European Journal of Obstetrics & Gynecology and Reproductive Biology, 46 (1992) 7-10 0 1992 Elsevier Science Publishers B.V. All rights reserved 0028-2243/92/$05.00
EUROBS 01357
Short-term effects of ritodrine, aminophylline and atropine on umbilical artery blood flow velocity waveform E.V. Cosmi a, G. Luzi b, P. Fusaro a, G. Caserta a and G.C. Di Renzo a ’ 2nd Institute of Gynecology and Obstetrics, University ‘La Sapienza’, Rome and b Institute of Gynecology and Obstetrics, University of Pen&a, Perugia, Italy
Accepted for publication 24 January 1992
Summary With the recent introduction of Doppler technology, a non-invasive methodology which enables to evaluate qualitative changes in circulatory vessels, it is possible to investigate the possible effects of various drugs on several parameters of utero-placental-fetal circulation. In the present study we evaluate the flow velocity waveform (FW) of umbilical artery (UA) during and after administration of aminophylline, atropine and ritodrine to healthy pregnant women. In our study we did not observe any significant short-term variation of PI after the administration of these drugs. Slight variations were detected, and they may be interpreted on the basis of the mode of action of these drugs. Doppler technology may be a useful tool for monitoring some effects on the fetus of the maternal administration of therapeutic agents. Ritodrine; Aminophylline; Atropine; Umbilical artery; Blood flow velocity
Introduction The effects of drugs on the feto-placental circulation have been mainly evaluated in animals, and results translated to humans [l]. With the recent introduction of Doppler technology, a non-invasive methodology which enables evaluation of qualitative changes in circulatory vessels [2], it is possible to investigate the possible effects of various drugs on several parameters of the utero-placental-fetal circulation.
Correspondence to: Gian Carlo Di Renzo, M.D., Ph.D., Institute of Gynecology and Obstetrics, University of Perugia, Policlinico Monteluce, 06100 Perugia, Italy.
In the present study we evaluate the flow velocity waveform (FW) of the umbilical artery (UA) during and after administration of aminophylline, atropine and ritodrine to the pregnant women. In obstetrics, aminophylline (A> is utilized mainly for tocolysis; this methylxanthine derivative inhibits the action of phosphodiesterase, thereby causing an accumulation of intracellular cyclic adenosine 3,5monophosphate (AMP) which is supposed to be the main mechanism by which contractions are inhibited [3]. This drug is reported to increase the heart rate and to induce periferic vasodilation in pregnant women 141. Atropine (AT) is a cholinergic postganglion blocking agent used usually during the induction
8
of general anaesthesia in obstetric care. It is a tertiary amine and crosses the placenta and the blood-brain barrier in the fetus [5]. Potential side effects include fetal bradycardia by central effect following fetal tachycardia by vagolitic effect. AT has been proposed also as a test in cardiotocography bl. Ritodrine (R) is one of the most utilized betamimetic agents for inhibition of preterm contractions [6]. It is known that ritodrine and its inactive metabolites cross the placenta, but only 20% of their maternal blood levels are found in cord blood [6]. The cardiovascular effects of the drug are dose-related; intravenous infusion of R increases both the maternal and fetal heart rates with about 20-40 and l-9 beats per minute, respectively [7,8]. It is proposed that the p-adrenergic stimulation produced by R results in an increase in plasma renin activity which activates angiotensin II and peripheral vasodilatation [9]. The aim of this study is to observe at various gestational ages the effect of therapeutic doses of the above-mentioned drugs in the human umbilical circulation studied with colour flow mapping and pulsed Doppler technology. Patients and Methods For the present study we employed an echotomographer with pulsed Doppler and colour flow mapping (Ansaldo model No. 560 CMF equipped with a 3.5 Mhz convex probe) and a cardiotocograph (Hewlett-Packard model 8OlOA). Pulsatility index (PI) was compared to our standard curve. All patients studied were healthy pregnant women and informed consent was obtained in each case. In six pregnant women at 26 and in six pregnant women at 36 weeks of gestation, the FVW in the UA was recorded continuously, from 15 min before to 15 min after slow i.v. infusion of 120 mg A; the cardiotocogram (CTG) was obtained before and after the Doppler examination. In three pregnant women at 30 weeks of gestational age we studied the effects of a bolus of 1 mg of i.v. AT. The FVW in the UA was recorded continuously from 10 min before administration of the drug to 10 min after it was given. The CTG
oc..cl
-20 150c
-15
-10
-5
0
5
10
15
_--- +
*________-*_-----
g
2;6 1 -1.5 E
aE 5
$ 3 I
20
looI---+---+ 50-
36
-1.0 : 4 WKS
BP1 l!=HR
LL -20 L
-15 1
-10
-5
0
5
10
15
Lz -0.5 gg
20 '0.0
TIME min
Fig. 1. Aminophylline effects at 26 (6 cases) and 36 weeks (6 cases) on PI of umbilical artery and fetal heart rate.
