- Email: [email protected]
Effect of tocolytic agents on fetal umbilical velocimetry
Effect of tocolytic agents on fetal umbilical velocimetry Jeffrey W. Wright, MD, Robert M. Patterson, MD, Louis E. Ridgway III, MD, and Michael D. Berkus, MD San Antonio, Texas In this prospective study, we sought to examine the changes in umbilical vascular resistance induced by tocolytic therapy. Umbilical artery velocimetry was performed in 46 patients with preterm labor before tocolysis and at 1 hour and 24 hours after tocolysis was initiated. Raw systolic/diastolic ratios were corrected for concomitant changes in fetal heart rate. Thirty patients received subcutaneous terbutaline and 16 were treated with intravenous magnesium. Systolic/diastolic ratios decreased in patients treated with terbutaline. This decline perSisted after correction for increases in fetal heart rate. No significant changes in systolic/diastolic ratios were seen in patients treated with magnesium. We conclude that terbutaline may affect umbilical vascular resistance. Possible clinical implications of these findings are discussed. (AM J OasTET GVNECOL 1990;163:748-50.)
Key words: Tocolytic, Doppler, umbilical velocimetry, terbutaline, magnesium
I3-Sympathomimetic tocolytic drugs have profound effects on the maternal and fetal cardiovascular systems. Beta receptors are known to be present in the umbilical and uterine vasculature l and 13sympathomimetic tocolytics are known to cross the placenta. 2 It is possible that the vasodilatory action of 13sympathomimetics may affect vascular resistance in the umbilical circuit. The recent development of fetal Doppler studies provides a noninvasive means of assessing umbilical vascular resistance. Brar et al. 3 used Doppler velocimetry to demonstrate a decline in umbilical vascular resistance in patients treated with ritodrine. However, these authors believed that increases in fetal heart rate may have confounded these results. The purpose of this study was to assess the effect of terbutaline on umbilical vascular resistance as measured by systolic/ diastolic ratio while controlling for the effect of an increase in fetal heart rate.
Material and methods In this prospective study 46 patients who were seen in the labor and delivery suite with preterm labor were enrolled. Preterm labor was defined as gestational age between 25 and 34 weeks, and uterine contractions persisting after hydration, with cervical change. Patients with ruptured membranes, fetal congenital anomalies,
From the Department of Obstetrics and Gynecology, The University of Texas Health Science Center at San Antonio. Presented at the Tenth Annual Meeting of the Society of Perinatal Obstetricians, Houston, Texas, january 23-27,1990. Reprint requests: jeffrey W. Wright, MD, Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78284-7836. 616122343
748
previous tocolytic therapy, or complications associated with utero placental insufficiency were excluded. The choice of tocolytic agent was made by the individual patient's physician. Thirty patients received terbutaline subcutaneously 0.25 mg every hour for 3 doses, every 3 hours for 8 doses, then 2.5 to 5 mg orally every 3 to 6 hours. Magnesium sulfate was given intravenously as a 4 gm loading dose followed by 2 to 3 gm/hr by infusion pump. After 8 to 12 hours of successful tocolysis with magnesium sulfate, patients were switched to oral magnesium oxide therapy, 200 to 400 mg every 4 hours. A continuous-wave Doppler velocimeter (Angioscan III, Ultrasonix, Inc. North Yonkers, N.Y.) with a 4 MHz transducer was used to obtain all systolic/ diastolic ratios. Patients were examined in the recumbent position with 15 to 30 degrees of lateral uterine displacement. Readings were taken between contractions in the absence of fetal breathing or fetal body