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Comparison of the effects of meperidine and nalbuphine on intrapartum fetal heart rate tracings
Comparison of the Effects of Meperidine and Nalbuphine on Intrapartum Fetal Heart Rate Tracings GREGG GIANNINA, MD, EDWIN R. GUZMAN, MD, YU-LING LAI, RNC, MSN, M A R I A N F. LAKE, RNC, MPH, MAUREEN CERNADAS, MD, AND A N T H O N Y M. VINTZILEOS , MD Objective: To examine the effects of meperidine and n a l b u p h i n e on intrapartum fetal heart rate (FHR) tracings using computer analysis. Methods: W e s t u d i e d 28 w o m e n w i t h u n c o m p l i c a t e d pregnancies in early labor at term w i t h reactive FHR tracings. The w o m e n were r a n d o m i z e d to receive either meperidine 50 mg or n a l b u p h i n e 10 mg intravenously on request. One-hour FHR recordings were obtained before and immediately after administration of the medications. Results: There were no significant differences in the FHR characteristics of the two groups during the pre-treatment period. N a l b u p h i n e significantly decreased the n u m b e r of accelerations of 10 beats per minute (17 versus 4, P = .003) and 15 beats per minute (10 versus 1.5, P = .001), time spent in e p i s o d e s of high variation (35.5 versus 10 minutes, P = .004), long-term variation (47 versus 29.8 m i l l i s e c o n d s , P = .002), and short-term variation (8.4 versus 6.4 milliseconds, P = .03). M e p e r i d i n e had no significant effect on any FHR characteristic. Conclusion: In the early intrapartum period of normal term pregnancies and at c o m m o n l y used dosages, nalbup h i n e had a significant effect on FHR tracings, w h e r e a s m e p e r i d i n e had no effect, as determined b y computer analysis. (Obstet Gynecol 1995;86:441-5)
For many years, meperidine has been the traditional drug of choice for intrapartum analgesia. Despite its efficacy in relieving intrapartum pain, meperidine has been associated with multiple adverse effects, including nausea and vomiting ~ as well as maternal and neonatal respiratory depression. 2'~ In addition, meperidine has
From the Division of Maternal Fetal Medicine, Department of Ob stetrics, Gynecology, and Reproductive Sciences, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, St. Peter's Medical Center, New Brunswick, New Jersey.
VOL. 86, NO. 3, SEPTEMBER 1995
been associated with a decrease in fetal heart rate (FHR) variability. 4 Recently, the narcotic agonist-antagonist class of medications (ie, nalbuphine) showed promise in obstetric analgesia because of fewer reported side effects, such as limited respiratory depression, s'6 and less nausea and vomitingJ "2"5; Because nalbuphine has a limited sideeffect profile, would there also be less of an affect on the FHR? There have been anecdotal reports on nalbuphine's effects on FHR tracings, including a sinusoidal pattern, s Wilson et al 5 reported no difference in the long-term variability of FHR tracings after administration of nalbuphine compared with meperidine. The assessment of intrapartum FHR tracings, especially FHR variability, is of p a r a m o u n t importance in m o d e r n obstetrics for evaluating fetal acid-base status. The inaccuracy of visual analysis of FHR tracings is well documented, with marked intra- and interobserver differences in the assessment of intrapartum cardiotocograms. 9 Because these inaccuracies exist, computer programs to evaluate FHR tracings objectively were developed to eliminate the differences in the interpretation of FHR tracings. 1° The purpose of this study was to assess prospectively the effects of meperidine versus nalbuphine on FHR tracings when used for intrapartum analgesia using computer analysis.