was obtained before and after the Doppler examination. In 24 pregnant women at risk for preterm labour (previously one or more preterm births) with a gestational age ranging between 25 and 35 weeks, we recorded the FVW in the UA before and after the administration of 50 mg of Ritodrine in 500 ml of saline solution by i.v. (4 pg/min>. CTG was performed during the period of the i.v. infusion. Results Maternal i.v. administration of 120 mg A was accompanied by a slight short-term increase in fetal heart rate (FHR) and of PI of UA at each gestational age (PI: from 0.90 it 0.1 to 0.98 f 0.1 at 26 weeks, P > 0.05, NS; and from 1.05 f 0.1 to 1.10 f 0.1 at 36 weeks, P > 0.05, NS, FHR: from 146 f 6 to 152 f 5 at 26 weeks and from 148 f 3 to 159 f 5 at 36 weeks) (Fig. 1); while maternal systolic blood pressure did not show any varia-
I__________-_--_----1_____ -1
0~‘oJl-10
-5
-15
0 TlK
5
10
15
(sin1
Fig. 2. Atropine effects on PI of umbilical artery and fetal heart rate (3 cases).
tion, the maternal heart rate increased significantly in the 36 week group 0’ < 0.05). The iv. administration of a 1 mg bolus of AT showed a statistically significant (P < 0.05) decrease of PI 5 min after injection and a slight decrease 10 min after (PI: from 0.81 +_0.06 to 0.71 _+0.04 5 min after i.v., P < 0.05, and to 0.75 + 0.1 to 8-10 min after i.v., P > 0.05, NS). The fetal heart rate showed only a slight decrease (Fig. 2). After administration of R, we observed no variation in the PI at a gestational age ranging from 25 to 32 weeks (14 cases) (PI: from 1.37 _+ 0.13 to 1.36 + 0.29) while at later gestational age (10 cases) the PI decrease was marked (PI: from 1.14 + 0.29 to 0.96 k 0.14; P < 0.05) (Fig. 3).
2.0 -
9 _
------_______ 1 ------________ 1 t _________-_---------------
i i
$
n2!i-32 nks'
pGl.05 0.0 L
In one case we observed a disturbance of the fetal heart rhythm (appearance of bigeminal rhythm) which disappeared with the suspension of the drug; the neonatal outcome was good (Fig. 4).
___?
1.5 t
Fig. 4. Flow velocity waveform of umbilical artery during ritodrine treatment (a case). (A) Bigeminal rhythm during ritodrine treatment at 34 weeks. (B) FVW after suspension of ritodrine treatment at 37 weeks.
Discussion
1 5
I3
~32-35 nks’ I
BEFORE INFUSION
AFTER INFUSION
Fig. 3. Ritodrine effects on PI of umbilical artery (24 cases total; 14 cases 25-32 wks; 10 cases 32-35 weeks).
In this study we did not observe any significant short-term variation of umbilical artery PI during administration of aminophylline, atropine and ritodrine. Slight variations were detected, and they maybe interpreted on the basis of the mode of action of these drugs. The effect of aminophylline may be due to the direct action of the substance on the smooth musculature of the fetal peripheral vessels with sequestration of blood and compensatory umbilical vasoconstriction.