movement. All studies were performed by one of the authors. The Doppler probe was positioned on the abdomen to obtain the best quality umbilical artery signals as recognized by the characteristic waveform and umbilical vein flow in the opposite direction. Peak systolic and lowest diastolic frequency shifts were measured with electronic calipers. Systolic/diastolic ratios were then calculated with five waveforms averaged to obtain each reading. Fetal heart rates were calculated by measuring the distance between waveform peaks with electronic calipers. Six patients in each group were initially studied before tocolysis was initiated, then at 30 minutes, 1 hour, 2 hours, 4 hours, 8 h~urs, 12 hours, 24 hours, and 48 hours after tocolysis was begun. This was done to estimate appropriate time intervals for study. On the basis of these preliminary results we studied the remaining
Effect of tocolytic agents on fetal umbilical velocimetry
Volume 163 Number 3
749
Table I. Raw umbilical artery systolic/diastolic ratios Baseline
Terbutaline Mean ± SD Magnesium Mean ± SD Between groups
n = 30 3.13 ± 0.80* n = 16 2.91 ± 0.66 p = NS
1 hr n = 30 2.73 ± 0.56*t n = 16 3.04 ± 0.53 P = 0.03
24 hr
n = 26 2.47 ± 0.48t n = 16 2.85 ± 0.51 P = 0.004
Time effect
P < 0.001 P = NS
*P = 0.004. tp = 0.04. Table II. Fetal heart rates Baseline
Terbutaline Mean ± SD Magnesium Mean ± SD Between groups
n = 30 136 ± 10.1* n = 16 140 ± 13.3 p = NS
1 hr n = 30 140 ± 11.7*t n = 16 136 ± ll.5 P = NS
24 hr
n = 26 144 ± 9.9t n = 16 136 ± 10.2 P < 0.001
Time effect
p < 0.001 P = NS
*p = NS. tp =
om.
Table III. Corrected umbilical artery systolic! diastolic ratios Baseline
Terbutaline Mean ± SD Magnesium Mean ± SD Between groups
*p
=
tp
=
n = 30 3.07 ± 0.79* n = 16 2.92 ± 0.57 P = NS
1 hr
n 2.73 n 2.98
=
30
± 0.51*t
16 ± 0.50 P = 0.05 =
24 hr
n 2.54 n 2.80
=
26
± 0.45t
16 ± 0.50 P < 0.05 =
Time effect
p < 0.001 P = NS
0.009. NS.
patients before tocolysis and at 1 hour and 24 hours after tocolysis was initiated. Systolic/ diastolic ratio data were analyzed in both raw form and after correction for fetal heart rate according to the method suggested by Mires et a\.4 For these systolic! diastolic ratio data and for fetal heart rate, analysis of variance for repeated measures was used to assess the effects of group and time. Duncan's new multiple range test was then performed for differences between individual means. The Statistical Analysis Systems statistical package was used for all analyses.
Results Thirty patients received terbutaline and 16 received magnesium. The average gestational age was 30.8 ± 2.6 weeks and did not differ between groups. Four patients in the terbutaline group failed tocolysis after 1 hour. Thus 26 patients in the terbutaline group were examined at 24 hours. All patients in the magnesium group had labor successfully arrested for at least 24 hours. Patients treated with terbutaline demonstrated a significant decrease in systolic/diastolic ratios (p < 0.001) (Table I). The majority of the decline in systolic!dia-
stolic ratio occurred within 1 hour after the first dose of terbutaline. These differences were significant between baseline and I-hour measurements, as well as between I-hour and 24-hour measurements. The terbutaline group also exhibited a concomitant increase in fetal heart rate (p < 0.001) (Table II). The overall decline in systolic! diastolic ratio was still significant after correction for changes in fetal heart rate (Table III); however, the difference between the I-hour and 24hour measurements was no longer significant. The magnesium group exhibited no change in systolic/diastolic ratios (Tables I and III) or fetal heart rate (Table II). There were significant differences between the two groups for both raw and corrected systolic/diastolic ratios at 1 hour and 24 hours.