Materials and Methods We enrolled 36 women with uncomplicated, singleton, vertex gestations at term (37-41 weeks) who presented to the labor and delivery suite of St. Peter's Medical Center in early labor from March 1, 1994 through August 30, 1994. All patients who met enrollment criteria were offered participation in the study. All
0029-7844/95/$9.50 SSDI 0029-7844(95)00164-M
441
patients who were approached gave written, informed consent to participate in the study; no patient refused to participate. The study was approved by the St. Peter's Medical Center Institutional Review Board. Enrollment criteria for the study included an initial cervical dilation of 4 cm or less, at least three uterine contractions in a 10-minute period, and no known maternal or fetal condition that could affect the FHR tracing. Before entry into the study, all fetuses had to exhibit a reactive FHR tracing (two accelerations of 15 beats per minute lasting at least 15 seconds in a 20minute period). Reactivity of the FHR tracings was determined visually by the house staff. Exclusion criteria included the following: premature rupture of membranes (PROM), meconium-stained fluid, pregnancy-induced hypertension, fetal bradycardia, fetal tachycardia, fetal arrhythmias or decelerations, chorioamnionitis, fetal growth restriction, abnormal placentation, maternal fever or infection, and any known fetal chromosomal or structural abnormality. Patients enrolled in the study had not received any medications (ie, narcotics, sedatives, etc) that could have potentially affected the FHR within 2 weeks of enrollment. Per standard protocol, all patients received an intravenous (IV) infusion of lactated Ringer's solution at 125 mL/hour. In addition, all patients were monitored with an external tocodynamometer as well as with continuous electronic fetal monitoring using the HewlettPackard Series 50IX M1350 Fetal Monitor (HewlettPackard, Boeblingen, Germany). After enrollment, additional recordings of the FHR were obtained over a continuous 60-minute period using a Sonicaid FM7 fetal monitor (Oxford/Sonicaid, Oxon, UK), which was interfaced with an Oxford computer (Oxford/Sonicaid) through its RS 232 port. Details of the FHR recordings were obtained as described elsewhere.l~ ~3 An FHR tracing signal loss of less than 10% over a 1-hour period was deemed acceptable. Upon requesting analgesia, all patients were again examined vaginally by the same initial examiner, then randomly assigned to receive either IV meperidine 50 mg or nalbuphine 10 mg (both are commonly used dosages). 7 The randomization was performed by a computergenerated random-number table with the Epilnfo program (USD Inc., Stone Mountain, GA). The medications were then randomly assigned with the Epilnfo program and placed into sequentially numbered, sealed envelopes. On a patient's request for analgesia, we opened each envelope in sequential order and administered the enclosed medication. The patients received no other medications during the study period. Immediately after receiving the assigned analgesic, another continuous 60-minute recording of the FHR was obtained by making simultaneous recordings with both the Hewlett-
442 Giannina et al
Mepcridille arid NtflbuFhiHc
Table 1. Comparison of Maternal and Neonatal Characteristics Between Meperidine and Nalbuphine Groups Characteristic Maternal age (y) Maternal weight (lb) Gestational age (wk) Birth weight (g) Initial cervical dilation (cm) Pre-treatment cervical dilation (cm) Umbilical artery pH at birth
Meperidine (N = 14)
Nalbuphine (N = 14)
20.5 (16-30) 25 (17-37) 150 (129 210) 163 (124-210) 40.1 (38.0-41.3) 39.9 (37.4-41.8) 3370 (2760-3870) 3320(2840-3750) 3 (2-4) 2 (1-4) 4 (2-5) 4 (2-5) 7.27 (7.18-7.37)
7.27 (7.22-7.35)
Data are presented as median (range). Comparisons between groups were not statistically significant.
Packard and Sonicaid monitors, as described previously. With the computer, we analyzed the entire 60-minute pre- and post-treatment periods for both the meperidine and nalbuphine groups. Also, to determine FHR reactivity objectively in the pre- and posttreatment periods, we searched for 20-minute epochs in which there were two computer-identified accelerations of ten or 15 beats per minute and of at least 15-seconds duration. Using the normal reference ranges for long-term variation and accelerations of ten beats per minute for a 15-second duration reported by Snijders et al, 14 we determined that the study would require 28 patients to achieve a power of 90% to detect a change from values at the 50th percentile to values below the fifth percentile at an alpha error of 0.05. Statistical analysis was performed using the Mann-Whitney U, Wilcoxon signedrank, X2, and Fisher exact tests when appropriate. Statistical significance was set at P < .05.