10
Atropine may act first on the vagus tone and then on the central mechanism; in fact, the FHR decreased 10 min after infusion, while a variation of PI was observed after the first 5 min of drug injection. During infusion of ritodrine, the PI showed variations only in patients at 32-35 weeks of gestation. This may be due partly to a greater effect on the myometrium in the last period of pregnancy compared to the early period, and partly to a direct effect on fetal circulation. The percentage of variation of the PI after drug administration was, however, very slight. This fact may be due to the good adaptation of the normal fetus to small stressful situations. We conclude that the resistance of the nonpathological human placenta, as reflected by the pulsatility index of the umbilical artery, is not influenced by the administration of aminophylline, atropine or ritodrine to pregnant women. Doppler technology may be a useful and safe method for investigating possible changes in feto-placental circulation under different maternal drug therapy.
References 1 Berman W, Goolding RC, Heymann MA, Rudolph AM. Effects of pharmacological agents on umbilical blood flow in fetal Iambs in utero. Biol Neonate 1978;33:225-235. 2 Moise KJ Jr, Mari G, Kirshon B et al. The effects of indomethacin on the pulsatility index of umbilical artery in human fetus. Am J Obstet Gynecol 1990;162:199-206. 3 Coutinbuo Viera Lopez AC. Inhibition of uterine mobility by aminophylline. Am J Obstet Gynecol 1971;110:726-735. 4 Hadjigeorgiou E, Kitsious S, Psadoudakis A, Kaskarelis D. Antepartum aminophylline treatment for prevention of respiratory distress syndrome in premature infants. Am J Obstet Gynecol 1979;135:257-263. 5 Cosmi EV. Obstetric anesthesia and perinatology, chapter 11, New York: Appleton Century Crofts, 1981. 6 Schifferli PY, Caldeyro-Barcia R. Effects of atropine and beta-adrenergic drugs on the heart rate of the human fetus. In: Boreus LO, ed. Fetal pharmacology. New York: Raven Press, 1973;259-287. 7 Katz VL, Seeds JW. Fetal neonatal cardiovascular complication from P-sympaticomimethic therapy for tocolysis. Am J Obstet Gynecol 1989;161:1-4. 8 Spielman FJ, Herbert WNP. Maternal cardiovascular effects of drugs that alter uterine activity. Obstet Gynecol Surv 198;43:516-520. 9 Ferguson JE, Dyson DC, Schutz T, Steventson DK. A comparation of tocolysis with nifedipine or ritodrine. Am J Obstet Gynecol 1990;163:105-111.
EUROBS 01357
Short-term effects of ritodrine, aminophylline and atropine on umbilical artery blood flow velocity waveform E.V. Cosmi a, G. Luzi b, P. Fusaro a, G. Caserta a and G.C. Di Renzo a ’ 2nd Institute of Gynecology and Obstetrics, University ‘La Sapienza’, Rome and b Institute of Gynecology and Obstetrics, University of Pen&a, Perugia, Italy
Accepted for publication 24 January 1992
Summary With the recent introduction of Doppler technology, a non-invasive methodology which enables to evaluate qualitative changes in circulatory vessels, it is possible to investigate the possible effects of various drugs on several parameters of utero-placental-fetal circulation. In the present study we evaluate the flow velocity waveform (FW) of umbilical artery (UA) during and after administration of aminophylline, atropine and ritodrine to healthy pregnant women. In our study we did not observe any significant short-term variation of PI after the administration of these drugs. Slight variations were detected, and they may be interpreted on the basis of the mode of action of these drugs. Doppler technology may be a useful tool for monitoring some effects on the fetus of the maternal administration of therapeutic agents. Ritodrine; Aminophylline; Atropine; Umbilical artery; Blood flow velocity
Introduction The effects of drugs on the feto-placental circulation have been mainly evaluated in animals, and results translated to humans [l]. With the recent introduction of Doppler technology, a non-invasive methodology which enables evaluation of qualitative changes in circulatory vessels [2], it is possible to investigate the possible effects of various drugs on several parameters of the utero-placental-fetal circulation.
Correspondence to: Gian Carlo Di Renzo, M.D., Ph.D., Institute of Gynecology and Obstetrics, University of Perugia, Policlinico Monteluce, 06100 Perugia, Italy.
