Journal of Perinatology (2014) 34, 192–196 & 2014 Nature America, Inc. All rights reserved 0743-8346/14 www.nature.com/jp
ORIGINAL ARTICLE
Effects of antenatal magnesium sulfate treatment on cerebral blood flow velocities in preterm neonates EY Imamoglu, T Gursoy, G Karatekin and F Ovali OBJECTIVE: The objective of this study is to investigate the effects of antenatal magnesium sulfate (MgSO4) on cerebral blood flow (CBF) velocities in preterm neonates. STUDY DESIGN: In this prospective case–control study, we included 53 neonates born between 26 and 34 weeks of gestation. Twenty neonates were exposed to MgSO4 antenatally and 33 were not. Serial daily Doppler flow measurements of middle cerebral artery (MCA) were performed. RESULT: Significantly increased MCA mean velocities were found in the MgSO4 group. A progressive increase in serial Doppler measurements of MCA mean velocity from day 1 to day 5 of life was detected in both groups. CONCLUSION: There is significant increase in MCA mean velocities in preterm neonates receiving antenatal MgSO4. This increment in CBF velocities might explain the protective role of MgSO4 in ischemic events and hypoxic brain damage. Journal of Perinatology (2014) 34, 192–196; doi:10.1038/jp.2013.182; published online 30 January 2014 Keywords: doppler; middle cerebral artery; magnesium; prematurity
INTRODUCTION The developing fetal brain is highly dependent on sustained blood flow due to the lack of its own energy and nutrient reserves.1 In the immature brain, the thin peripheral vessels do not present many collateral routes or anastomoses and their walls are immature. Thus, they cannot sustain effective blood flow and their limited vasodilatation capacity cannot compensate the hypoxicischemic injury.2 Exposure to antenatal magnesium sulfate (MgSO4) treatment and increased cord serum magnesium concentrations have been associated with a decreased incidence of hypoxic brain damage.3,4 Neuroprotection is the inhibition of the biochemical response to ischemia in order to prevent neuronal death. However, the biochemical cascade during ischemia originates from insufficiency and failure of the microcirculation. Thus, preservation of the microvasculature would lead to neuroprotection.5 MgSO4 has been shown to have beneficial hemodynamic effects by stabilizing the blood pressure, reducing the constriction in cerebral arteries and restoring the perfusion in preterm neonates.6–8 Cerebral blood flow (CBF) velocities have been validated as a reliable indicator of CBF, and changes in CBF are assumed to have a key role in the development of various cerebral lesions in preterm infants.9,10 In this study, our aim was to investigate the effects of antenatal MgSO4 on CBF velocities in preterm neonates.
maternal MgSO4 treatment antenatally (MgSO4 group) and 33 were not (control group). Neonates without antenatal Doppler examination and with absent/ reversed end diastolic velocity in umbilical artery were excluded from the study. Neonates with clinical conditions such as congenital malformation, chromosomal anomaly, perinatal asphyxia, sepsis, premature rupture of membranes, choriamnionitis, polycythemia (Hb422 g dl 1), anemia (Hbo10 g dl 1) and whose mothers had multiple pregnancies were not included in the study (delayed cord clamping was not performed in any case during delivery). Gestational age was calculated from the beginning of the last menstrual period of the mother and verified using early trimester ultrasonographic data. Neonates with uncertain gestational age were excluded. Twenty mothers had received an intravenous infusion of MgSO4 either for preeclampsia (n ¼ 14) or tocolysis (n ¼ 6). A loading dose of 6 g was infused over 30 min and was followed by a maintenance infusion of 0.8 g h 1 until the time of delivery according to our institution protocol. Mothers having ritodrine for tocolysis were excluded from the study. Maternal serum magnesium concentration just before labour was recruited from the maternal records. Atomic absorption spectrophotometry (Cobas Integra 800, Roche, Basel, Switzerland) was used to determine serum magnesium levels in the maternal and umbilical cord blood. Maternal cumulative MgSO4 dose and total infusion time (hours) were calculated. The control group consisted of neonates born immediately after reaching the hospital or whose mothers did not receive any MgSO4 or tocolytic treatments but fulfilled the abovementioned enrollment criteria. Informed consent was obtained from the parents, and study protocol and consent forms were approved by local ethics committee. Blood pressure was determined as an average of three measurements made from the right upper arm before Doppler examination.