Results Of the 36 patients enrolled, 28 women were studied. Eight patients were eliminated from the analysis because we obtained insufficient tracings for the computer to analyze. There was no statistical difference between the meperidine and nalbuphine groups with respect to the maternal and fetal characteristics listed in Tables 1 and 2. In the nalbuphine group, the one infant with a 1-minute Apgar score less than 7 had an umbilical artery pH of 7.28 at birth. Also, in both cases, the indication for the two cesarean deliveries in the nalbuphine group was arrest of dilation (Table 2). There was 11o intervention for fetal distress in either group. Using a cord artery pH value of less than 7.15 after labor as the definition of acidemia, is we found that no infant demonstrated acidemia at birth in either study group. No
Obstetrics & Gynecology
p a t i e n t in the s t u d y h a d c h o r i o a m n i o n i t i s or r e c e i v e d p r o p h y l a c t i c a n t i b i o t i c s for b e i n g a k n o w n g r o u p B s t r e p t o c o c c u s c a r r i e r d u r i n g t h e e n t i r e i n t r a p a r t u m period. T h e r e w e r e n o statistical d i f f e r e n c e s in the c o m p u t e r F H R c h a r a c t e r i s t i c s b e t w e e n the t w o g r o u p s d u r i n g the p r e - t r e a t m e n t p e r i o d . T h e m e a n p e r c e n t c o m p u t e r signal loss b e t w e e n t h e p r e - a n d p o s t - t r e a t m e n t p e r i o d s in the n a l b u p h i n e g r o u p (5.6 v e r s u s 8.7%) a n d m e p e r i d i n e g r o u p (5.5 v e r s u s 8.4%) w a s n o t s i g n i f i c a n t l y different. T h e m e d i a n t i m e i n t e r v a l b e t w e e n the start of t h e first a n d s e c o n d 6 0 - m i n u t e F H R r e c o r d i n g s w a s n o t signific a n t l y d i f f e r e n t b e t w e e n the n a l b u p h i n e g r o u p (2.4 h o u r s ] r a n g e 1.2-6.3]) a n d the m e p e r i d i n e g r o u p (1.9 h o u r s [ r a n g e 1.2-4.9]). T h e r e w a s n o d i f f e r e n c e in t h e m e a n n u m b e r of c o n t r a c t i o n s p e r h o u r b e t w e e n t h e p r e - t r e a t m e n t a n d p o s t - t r e a t m e n t p e r i o d s in the m e p e r i d i n e g r o u p (19.1 + 0.83 v e r s u s 19.5 + 0.94 c o n t r a c t i o n s p e r h o u r , P = 0.17) as w e l l as in the n a l b u p h i n e g r o u p (19.1 + 1 v e r s u s 19.7 + 0.9 c o n t r a c t i o n s p e r h o u r , P 0.15). T h e r e also w a s n o d i f f e r e n c e in the c o n t r a c t i o n f r e q u e n c y w h e n a c o m p a r i s o n w a s m a d e b e t w e e n the p o s t - t r e a t m e n t p e r i o d s of b o t h g r o u p s (P = 0.62). T h e r e w a s n o s i g n i f i c a n t d i f f e r e n c e in a n y of the computer FHR characteristics between the pret r e a t m e n t a n d p o s t - t r e a t m e n t p e r i o d s in t h e m e p e r i d i n e g r o u p (Table 3). C o m p a r e d w i t h the p r e - t r e a t m e n t p e r i o d , n a l b u p h i n e s i g n i f i c a n t l y d e c r e a s e d the n u m b e r of a c c e l e r a t i o n s of ten a n d 15 b e a t s p e r m i n u t e , a n d the m i n u t e s s p e n t in e p i s o d e s of h i g h v a r i a t i o n , l o n g - t e r m variation, and short-term variation. Nalbuphine did not
Table 2. Comparison of Selected Maternal and Neonatal Characteristics Between Meperidine and Nalbuphine Groups Characteristic
Meperidine (N = 14)
Nalbuphine (N 14)
1 (7.1%) 2 (14.3%) 5 (35.7%) 6 (42.9%)
1 (7.1~7~) 3 (21.4q~) 7 (50~7,) 3 (21.4~a)
9 (64.3~/,) 5 (35.7%)
6 (42.9'~) 8 (57.19~)
0 0
1 (7.19~) 0
Race Asian Black Hispanic White Parity Primiparous Multiparous Apgar score <-7 at 1 min <-7 at 5 min Mode of delivery Cesarean Vaginal Umbilical artery pH at birth <7.15 ~>7.15
0 14 (100%)
2 (14.3'~) 12 (85.7¢,~)
0 14 (100%)
0 14 (100~7,)
Data are presented as n (%). Comparisons between groups were not statistically significant.