In the present study we evaluate the flow velocity waveform (FW) of the umbilical artery (UA) during and after administration of aminophylline, atropine and ritodrine to the pregnant women. In obstetrics, aminophylline (A> is utilized mainly for tocolysis; this methylxanthine derivative inhibits the action of phosphodiesterase, thereby causing an accumulation of intracellular cyclic adenosine 3,5monophosphate (AMP) which is supposed to be the main mechanism by which contractions are inhibited [3]. This drug is reported to increase the heart rate and to induce periferic vasodilation in pregnant women 141. Atropine (AT) is a cholinergic postganglion blocking agent used usually during the induction
8
of general anaesthesia in obstetric care. It is a tertiary amine and crosses the placenta and the blood-brain barrier in the fetus [5]. Potential side effects include fetal bradycardia by central effect following fetal tachycardia by vagolitic effect. AT has been proposed also as a test in cardiotocography bl. Ritodrine (R) is one of the most utilized betamimetic agents for inhibition of preterm contractions [6]. It is known that ritodrine and its inactive metabolites cross the placenta, but only 20% of their maternal blood levels are found in cord blood [6]. The cardiovascular effects of the drug are dose-related; intravenous infusion of R increases both the maternal and fetal heart rates with about 20-40 and l-9 beats per minute, respectively [7,8]. It is proposed that the p-adrenergic stimulation produced by R results in an increase in plasma renin activity which activates angiotensin II and peripheral vasodilatation [9]. The aim of this study is to observe at various gestational ages the effect of therapeutic doses of the above-mentioned drugs in the human umbilical circulation studied with colour flow mapping and pulsed Doppler technology. Patients and Methods For the present study we employed an echotomographer with pulsed Doppler and colour flow mapping (Ansaldo model No. 560 CMF equipped with a 3.5 Mhz convex probe) and a cardiotocograph (Hewlett-Packard model 8OlOA). Pulsatility index (PI) was compared to our standard curve. All patients studied were healthy pregnant women and informed consent was obtained in each case. In six pregnant women at 26 and in six pregnant women at 36 weeks of gestation, the FVW in the UA was recorded continuously, from 15 min before to 15 min after slow i.v. infusion of 120 mg A; the cardiotocogram (CTG) was obtained before and after the Doppler examination. In three pregnant women at 30 weeks of gestational age we studied the effects of a bolus of 1 mg of i.v. AT. The FVW in the UA was recorded continuously from 10 min before administration of the drug to 10 min after it was given. The CTG
oc..cl
-20 150c
-15
-10
-5
0
5
10
15
_--- +
*________-*_-----
g
2;6 1 -1.5 E
aE 5
$ 3 I
20
looI---+---+ 50-
36
-1.0 : 4 WKS
BP1 l!=HR
LL -20 L
-15 1
-10
-5
0
5
10
15
Lz -0.5 gg
20 '0.0
TIME min
Fig. 1. Aminophylline effects at 26 (6 cases) and 36 weeks (6 cases) on PI of umbilical artery and fetal heart rate.
was obtained before and after the Doppler examination. In 24 pregnant women at risk for preterm labour (previously one or more preterm births) with a gestational age ranging between 25 and 35 weeks, we recorded the FVW in the UA before and after the administration of 50 mg of Ritodrine in 500 ml of saline solution by i.v. (4 pg/min>. CTG was performed during the period of the i.v. infusion. Results Maternal i.v. administration of 120 mg A was accompanied by a slight short-term increase in fetal heart rate (FHR) and of PI of UA at each gestational age (PI: from 0.90 it 0.1 to 0.98 f 0.1 at 26 weeks, P > 0.05, NS; and from 1.05 f 0.1 to 1.10 f 0.1 at 36 weeks, P > 0.05, NS, FHR: from 146 f 6 to 152 f 5 at 26 weeks and from 148 f 3 to 159 f 5 at 36 weeks) (Fig. 1); while maternal systolic blood pressure did not show any varia-
I__________-_--_----1_____ -1
0~‘oJl-10
-5
-15
0 TlK
5
10
15
(sin1
Fig. 2. Atropine effects on PI of umbilical artery and fetal heart rate (3 cases).
tion, the maternal heart rate increased significantly in the 36 week group 0’ < 0.05). The iv. administration of a 1 mg bolus of AT showed a statistically significant (P < 0.05) decrease of PI 5 min after injection and a slight decrease 10 min after (PI: from 0.81 +_0.06 to 0.71 _+0.04 5 min after i.v., P < 0.05, and to 0.75 + 0.1 to 8-10 min after i.v., P > 0.05, NS). The fetal heart rate showed only a slight decrease (Fig. 2). After administration of R, we observed no variation in the PI at a gestational age ranging from 25 to 32 weeks (14 cases) (PI: from 1.37 _+ 0.13 to 1.36 + 0.29) while at later gestational age (10 cases) the PI decrease was marked (PI: from 1.14 + 0.29 to 0.96 k 0.14; P < 0.05) (Fig. 3).