METHODS In this prospective case–control study, we included a total of 53 neonates between 26 and 34 weeks of gestation born at the Zeynep Kamil Maternity and Children’s Training and Research Hospital, Istanbul, Turkey, between December 2011 and December 2012. Twenty neonates were exposed to
Doppler ultrasonography measurements During measurements, neonates were in a resting state and lying in a supine position.11–13 Environmental light intensity was low and constant. Phototherapy was suspended during measurements. To avoid crying
Zeynep Kamil Maternity and Children’s Training and Research Hospital, Neonatal Intensive Care Unit Istanbul, Istanbul, Turkey. Correspondence: Dr EY Imamoglu, Zeynep Kamil Kadın ve Çocuk Hastalıkları Eg˘itim ve Aras¸tırma Hastanesi Opr., Dr Burhanettin U¨stu¨nel Cad. No:10, U¨sku¨dar, ˙Istanbul 34668, Turkey. E-mail: [email protected] Received 26 September 2013; revised 15 November 2013; accepted 4 December 2013; published online 30 January 2014
Mg and CBF velocities EY Imamoglu et al
193 episodes and stress conditions, gentle handling consisting of administration of oral dextrose drops in order to pacify the baby when needed, stimulation of non-nutritional sucking, delicate touching and calm voice tones was applied.10 The measurements have been made before the administration of daily caffeine dose.14 Neonates who suffered from hypotension, exposed to drug therapies that could change CBF velocity or arterial blood pressure and any metabolic pathology were excluded from the study.15–19 Flow imaging and blood flow velocity were obtained with a color Doppler unit (Philips En Visor C, Amsterdam, The Netherlands) and a multifrequency 5-12 MHz sector probe was used. In order to eliminate interobserver variability, serial pulse-wave Doppler ultrasound measurements were made by the same experienced neonatologist (EI), blinded to the group assignment of the neonate. Measurements of mean velocity have been made in the left and right middle cerebral artery (MCA) on day 1, 2, 3, 4 and 5 of life. All measurements were performed after the first 8-12 h of life in order to reduce the possible effects of immediate postnatal cardiovascular adaptation on flowmetric data. Doppler flow measurements of MCA were performed by scanning through the anterolateral fontanelle (temporal window). The transducer is placed above the ear, B1 cm superior and anterior to the external auditory meatus, posterior to the orbit and zygomatic arch, with the marker in a horizontal position.20,21 With the transducer angled slightly inferiorly, it overlays the appropriate window for visualizing the midbrain, defined by the characteristic contour of the cerebral peduncles anteriorly.21 The color gain was set to maximize vascular signal and minimize tissue motion artifacts. The transducer position was subsequently adjusted until visualization of the red MCA flow. The angle between the ultrasound beam and the direction of blood flow was kept below 151.22 To maintain accuracy, a minimum of five sequential homogenous cardiac cycles of optimal quality were subjected to real-time spectral analysis. MCA mean flow velocity was obtained by integrating the area under the velocity curve over one cardiac cycle.10 A minimum of three measurements were obtained and then averaged. MCA mean velocity served as a surrogate for CBF.23–25 Examination time was B5 min. Along with the Doppler studies, cranial ultrasonography was performed in all cases. The grade of intraventricular hemorrhage was reported according to the criteria of Papile et al.26 The shunt across the patent ductus arteriosus (PDA) was evaluated from a high parasternal/suprasternal view by the same investigator (TG) experienced in echocardiography.27 Moreover, the presence of respiratory distress syndrome, phototherapy, caffeine, ibuprofen and inotrope use were recorded.
Statistical analysis Statistical analysis was performed by using SPSS software version 20.0 (IBM Statistics, IBM, Somers, NY). The variables were investigated using visual histograms, probability plots and Shapiro–Wilk’s test to determine whether or not they are normally distributed. Descriptive analyses were presented using means±s.d. for normally distributed variables, as medians (25–75%) for the non-normally distributed variables and as percentages for categorical variables. Normally distributed variables were compared by Student’s t-test, nonparametric variables by Mann–Whitney’s U-test and categorical variables by w2-test. Friedman tests were conducted to test whether there is significant change in MCA velocities in the consecutive days. Correlation between maternal and cord blood magnesium levels was evaluated by using Spearman’s correlation coefficient. Intraobserver variability was assessed in an arbitrary sample of 20 neonates. The measurements were repeated by the same investigator who was blinded to the previous results. The coefficient of variation was calculated in order to show intraobserver variability.
Demographic characteristics, hemodynamic and clinical variables of the neonates are shown in Table 1. There was no significant difference between the groups. All attempts to obtain MCA mean velocities were successful. As the changes of the hemodynamic variables in the left and right MCA were similar and correlated significantly, only the data of the left MCA were presented. Significantly increased MCA mean velocities were found in the MgSO4 group compared with that in the control group (Table 2). Figure 1 shows the progressive increase in serial Doppler measurements of MCA mean velocity from day 1 to day 5 of life in both groups (Po0.001 in the control group and P ¼ 0.027 in the MgSO4 group). There was no correlation between cord blood Mg levels and MCA Doppler velocities in both groups (MgSO4 group: r ¼ 0.25, P ¼ 0.29; control group: r ¼ 0.16, P ¼ 0.39). There was no difference between the two groups in terms of the presence of ductal patency during serial daily measurements and ibuprofen use.
