 b0.001 0.001 N0.99 b0.001

0.009 b0.001 0.27 0.3 N0.99 0.02

N0.99 N0.99 0.007 0.001 N0.99 0.28

Abbreviations: UA, uterine artery; PI, pulsatility index; UmA, umbilical artery; S/D, systolic/diastolic ratio; RI, resistance index; MCA, middle cerebral artery. a Values are given as P values.

study, none of the pregnant women experienced fetal death or emergency termination of pregnancy. Patients with diabetes mellitus type 1 or 2 were excluded, whereas women with gestational diabetes could be included in the present study. Of the 40 participants, two-fifths had pre-eclampsia and slightly more than one-fifth had gestational diabetes. Notably, none had both pre-eclampsia and gestational diabetes. A clinical trial by Liggins and Howie [3] reported a high rate of fetal death after corticosteroid therapy among premature deliveries complicated by severe gestational hypertension [3]. In the present study, complications such as gestational diabetes or pre-eclampsia were not found to affect the Doppler flow velocity of the UA, UmA, and MCA. The study is limited by its small sample size. However, the proportion of pregnancies with FGR is low and assessing a higher number of participants would require a longer study duration. In conclusion, two doses of prenatal betamethasone (12 mg) in pregnancies complicated by FGR led to significant but transient changes in the UA PI, UmA PI, UmA RI, UmA S/D ratio, and MCA/UmA RI ratio. It is important to note that all these changes were transient, and the MCA RI did not change significantly during the longitudinal assessment of the study. Prenatal betamethasone led to transient improvements in blood flow in the uterine and umbilical arteries among pregnancies affected by FGR. Acknowledgments The Tehran University of Medical Sciences funded this research. Conflict of interest The authors have no conflicts of interest. References [1] Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A. Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction. The Vermont Oxford Network. Am J Obstet Gynecol 2000;182(1 Pt 1):198–206. [2] Seyam YS, Al-Mahmeid MS, Al-Tamimi HK. Umbilical artery Doppler flow velocimetry in intrauterine growth restriction and its relation to perinatal outcome. Int J Gynecol Obstet 2002;77(2):131–7. [3] Resnik R. Intrauterine growth restriction. Obstet Gynecol 2002;99(3):490–6. [4] Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50(4):515–25. [5] Miracle X, Di Renzo GC, Stark A, Fanaroff A, Carbonell-Estrany X. Guideline for the use of antenatal corticosteroids for fetal maturation. J Perinat Med 2008;36(3):191–6. [6] Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006;3:CD004454. [7] van Stralen G, van der Bos J, Lopriore E, te Pas AB, Bloemenkamp KW, Walther FJ, et al. No short-term benefits of antenatal corticosteroid treatment in severely preterm growth restricted fetuses: A case–control study. Early Hum Dev 2009; 85(4):253–7. [8] Berkley E, Chauhan SP, Abuhamad A. Doppler assessment of the fetus with intrauterine growth restriction. Am J Obstet Gynecol 2012;206(4):300–8.

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Please cite this article as: Niroomanesh S, et al, Effect of prenatal betamethasone on fetal, uteroplacental, and maternal blood flow velocity in pregnancies complicated by fetal growth restriction, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.04.043

Effect of prenatal betamethasone on fetal, uteroplacental, and maternal blood flow velocity in pregnancies complicated by fetal growth restriction.

To assess Doppler flow velocity in fetal, uteroplacental, and maternal arteries before and after betamethasone therapy among singleton pregnancies com...
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