2.0 -
9 _
------_______ 1 ------________ 1 t _________-_---------------
i i
$
n2!i-32 nks'
pGl.05 0.0 L
In one case we observed a disturbance of the fetal heart rhythm (appearance of bigeminal rhythm) which disappeared with the suspension of the drug; the neonatal outcome was good (Fig. 4).
___?
1.5 t
Fig. 4. Flow velocity waveform of umbilical artery during ritodrine treatment (a case). (A) Bigeminal rhythm during ritodrine treatment at 34 weeks. (B) FVW after suspension of ritodrine treatment at 37 weeks.
Discussion
1 5
I3
~32-35 nks’ I
BEFORE INFUSION
AFTER INFUSION
Fig. 3. Ritodrine effects on PI of umbilical artery (24 cases total; 14 cases 25-32 wks; 10 cases 32-35 weeks).
In this study we did not observe any significant short-term variation of umbilical artery PI during administration of aminophylline, atropine and ritodrine. Slight variations were detected, and they maybe interpreted on the basis of the mode of action of these drugs. The effect of aminophylline may be due to the direct action of the substance on the smooth musculature of the fetal peripheral vessels with sequestration of blood and compensatory umbilical vasoconstriction.
10
Atropine may act first on the vagus tone and then on the central mechanism; in fact, the FHR decreased 10 min after infusion, while a variation of PI was observed after the first 5 min of drug injection. During infusion of ritodrine, the PI showed variations only in patients at 32-35 weeks of gestation. This may be due partly to a greater effect on the myometrium in the last period of pregnancy compared to the early period, and partly to a direct effect on fetal circulation. The percentage of variation of the PI after drug administration was, however, very slight. This fact may be due to the good adaptation of the normal fetus to small stressful situations. We conclude that the resistance of the nonpathological human placenta, as reflected by the pulsatility index of the umbilical artery, is not influenced by the administration of aminophylline, atropine or ritodrine to pregnant women. Doppler technology may be a useful and safe method for investigating possible changes in feto-placental circulation under different maternal drug therapy.
References 1 Berman W, Goolding RC, Heymann MA, Rudolph AM. Effects of pharmacological agents on umbilical blood flow in fetal Iambs in utero. Biol Neonate 1978;33:225-235. 2 Moise KJ Jr, Mari G, Kirshon B et al. The effects of indomethacin on the pulsatility index of umbilical artery in human fetus. Am J Obstet Gynecol 1990;162:199-206. 3 Coutinbuo Viera Lopez AC. Inhibition of uterine mobility by aminophylline. Am J Obstet Gynecol 1971;110:726-735. 4 Hadjigeorgiou E, Kitsious S, Psadoudakis A, Kaskarelis D. Antepartum aminophylline treatment for prevention of respiratory distress syndrome in premature infants. Am J Obstet Gynecol 1979;135:257-263. 5 Cosmi EV. Obstetric anesthesia and perinatology, chapter 11, New York: Appleton Century Crofts, 1981. 6 Schifferli PY, Caldeyro-Barcia R. Effects of atropine and beta-adrenergic drugs on the heart rate of the human fetus. In: Boreus LO, ed. Fetal pharmacology. New York: Raven Press, 1973;259-287. 7 Katz VL, Seeds JW. Fetal neonatal cardiovascular complication from P-sympaticomimethic therapy for tocolysis. Am J Obstet Gynecol 1989;161:1-4. 8 Spielman FJ, Herbert WNP. Maternal cardiovascular effects of drugs that alter uterine activity. Obstet Gynecol Surv 198;43:516-520. 9 Ferguson JE, Dyson DC, Schutz T, Steventson DK. A comparation of tocolysis with nifedipine or ritodrine. Am J Obstet Gynecol 1990;163:105-111.