Table 1. Demographic characteristics, hemodynamic and clinical variables of the preterm neonates involved in the study
Maternal age (years) Gestational age (weeks) Birth weight (g)
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Control group (n ¼ 33)
P-values
28±3.9 32±1.6 1497±347
28±5.1 31.1±2 1533±299
0.47 0.13 0.67
9 (45) 11 (55)
13 (40) 20 (60)
0.68
Gender (n) Males (%) Females (%) SGA 5 min APGAR score Cesarean section Heart rate (bpm) Mean arterial pressure (mm Hg) RDS PDA IVH Caffeine therapy Ibuprofen Inotrope use Phototherapy
6 (30%) 9 (8.2–9) 18 (90%) 148±13.5 49.4±9.8 6 8 3 6 3 1 16
(30%) (40%) (15%) (30%) (15%) (5%) (80%)
3 (9.1%) 9 (8–9) 27 (81.8%) 149±15.4 45.4±6.6 11 15 2 11 6 2 27
(33.3%) (45.5%) (6%) (33.3%) (18.2%) (6.1%) (81%)
0.07 0.62 0.42 0.95 0.11 0.8 0.7 0.52 0.8 0.54 0.87 0.9
Abbreviations: IVH, intraventricular hemorrhage; MgSO4, magnesium sulfate; PDA, patent ductus arteriosus; RDS, respiratory distress syndrome; SGA, small for gestatioal age. Values are presented as mean±s.d. for maternal age, gestational age, birth weight, heart rate, mean arterial pressure. Five-minute APGAR score is presented as median (25–75%).
Table 2. Serial Doppler measurements of MCA-MV from day 1 to day 5 of life in two groups of preterm infants who were or were not exposed to antenatal magnesium sulfate MCA-MV (cm s 1)
RESULTS Twenty neonates constituted the MgSO4 group and 33 neonates constituted the control group. MgSO4 was administered for treatment of preeclampsia in 14 cases and for tocolysis in 6 cases. Median total dose of MgSO4 given to the mother before labour was 34.2 (12.5–54.4) g. Median total infusion time was 15 (3.8–26) h. Median serum magnesium levels in maternal and cord blood were 5.5 (4.6–6.5) and 3.5 (3.1–4) mg dl 1, respectively. Maternal serum magnesium levels were correlated with cord blood magnesium levels of the neonates (r ¼ 0.62, P ¼ 0.004).
MgSO4 group (n ¼ 20)
Day Day Day Day Day
1 2 3 4 5
MgSO4 group 21.2 22.1 24.8 23.2 27.7
(16.4–22.4) (15.9–28.2) (18.2–30.7) (21.5–29.4) (21.1–31.5)
Control group 15.8 17.8 18.1 20.3 22.2
(13–18.5) (14.3–20.3) (16.3–23.3) (17.2–25.2) (18–28)
P-values 0.001a 0.014a 0.005a 0.004a 0.022a
Abbreviations: MCA-MV, middle cerebral artery mean velocity; MgSO4, magnesium sulfate. a Significant difference between two groups, values are presented as median (25–75%).
Journal of Perinatology (2014), 192 – 196
Mg and CBF velocities EY Imamoglu et al
194
Figure 1. Serial Doppler measurements of middle cerebral artery mean velocities from day 1 to day 5 of life in both groups. Solid line presents the control group and dotted line presents the magnesium sulfate group.
Intraobserver error was minimal (2%) and there was no significant difference between consecutive measurements. DISCUSSION In the cerebrovascular bed, increased magnesium ion concentration was shown to reduce the contractile responses of isolated cerebral arteries resulting in vasodilatation.28–31 MgSO4 treatment has also vasodilatory effects on both cerebral circulation and systemic arteries.32–34 Belfort et al.34 investigated the effect of MgSO4 on the cerebral circulation in patients with pregnancyinduced hypertension and showed a significant increase in mean velocity in the maternal MCA in response to intravenous MgSO4 that was interpreted as distal artery vasodilatation. Less is known about antenatal effects of MgSO4 on the fetus and newborn circulatory systems. In late-term goat fetuses, direct infusion of MgSO4 increases the brain blood flow during acute hypoxemia.35 However, there are limited studies investigating the effects of antenatal MgSO4 on neonatal circulation. In neonates, elevated levels of MgSO4 may persist for up to 7 days, with an elimination half life of 43.2 h.36 Therefore, we aimed to investigate whether there was any change in MCA mean velocities or not with serial daily Doppler measurements. To our knowledge, this is the first study in the literature performing serial daily Doppler measurements of MCA in preterm neonates exposed to antenatal MgSO4. We did not measure CBF, but assessed its surrogate MCA mean velocity. Although MCA mean velocity correlates well with CBF, we cannot exclude the possibility that changes in MCA diameter affected velocity without affecting flow, which was a limitation of this study.23–25 Absent and reversed end diastolic velocities in Doppler examination of umbilical artery are late vascular responses in growth-restricted fetus.37 These late Doppler findings result from altered forward cardiac function and abnormal organ autoregulation, generally signifying the onset of compromise and redistribution in organ blood flows.38 For this reason, we did not include the neonates having these abnormal Doppler findings in our study. Journal of Perinatology (2014), 192 – 196