Comment Our study shows a decline in umbilical artery systolic/ diastolic ratios associated with use of terbutaline. This decline persisted after correction for fetal heart rate, which is the major known confounding variable. We found no similar change in the systolic! diastolic ratios of fetuses exposed to magnesium. Brar et a\. 3 recently found a significant decrease in
750
Wright et al.
the uterine and umbilical artery systolic/ diastolic ratios in patients treated with ritodrine for preterm labor. There was also a concomitant increase in the maternal and fetal heart rates, which the authors thought might have changed the systolic! diastolic ratios. They found no change in systolic/diastolic ratios or heart rates in patients treated with magnesium sulfate. In our study we corrected for the effects of fetal heart rate changes and confirmed that this decline in umbilical artery systolic/ diastolic ratio is present in patients exposed to ~ sympathomimetic. Many patients and fetuses are exposed to tocolytic agents during pregnancy. Maternal side effects from these agents are well known and are sometimes serious. Conversely, fetal effects are less often considered. ~ Sympathomimetic tocolytics have been associated with fetal cardiac dysrythmia, heart failure, myocardial ischemia, ventricular septal hypertrophy, and neonatal death. 5 The possibility that ~-sympathomimetic agents may affect fetal vascular resistance is physiologically sound. This study and that of Brar et aI.' offer scientific data as confirmation. It may seem that vasodilation should promote better blood flow and oxygen delivery. How-
September 1990 Am J Obstet Gynecol
ever, Parisi and Walsh 6 have shown that vasodilation in the fetus may actually decrease placental blood flow by shunting blood to other vascular beds. It is possible that a decrease in vascular resistance caused by ~ sympathomimetic tocolytics could be harmful to the fetus. Additionally, consideration also should be given to a patient's current drug therapy when interpreting diagnostic umbilical velocimetry measurements. REFERENCES 1. Greiss FC ]r, Pick]R]r. The uterine vascular bed: adrenergic receptors. Obstet Gynecol 1964;23:209-13. 2. Gross T], Kuhnert BR, Kuhnan PM, et al. Maternal and fetal plasma concentration of ritodrine. Obstet Gynecol 1985;65:793-7. 3. Brar HS, Medearis AL, DeVore GR, Platt LD. Maternal and fetal blood flow velocity waveforms in patients with preterm labor: effects of tocolytics. Obstet Gynecol 1988; 72:209-14. 4. Mires G, Dempster], Patel NB, Crawford ]W. The effect of fetal heart rate on umbilical artery flow velocity waveforms. Br] Obstet Gynaecol 1987;94:665-9. 5. Katz VL, Seeds ]W. Fetal and neonatal cardiovascular complications from l3-sympathomimetic therapy for tocolysis. AM] OBSTET GVNECOL 1989;161:1-4. 6. Parisi VM, Walsh SW. Fetoplacental vascular responses to prostacyclin after thromboxane-induced vasoconstriction. AM] OBSTET GVNECOL 1989;160:502-7.
Key words: Tocolytic, Doppler, umbilical velocimetry, terbutaline, magnesium
I3-Sympathomimetic tocolytic drugs have profound effects on the maternal and fetal cardiovascular systems. Beta receptors are known to be present in the umbilical and uterine vasculature l and 13sympathomimetic tocolytics are known to cross the placenta. 2 It is possible that the vasodilatory action of 13sympathomimetics may affect vascular resistance in the umbilical circuit. The recent development of fetal Doppler studies provides a noninvasive means of assessing umbilical vascular resistance. Brar et al. 3 used Doppler velocimetry to demonstrate a decline in umbilical vascular resistance in patients treated with ritodrine. However, these authors believed that increases in fetal heart rate may have confounded these results. The purpose of this study was to assess the effect of terbutaline on umbilical vascular resistance as measured by systolic/ diastolic ratio while controlling for the effect of an increase in fetal heart rate.