Pezzati et al.39 obtained normal standards of CBF velocity in healthy preterm and term infants relating to the first hours of life, a period in which the flowmetric modifications could be influenced in a significant manner by postnatal adaptation.10 Thus, we performed our Doppler measurements after the 8-12 h of life. In another study evaluating the effect of antenatal tocolytic administration of MgSO4 and ritodrine on CBF velocity in preterm neonates by Pezzati et al.40, they measured CBF velocities in the anterior cerebral artery, right and left MCA in the first hours of life (2–8 h) and did not find any significant difference in blood flow velocities in the three cerebral arteries between the two treatment groups. They made a comparison in between the MgSO4 and ritodrine groups; however, they did not have any control group in which no tocolytic medication was used. This was a major limitation of their study, as ritodrine as a tocolytic agent may affect CBF velocities.10 Besides, their measurements of CBF velocities were lower than those in our both the MgSO4 and the control group, which may be explained by the time of their measurements as they had made the measurements in the first 2–8 h, which was early when compared with our study. On the other hand, Rantonen et al.41 performed serial Doppler examinations of anterior cerebral artery and internal carotid artery at the mean ages of 6, 12, 24, 36, 48, 72 and 96 h and 1 week in preterm neonates exposed to antenatal MgSO4 (n ¼ 19), ritodrine treatment (n ¼ 17) and in 19 nonexposed preterm controls. They found that maternal MgSO4 had no significant effect on blood flow velocities in the neonatal cerebral vessels. As MCA mean velocity is a surrogate for CBF, we preferred to perform our measurements on MCA in order to evaluate CBF.22 In contrast to the study of Rantonen et al.,41 we found increased MCA mean velocities in the MgSO4 group when compared with control group from day 1 to day 5 of life. However, they did not give the actual results of CBF velocities, instead they gave the cerebral perfusion pressure and blood flow indices, which were calculated values that also included the blood pressure values in the equation. Hence, we could not compare our results with theirs. Romagloni et al.10 provided normal reference values of CBF velocities in healthy preterm infants in the first month of life (day 1, 3, 7, 14, 21 and 28). MCA mean velocities of our control group were found similar to those reference values. They also showed the existence of a progressive increase of systolic, diastolic and mean flow velocities in the anterior cerebral artery and MCA as the postnatal age increases, such as that observed in our study population in both the MgSO4 and the control groups, and related this progressive increase in CBF velocities to the progressive opening of cerebral vascular bed associated with a reduction of microcirculation resistances. Theoretically, vasodilators should be able to increase blood flow via a change in vessel diameter at the entrance of microcirculation.42 In addition to vasodilatory effects, infusion of MgSO4 is also associated with other potential promicrocirculatory effects, such as an increase in red blood cell deformability, reduction of platelet aggregation, anti-inflammatory effects and maintenance of endothelial integrity.43–46 Through all these mechanisms, MgSO4 could facilitate the decrease in microcirculation resistances in the cerebrovascular bed and improve microvascular perfusion, and this may explain the increase in MCA flow velocities observed in our study. Shokry et al.47 studied 48 preterm neonates divided into two groups based on maternal exposure to MgSO4 (n ¼ 28) or not (n ¼ 20), and performed CBF velocity measurements on anterior cerebral artery and MCA. They found significantly lower peak systolic, mean and end diastolic velocities in these cerebral arteries, and also a significantly higher incidence of PDA in the MgSO4 group. They concluded that magnesium relaxed ductal muscles with resultant ductal patency and decreased cerebral perfusion was associated with an increased incidence of PDA. In our study, contrary to their study, PDA incidence was similar in both groups. On the other hand, Elimian et al.48 studied 190 & 2014 Nature America, Inc.
Mg and CBF velocities EY Imamoglu et al
195 neonates exposed to MgSO4 and 211 neonates not exposed to MgSO4. Similar to our results, they found no difference between groups with regard to the rates of PDA. Effects of ibuprofen on MCA Doppler measurements were not evaluated. This was a limitation of our study. There are several studies reporting that maternal administration of MgSO4 was associated with a reduced risk of intraventricular hemorrhage in infants.4,49 In our study, we did not find any significant difference in terms of intraventricular hemorrhage between the two groups. Morover, similar to our results, Crowther et al.50 did not find any effect of MgSO4 on the rate of intraventricular hemorrhage, and they speculated that any neuroprotective effect of MgSO4 on motor dysfunction might work through stabilization of CBF and ameliorating the effects of ischemic episodes, which might be explained by increased CBF. In conclusion, this is the first study in the literature highlighting the increase in MCA mean velocities in preterm neonates receiving antenatal MgSO4. This increment in CBF velocities might explain the protective role of MgSO4 in ischemic events and hypoxic brain damage. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS We express our gratitude to the families who gave us permission to evaluate their babies.
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Effect of changes in magnesium ion concentration on cat cerebral arterioles. Am J Physiol 1983; 245(1): 22–26. 31 Euser AG, Cipolla MJ. Resistance artery vasodilation to magnesium sulfate during pregnancy and the postpartum state. Am J Physiol Heart Circ Physiol 2005; 288(4): 1521–1525. 32 Aloamaka CP, Ezimokhai M, Morrison J, Cherian T. Effect of pregnancy on relaxation of rat aorta to magnesium. Cardiovasc Res 1993; 27(9): 1629–1633. 33 Belfort MA, Moise Jr. KJ. Effect of magnesium sulfate on maternal brain blood flow in preeclampsia: a randomized, placebo-controlled study. Am J Obstet Gynecol 1992; 167(3): 661–666. 34 Belfort MA, Saade GR, Moise Jr. KJ. The effect of magnesium sulfate on maternal and fetal blood flow in pregnancy-induced hypertension. Acta Obstet Gynecol Scand 1993; 72(7): 526–530. 35 Tanaka S, Sameshima H, Ikenoue T, Sakamoto H. Magnesium sulfate exposure increases fetal blood flow redistribution to the brain during acute non-acidemic hypoxemia in goats. Early Hum Dev 2006; 82(9): 597–602. 36 Dangman BC, Rosen TS, James LS. Magnesium levels in infants of mothers treated with MgSO4. Pediatr Res 1977; 11: 415. 37 Baschat AA. Venous Doppler evaluation of the growth-restricted fetus. Clin Perinatol 2011; 38(1): 103–112. 38 Ferrazzi E, Bozzo M, Rigano S, Bellotti M, Morabito A, Pardi G et al. Temporal sequence of abnormal Doppler changes in the peripheral and central circulatory systems of the severely growth-restricted fetus. Ultrasound Obstet Gynecol 2002; 19(2): 140–146. 39 Pezzati M, Dani C, Biadaioli R, Filippi L, Biagiotti R, Giani T et al. Early postnatal doppler assessment of cerebral blood flow velocity in healthy preterm and term infants. Dev Med Child Neurol 2002; 44(11): 745–752. 40 Pezzati M, Giani T, Gambi B, Dani C, Bertini G, Biagiotti R et al. Influence of maternal magnesium sulphate and ritodrine treatment on cerebral blood flow velocity of the preterm newborn. 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ORIGINAL ARTICLE
Effects of antenatal magnesium sulfate treatment on cerebral blood flow velocities in preterm neonates EY Imamoglu, T Gursoy, G Karatekin and F Ovali OBJECTIVE: The objective of this study is to investigate the effects of antenatal magnesium sulfate (MgSO4) on cerebral blood flow (CBF) velocities in preterm neonates. STUDY DESIGN: In this prospective case–control study, we included 53 neonates born between 26 and 34 weeks of gestation. Twenty neonates were exposed to MgSO4 antenatally and 33 were not. Serial daily Doppler flow measurements of middle cerebral artery (MCA) were performed. RESULT: Significantly increased MCA mean velocities were found in the MgSO4 group. A progressive increase in serial Doppler measurements of MCA mean velocity from day 1 to day 5 of life was detected in both groups. CONCLUSION: There is significant increase in MCA mean velocities in preterm neonates receiving antenatal MgSO4. This increment in CBF velocities might explain the protective role of MgSO4 in ischemic events and hypoxic brain damage. Journal of Perinatology (2014) 34, 192–196; doi:10.1038/jp.2013.182; published online 30 January 2014 Keywords: doppler; middle cerebral artery; magnesium; prematurity
INTRODUCTION The developing fetal brain is highly dependent on sustained blood flow due to the lack of its own energy and nutrient reserves.1 In the immature brain, the thin peripheral vessels do not present many collateral routes or anastomoses and their walls are immature. Thus, they cannot sustain effective blood flow and their limited vasodilatation capacity cannot compensate the hypoxicischemic injury.2 Exposure to antenatal magnesium sulfate (MgSO4) treatment and increased cord serum magnesium concentrations have been associated with a decreased incidence of hypoxic brain damage.3,4 Neuroprotection is the inhibition of the biochemical response to ischemia in order to prevent neuronal death. However, the biochemical cascade during ischemia originates from insufficiency and failure of the microcirculation. Thus, preservation of the microvasculature would lead to neuroprotection.5 MgSO4 has been shown to have beneficial hemodynamic effects by stabilizing the blood pressure, reducing the constriction in cerebral arteries and restoring the perfusion in preterm neonates.6–8 Cerebral blood flow (CBF) velocities have been validated as a reliable indicator of CBF, and changes in CBF are assumed to have a key role in the development of various cerebral lesions in preterm infants.9,10 In this study, our aim was to investigate the effects of antenatal MgSO4 on CBF velocities in preterm neonates.
maternal MgSO4 treatment antenatally (MgSO4 group) and 33 were not (control group). Neonates without antenatal Doppler examination and with absent/ reversed end diastolic velocity in umbilical artery were excluded from the study. Neonates with clinical conditions such as congenital malformation, chromosomal anomaly, perinatal asphyxia, sepsis, premature rupture of membranes, choriamnionitis, polycythemia (Hb422 g dl 1), anemia (Hbo10 g dl 1) and whose mothers had multiple pregnancies were not included in the study (delayed cord clamping was not performed in any case during delivery). Gestational age was calculated from the beginning of the last menstrual period of the mother and verified using early trimester ultrasonographic data. Neonates with uncertain gestational age were excluded. Twenty mothers had received an intravenous infusion of MgSO4 either for preeclampsia (n ¼ 14) or tocolysis (n ¼ 6). A loading dose of 6 g was infused over 30 min and was followed by a maintenance infusion of 0.8 g h 1 until the time of delivery according to our institution protocol. Mothers having ritodrine for tocolysis were excluded from the study. Maternal serum magnesium concentration just before labour was recruited from the maternal records. Atomic absorption spectrophotometry (Cobas Integra 800, Roche, Basel, Switzerland) was used to determine serum magnesium levels in the maternal and umbilical cord blood. Maternal cumulative MgSO4 dose and total infusion time (hours) were calculated. The control group consisted of neonates born immediately after reaching the hospital or whose mothers did not receive any MgSO4 or tocolytic treatments but fulfilled the abovementioned enrollment criteria. Informed consent was obtained from the parents, and study protocol and consent forms were approved by local ethics committee. Blood pressure was determined as an average of three measurements made from the right upper arm before Doppler examination.