Material and methods In this prospective study 46 patients who were seen in the labor and delivery suite with preterm labor were enrolled. Preterm labor was defined as gestational age between 25 and 34 weeks, and uterine contractions persisting after hydration, with cervical change. Patients with ruptured membranes, fetal congenital anomalies,
From the Department of Obstetrics and Gynecology, The University of Texas Health Science Center at San Antonio. Presented at the Tenth Annual Meeting of the Society of Perinatal Obstetricians, Houston, Texas, january 23-27,1990. Reprint requests: jeffrey W. Wright, MD, Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78284-7836. 616122343
748
previous tocolytic therapy, or complications associated with utero placental insufficiency were excluded. The choice of tocolytic agent was made by the individual patient's physician. Thirty patients received terbutaline subcutaneously 0.25 mg every hour for 3 doses, every 3 hours for 8 doses, then 2.5 to 5 mg orally every 3 to 6 hours. Magnesium sulfate was given intravenously as a 4 gm loading dose followed by 2 to 3 gm/hr by infusion pump. After 8 to 12 hours of successful tocolysis with magnesium sulfate, patients were switched to oral magnesium oxide therapy, 200 to 400 mg every 4 hours. A continuous-wave Doppler velocimeter (Angioscan III, Ultrasonix, Inc. North Yonkers, N.Y.) with a 4 MHz transducer was used to obtain all systolic/ diastolic ratios. Patients were examined in the recumbent position with 15 to 30 degrees of lateral uterine displacement. Readings were taken between contractions in the absence of fetal breathing or fetal body movement. All studies were performed by one of the authors. The Doppler probe was positioned on the abdomen to obtain the best quality umbilical artery signals as recognized by the characteristic waveform and umbilical vein flow in the opposite direction. Peak systolic and lowest diastolic frequency shifts were measured with electronic calipers. Systolic/diastolic ratios were then calculated with five waveforms averaged to obtain each reading. Fetal heart rates were calculated by measuring the distance between waveform peaks with electronic calipers. Six patients in each group were initially studied before tocolysis was initiated, then at 30 minutes, 1 hour, 2 hours, 4 hours, 8 h~urs, 12 hours, 24 hours, and 48 hours after tocolysis was begun. This was done to estimate appropriate time intervals for study. On the basis of these preliminary results we studied the remaining
Effect of tocolytic agents on fetal umbilical velocimetry
Volume 163 Number 3
749
Table I. Raw umbilical artery systolic/diastolic ratios Baseline
Terbutaline Mean ± SD Magnesium Mean ± SD Between groups
n = 30 3.13 ± 0.80* n = 16 2.91 ± 0.66 p = NS
1 hr n = 30 2.73 ± 0.56*t n = 16 3.04 ± 0.53 P = 0.03
24 hr
n = 26 2.47 ± 0.48t n = 16 2.85 ± 0.51 P = 0.004
Time effect
P < 0.001 P = NS
*P = 0.004. tp = 0.04. Table II. Fetal heart rates Baseline
Terbutaline Mean ± SD Magnesium Mean ± SD Between groups
n = 30 136 ± 10.1* n = 16 140 ± 13.3 p = NS
1 hr n = 30 140 ± 11.7*t n = 16 136 ± ll.5 P = NS
24 hr
n = 26 144 ± 9.9t n = 16 136 ± 10.2 P < 0.001
Time effect
p < 0.001 P = NS
*p = NS. tp =
om.
Table III. Corrected umbilical artery systolic! diastolic ratios Baseline
Terbutaline Mean ± SD Magnesium Mean ± SD Between groups
*p
=
tp
=
n = 30 3.07 ± 0.79* n = 16 2.92 ± 0.57 P = NS
1 hr
n 2.73 n 2.98
=
30
± 0.51*t
16 ± 0.50 P = 0.05 =
24 hr
n 2.54 n 2.80
=
26
± 0.45t
16 ± 0.50 P < 0.05 =
Time effect
p < 0.001 P = NS
0.009. NS.
patients before tocolysis and at 1 hour and 24 hours after tocolysis was initiated. Systolic/ diastolic ratio data were analyzed in both raw form and after correction for fetal heart rate according to the method suggested by Mires et a\.4 For these systolic! diastolic ratio data and for fetal heart rate, analysis of variance for repeated measures was used to assess the effects of group and time. Duncan's new multiple range test was then performed for differences between individual means. The Statistical Analysis Systems statistical package was used for all analyses.