METHODS In this prospective case–control study, we included a total of 53 neonates between 26 and 34 weeks of gestation born at the Zeynep Kamil Maternity and Children’s Training and Research Hospital, Istanbul, Turkey, between December 2011 and December 2012. Twenty neonates were exposed to
Doppler ultrasonography measurements During measurements, neonates were in a resting state and lying in a supine position.11–13 Environmental light intensity was low and constant. Phototherapy was suspended during measurements. To avoid crying
Zeynep Kamil Maternity and Children’s Training and Research Hospital, Neonatal Intensive Care Unit Istanbul, Istanbul, Turkey. Correspondence: Dr EY Imamoglu, Zeynep Kamil Kadın ve Çocuk Hastalıkları Eg˘itim ve Aras¸tırma Hastanesi Opr., Dr Burhanettin U¨stu¨nel Cad. No:10, U¨sku¨dar, ˙Istanbul 34668, Turkey. E-mail: [email protected] Received 26 September 2013; revised 15 November 2013; accepted 4 December 2013; published online 30 January 2014
Mg and CBF velocities EY Imamoglu et al
193 episodes and stress conditions, gentle handling consisting of administration of oral dextrose drops in order to pacify the baby when needed, stimulation of non-nutritional sucking, delicate touching and calm voice tones was applied.10 The measurements have been made before the administration of daily caffeine dose.14 Neonates who suffered from hypotension, exposed to drug therapies that could change CBF velocity or arterial blood pressure and any metabolic pathology were excluded from the study.15–19 Flow imaging and blood flow velocity were obtained with a color Doppler unit (Philips En Visor C, Amsterdam, The Netherlands) and a multifrequency 5-12 MHz sector probe was used. In order to eliminate interobserver variability, serial pulse-wave Doppler ultrasound measurements were made by the same experienced neonatologist (EI), blinded to the group assignment of the neonate. Measurements of mean velocity have been made in the left and right middle cerebral artery (MCA) on day 1, 2, 3, 4 and 5 of life. All measurements were performed after the first 8-12 h of life in order to reduce the possible effects of immediate postnatal cardiovascular adaptation on flowmetric data. Doppler flow measurements of MCA were performed by scanning through the anterolateral fontanelle (temporal window). The transducer is placed above the ear, B1 cm superior and anterior to the external auditory meatus, posterior to the orbit and zygomatic arch, with the marker in a horizontal position.20,21 With the transducer angled slightly inferiorly, it overlays the appropriate window for visualizing the midbrain, defined by the characteristic contour of the cerebral peduncles anteriorly.21 The color gain was set to maximize vascular signal and minimize tissue motion artifacts. The transducer position was subsequently adjusted until visualization of the red MCA flow. The angle between the ultrasound beam and the direction of blood flow was kept below 151.22 To maintain accuracy, a minimum of five sequential homogenous cardiac cycles of optimal quality were subjected to real-time spectral analysis. MCA mean flow velocity was obtained by integrating the area under the velocity curve over one cardiac cycle.10 A minimum of three measurements were obtained and then averaged. MCA mean velocity served as a surrogate for CBF.23–25 Examination time was B5 min. Along with the Doppler studies, cranial ultrasonography was performed in all cases. The grade of intraventricular hemorrhage was reported according to the criteria of Papile et al.26 The shunt across the patent ductus arteriosus (PDA) was evaluated from a high parasternal/suprasternal view by the same investigator (TG) experienced in echocardiography.27 Moreover, the presence of respiratory distress syndrome, phototherapy, caffeine, ibuprofen and inotrope use were recorded.
Statistical analysis Statistical analysis was performed by using SPSS software version 20.0 (IBM Statistics, IBM, Somers, NY). The variables were investigated using visual histograms, probability plots and Shapiro–Wilk’s test to determine whether or not they are normally distributed. Descriptive analyses were presented using means±s.d. for normally distributed variables, as medians (25–75%) for the non-normally distributed variables and as percentages for categorical variables. Normally distributed variables were compared by Student’s t-test, nonparametric variables by Mann–Whitney’s U-test and categorical variables by w2-test. Friedman tests were conducted to test whether there is significant change in MCA velocities in the consecutive days. Correlation between maternal and cord blood magnesium levels was evaluated by using Spearman’s correlation coefficient. Intraobserver variability was assessed in an arbitrary sample of 20 neonates. The measurements were repeated by the same investigator who was blinded to the previous results. The coefficient of variation was calculated in order to show intraobserver variability.
Demographic characteristics, hemodynamic and clinical variables of the neonates are shown in Table 1. There was no significant difference between the groups. All attempts to obtain MCA mean velocities were successful. As the changes of the hemodynamic variables in the left and right MCA were similar and correlated significantly, only the data of the left MCA were presented. Significantly increased MCA mean velocities were found in the MgSO4 group compared with that in the control group (Table 2). Figure 1 shows the progressive increase in serial Doppler measurements of MCA mean velocity from day 1 to day 5 of life in both groups (Po0.001 in the control group and P ¼ 0.027 in the MgSO4 group). There was no correlation between cord blood Mg levels and MCA Doppler velocities in both groups (MgSO4 group: r ¼ 0.25, P ¼ 0.29; control group: r ¼ 0.16, P ¼ 0.39). There was no difference between the two groups in terms of the presence of ductal patency during serial daily measurements and ibuprofen use.
Table 1. Demographic characteristics, hemodynamic and clinical variables of the preterm neonates involved in the study
Maternal age (years) Gestational age (weeks) Birth weight (g)
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Control group (n ¼ 33)
P-values
28±3.9 32±1.6 1497±347
28±5.1 31.1±2 1533±299
0.47 0.13 0.67
9 (45) 11 (55)
13 (40) 20 (60)
0.68
Gender (n) Males (%) Females (%) SGA 5 min APGAR score Cesarean section Heart rate (bpm) Mean arterial pressure (mm Hg) RDS PDA IVH Caffeine therapy Ibuprofen Inotrope use Phototherapy
6 (30%) 9 (8.2–9) 18 (90%) 148±13.5 49.4±9.8 6 8 3 6 3 1 16
(30%) (40%) (15%) (30%) (15%) (5%) (80%)
3 (9.1%) 9 (8–9) 27 (81.8%) 149±15.4 45.4±6.6 11 15 2 11 6 2 27
(33.3%) (45.5%) (6%) (33.3%) (18.2%) (6.1%) (81%)
0.07 0.62 0.42 0.95 0.11 0.8 0.7 0.52 0.8 0.54 0.87 0.9
Abbreviations: IVH, intraventricular hemorrhage; MgSO4, magnesium sulfate; PDA, patent ductus arteriosus; RDS, respiratory distress syndrome; SGA, small for gestatioal age. Values are presented as mean±s.d. for maternal age, gestational age, birth weight, heart rate, mean arterial pressure. Five-minute APGAR score is presented as median (25–75%).
Table 2. Serial Doppler measurements of MCA-MV from day 1 to day 5 of life in two groups of preterm infants who were or were not exposed to antenatal magnesium sulfate MCA-MV (cm s 1)
RESULTS Twenty neonates constituted the MgSO4 group and 33 neonates constituted the control group. MgSO4 was administered for treatment of preeclampsia in 14 cases and for tocolysis in 6 cases. Median total dose of MgSO4 given to the mother before labour was 34.2 (12.5–54.4) g. Median total infusion time was 15 (3.8–26) h. Median serum magnesium levels in maternal and cord blood were 5.5 (4.6–6.5) and 3.5 (3.1–4) mg dl 1, respectively. Maternal serum magnesium levels were correlated with cord blood magnesium levels of the neonates (r ¼ 0.62, P ¼ 0.004).
MgSO4 group (n ¼ 20)
Day Day Day Day Day
1 2 3 4 5
MgSO4 group 21.2 22.1 24.8 23.2 27.7
(16.4–22.4) (15.9–28.2) (18.2–30.7) (21.5–29.4) (21.1–31.5)
Control group 15.8 17.8 18.1 20.3 22.2
(13–18.5) (14.3–20.3) (16.3–23.3) (17.2–25.2) (18–28)
P-values 0.001a 0.014a 0.005a 0.004a 0.022a
Abbreviations: MCA-MV, middle cerebral artery mean velocity; MgSO4, magnesium sulfate. a Significant difference between two groups, values are presented as median (25–75%).
Journal of Perinatology (2014), 192 – 196
Mg and CBF velocities EY Imamoglu et al
194
Figure 1. Serial Doppler measurements of middle cerebral artery mean velocities from day 1 to day 5 of life in both groups. Solid line presents the control group and dotted line presents the magnesium sulfate group.