Results Thirty patients received terbutaline and 16 received magnesium. The average gestational age was 30.8 ± 2.6 weeks and did not differ between groups. Four patients in the terbutaline group failed tocolysis after 1 hour. Thus 26 patients in the terbutaline group were examined at 24 hours. All patients in the magnesium group had labor successfully arrested for at least 24 hours. Patients treated with terbutaline demonstrated a significant decrease in systolic/diastolic ratios (p < 0.001) (Table I). The majority of the decline in systolic!dia-
stolic ratio occurred within 1 hour after the first dose of terbutaline. These differences were significant between baseline and I-hour measurements, as well as between I-hour and 24-hour measurements. The terbutaline group also exhibited a concomitant increase in fetal heart rate (p < 0.001) (Table II). The overall decline in systolic! diastolic ratio was still significant after correction for changes in fetal heart rate (Table III); however, the difference between the I-hour and 24hour measurements was no longer significant. The magnesium group exhibited no change in systolic/diastolic ratios (Tables I and III) or fetal heart rate (Table II). There were significant differences between the two groups for both raw and corrected systolic/diastolic ratios at 1 hour and 24 hours.
Comment Our study shows a decline in umbilical artery systolic/ diastolic ratios associated with use of terbutaline. This decline persisted after correction for fetal heart rate, which is the major known confounding variable. We found no similar change in the systolic! diastolic ratios of fetuses exposed to magnesium. Brar et a\. 3 recently found a significant decrease in
750
Wright et al.
the uterine and umbilical artery systolic/ diastolic ratios in patients treated with ritodrine for preterm labor. There was also a concomitant increase in the maternal and fetal heart rates, which the authors thought might have changed the systolic! diastolic ratios. They found no change in systolic/diastolic ratios or heart rates in patients treated with magnesium sulfate. In our study we corrected for the effects of fetal heart rate changes and confirmed that this decline in umbilical artery systolic/ diastolic ratio is present in patients exposed to ~ sympathomimetic. Many patients and fetuses are exposed to tocolytic agents during pregnancy. Maternal side effects from these agents are well known and are sometimes serious. Conversely, fetal effects are less often considered. ~ Sympathomimetic tocolytics have been associated with fetal cardiac dysrythmia, heart failure, myocardial ischemia, ventricular septal hypertrophy, and neonatal death. 5 The possibility that ~-sympathomimetic agents may affect fetal vascular resistance is physiologically sound. This study and that of Brar et aI.' offer scientific data as confirmation. It may seem that vasodilation should promote better blood flow and oxygen delivery. How-
September 1990 Am J Obstet Gynecol
ever, Parisi and Walsh 6 have shown that vasodilation in the fetus may actually decrease placental blood flow by shunting blood to other vascular beds. It is possible that a decrease in vascular resistance caused by ~ sympathomimetic tocolytics could be harmful to the fetus. Additionally, consideration also should be given to a patient's current drug therapy when interpreting diagnostic umbilical velocimetry measurements. REFERENCES 1. Greiss FC ]r, Pick]R]r. The uterine vascular bed: adrenergic receptors. Obstet Gynecol 1964;23:209-13. 2. Gross T], Kuhnert BR, Kuhnan PM, et al. Maternal and fetal plasma concentration of ritodrine. Obstet Gynecol 1985;65:793-7. 3. Brar HS, Medearis AL, DeVore GR, Platt LD. Maternal and fetal blood flow velocity waveforms in patients with preterm labor: effects of tocolytics. Obstet Gynecol 1988; 72:209-14. 4. Mires G, Dempster], Patel NB, Crawford ]W. The effect of fetal heart rate on umbilical artery flow velocity waveforms. Br] Obstet Gynaecol 1987;94:665-9. 5. Katz VL, Seeds ]W. Fetal and neonatal cardiovascular complications from l3-sympathomimetic therapy for tocolysis. AM] OBSTET GVNECOL 1989;161:1-4. 6. Parisi VM, Walsh SW. Fetoplacental vascular responses to prostacyclin after thromboxane-induced vasoconstriction. AM] OBSTET GVNECOL 1989;160:502-7.