Intraobserver error was minimal (2%) and there was no significant difference between consecutive measurements. DISCUSSION In the cerebrovascular bed, increased magnesium ion concentration was shown to reduce the contractile responses of isolated cerebral arteries resulting in vasodilatation.28–31 MgSO4 treatment has also vasodilatory effects on both cerebral circulation and systemic arteries.32–34 Belfort et al.34 investigated the effect of MgSO4 on the cerebral circulation in patients with pregnancyinduced hypertension and showed a significant increase in mean velocity in the maternal MCA in response to intravenous MgSO4 that was interpreted as distal artery vasodilatation. Less is known about antenatal effects of MgSO4 on the fetus and newborn circulatory systems. In late-term goat fetuses, direct infusion of MgSO4 increases the brain blood flow during acute hypoxemia.35 However, there are limited studies investigating the effects of antenatal MgSO4 on neonatal circulation. In neonates, elevated levels of MgSO4 may persist for up to 7 days, with an elimination half life of 43.2 h.36 Therefore, we aimed to investigate whether there was any change in MCA mean velocities or not with serial daily Doppler measurements. To our knowledge, this is the first study in the literature performing serial daily Doppler measurements of MCA in preterm neonates exposed to antenatal MgSO4. We did not measure CBF, but assessed its surrogate MCA mean velocity. Although MCA mean velocity correlates well with CBF, we cannot exclude the possibility that changes in MCA diameter affected velocity without affecting flow, which was a limitation of this study.23–25 Absent and reversed end diastolic velocities in Doppler examination of umbilical artery are late vascular responses in growth-restricted fetus.37 These late Doppler findings result from altered forward cardiac function and abnormal organ autoregulation, generally signifying the onset of compromise and redistribution in organ blood flows.38 For this reason, we did not include the neonates having these abnormal Doppler findings in our study. Journal of Perinatology (2014), 192 – 196
Pezzati et al.39 obtained normal standards of CBF velocity in healthy preterm and term infants relating to the first hours of life, a period in which the flowmetric modifications could be influenced in a significant manner by postnatal adaptation.10 Thus, we performed our Doppler measurements after the 8-12 h of life. In another study evaluating the effect of antenatal tocolytic administration of MgSO4 and ritodrine on CBF velocity in preterm neonates by Pezzati et al.40, they measured CBF velocities in the anterior cerebral artery, right and left MCA in the first hours of life (2–8 h) and did not find any significant difference in blood flow velocities in the three cerebral arteries between the two treatment groups. They made a comparison in between the MgSO4 and ritodrine groups; however, they did not have any control group in which no tocolytic medication was used. This was a major limitation of their study, as ritodrine as a tocolytic agent may affect CBF velocities.10 Besides, their measurements of CBF velocities were lower than those in our both the MgSO4 and the control group, which may be explained by the time of their measurements as they had made the measurements in the first 2–8 h, which was early when compared with our study. On the other hand, Rantonen et al.41 performed serial Doppler examinations of anterior cerebral artery and internal carotid artery at the mean ages of 6, 12, 24, 36, 48, 72 and 96 h and 1 week in preterm neonates exposed to antenatal MgSO4 (n ¼ 19), ritodrine treatment (n ¼ 17) and in 19 nonexposed preterm controls. They found that maternal MgSO4 had no significant effect on blood flow velocities in the neonatal cerebral vessels. As MCA mean velocity is a surrogate for CBF, we preferred to perform our measurements on MCA in order to evaluate CBF.22 In contrast to the study of Rantonen et al.,41 we found increased MCA mean velocities in the MgSO4 group when compared with control group from day 1 to day 5 of life. However, they did not give the actual results of CBF velocities, instead they gave the cerebral perfusion pressure and blood flow indices, which were calculated values that also included the blood pressure values in the equation. Hence, we could not compare our results with theirs. Romagloni et al.10 provided normal reference values of CBF velocities in healthy preterm infants in the first month of life (day 1, 3, 7, 14, 21 and 28). MCA mean velocities of our control group were found similar to those reference values. They also showed the existence of a progressive increase of systolic, diastolic and mean flow velocities in the anterior cerebral artery and MCA as the postnatal age increases, such as that observed in our study population in both the MgSO4 and the control groups, and related this progressive increase in CBF velocities to the progressive opening of cerebral vascular bed associated with a reduction of microcirculation resistances. Theoretically, vasodilators should be able to increase blood flow via a change in vessel diameter at the entrance of microcirculation.42 In addition to vasodilatory effects, infusion of MgSO4 is also associated with other potential promicrocirculatory effects, such as an increase in red blood cell deformability, reduction of platelet aggregation, anti-inflammatory effects and maintenance of endothelial integrity.43–46 Through all these mechanisms, MgSO4 could facilitate the decrease in microcirculation resistances in the cerebrovascular bed and improve microvascular perfusion, and this may explain the increase in MCA flow velocities observed in our study. Shokry et al.47 studied 48 preterm neonates divided into two groups based on maternal exposure to MgSO4 (n ¼ 28) or not (n ¼ 20), and performed CBF velocity measurements on anterior cerebral artery and MCA. They found significantly lower peak systolic, mean and end diastolic velocities in these cerebral arteries, and also a significantly higher incidence of PDA in the MgSO4 group. They concluded that magnesium relaxed ductal muscles with resultant ductal patency and decreased cerebral perfusion was associated with an increased incidence of PDA. In our study, contrary to their study, PDA incidence was similar in both groups. On the other hand, Elimian et al.48 studied 190 & 2014 Nature America, Inc.
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195 neonates exposed to MgSO4 and 211 neonates not exposed to MgSO4. Similar to our results, they found no difference between groups with regard to the rates of PDA. Effects of ibuprofen on MCA Doppler measurements were not evaluated. This was a limitation of our study. There are several studies reporting that maternal administration of MgSO4 was associated with a reduced risk of intraventricular hemorrhage in infants.4,49 In our study, we did not find any significant difference in terms of intraventricular hemorrhage between the two groups. Morover, similar to our results, Crowther et al.50 did not find any effect of MgSO4 on the rate of intraventricular hemorrhage, and they speculated that any neuroprotective effect of MgSO4 on motor dysfunction might work through stabilization of CBF and ameliorating the effects of ischemic episodes, which might be explained by increased CBF. In conclusion, this is the first study in the literature highlighting the increase in MCA mean velocities in preterm neonates receiving antenatal MgSO4. This increment in CBF velocities might explain the protective role of MgSO4 in ischemic events and hypoxic brain damage. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS We express our gratitude to the families who gave us permission to evaluate their babies.
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