VOL. 86, NO. 3, SEPTEMBER 1995
Table 3. Effects of Meperidine Compared With PreTreatment Periods on Computer-Analyzed Fetal Heart Rate Characteristics Characteristic
Pre-treatment
Post-treatment
Baseline EHR (bpm) Accelerations of at least 10 bpm Accelerations of at least 15 bpm Episodes of high variation (rain) Episodes of low variation (min) Long-term variation (msec) Short-term variation (msec)
138.5 (120-154)
141.5(119-157)
Median % change 2.2
13.5 (2-24)
10.5 (1-23)
22.2
5.0 (0-15)
6.0 (0-18)
20.0
19.0 (6-42)
19.0 (0-42)
0
10.5 (0 19)
6.0 (0-40)
42.9
40.1 (24.8 69.5)
43.6 (18.6-80.3)
8.7
6.5 (5.0-10.6)
7.1 (3.7-14.4)
9.2
FHR fetal heart rate; bpm - beats per minute. Data are presented as median (range), unless specified. Comparisons between groups were not statistically significant. -
alter the b a s e l i n e F H R o r t h e m i n u t e s s p e n t in e p i s o d e s of l o w v a r i a t i o n w h e n c o m p a r e d w i t h t h e p r e - t r e a t m e n t p e r i o d (Table 4). W h e n c o m p a r i n g t h e effects of n a l b u p h i n e a n d m e peridine on computer-determined FHR tracing reactivity ( d e f i n e d as h a v i n g t w o a c c e l e r a t i o n s of 15 b e a t s p e r m i n u t e a b o v e b a s e l i n e for at least 15 s e c o n d s ) , n a l b u p h i n e s i g n i f i c a n t l y d e c r e a s e d the i n c i d e n c e of r e a c t i v e F H R t r a c i n g s (93 v e r s u s 57%, P = .04), w h e r e a s m e p e r i d i n e d i d n o t (71 v e r s u s 86%). W h e n F H R r e a c t i v i t y w a s d e f i n e d as h a v i n g t w o a c c e l e r a t i o n s of ten b e a t s p e r m i n u t e a b o v e b a s e l i n e for at least 15 s e c o n d s , the
Table 4. Effects of Nalbuphine Compared With PreTreatment Periods of Computer-Analyzed Fetal Heart Rate Characteristics Characteristics
Pre-treatment
Median Post-treatment % change
Baseline FHR 135.5 (125-140) 134.5(120-149) (bpm) Accelerations of 17.0 (3-23) 4.0 (1-24) at least 10 bpm Accelerations of 10.0 (2-20) 1.5 (0 6) at least 15 bpm Episodes of high 35.5 (0-48) 10.0 (0-29) variation (min) Episodes of low 5.5 (0 22) 11.0 (0-38) variation (rain) Long-term 47.0 (23.8-72.8) 29.8 (21.2-50.3) variation (msec) Short-term 8.4 (4 12.9) 6.4 (4.4-10.9) variation (msec)
-0.74
P NS
76.50 .003 -85.0
.001
-71.8
.004
100.0
NS
-36.6
.002
23.8
.03
FHR fetal heart rate; NS = not significant; bpm = beats per minute. Data are presented as median (range), unless specified.
G i a n n i n a et al
Meperidine and Nalbuphine 443
Table 5. Comparison of Effects of Meperidine and Nalbuphine on Fetal Heart Rate Tracing Reactivity Using Computer Analysis Two accels of 10 bpm in 20 rain Medication
Pre-treatment
Meperidine 13/14 (93',;) Nalbuphine 13/14 (93~,i) accels accelerations;bpm beatsper minute. * P .04.
Pre-treatment
Post-treatment
13/14 (93';'i) 12/14 (86~~,)
10/14 (71'>~) 13/14 (93~)
12/14 (86%) 8/14 (57%)*
Discussion Despite the increasing use of epidural analgesia during labor, parenteral narcotic agents remain frequently used for intrapartum analgesia. Traditionally, meperidine has been the drug of choice in many institutions for relieving the pain of labor. Although meperidine is effective as an analgesic, it has marked adverse effects when used in labor, including maternal nausea and vomiting, ~ maternal and neonatal depression, 2"3 and FHR changes.~'4 Petrie et al 4 demonstrated a decrease in the FHR variability that began 10 minutes after administration of meperidine and recovered 30 minutes after the injection. We could not demonstrate an effect on the short- and long-term variation with the use of meperidine. Noting the adverse effects of meperidine when used intrapartum, others have evaluated the narcotic agonistantagonist agents (ie, nalbuphine) during labor] ~,5,7.~ Nalbuphine seemed to be an attractive alternative for intrapartum analgesia, particularly because of its ceiling effect on respiratory depression. The maximum respiratory depression noted with nalbuphine occurs at a dose of 30 mg per 70 kg and is easily reversed with 0.4 mg of nalaxone." Nalbuphine has been studied extensively when used in labor. Wilson et al 5 investigated the pharmacokinetics of nalbuphine in labor and found an initial distribution phase of 4-20 minutes and a terminal half-life of 2.4 _+ 0.4 hours. Wilson et al also reported that nalbuphine entered the fetal circulation with values ranging from one-third to six times the simultaneous maternal concentration. The placental transfer of nalbuphine after IV administration is believed to be more rapid than meperidine, as reported in an abstract by Dadabohoy et al (Dadabohoy ZP, Tapia DP, Zsigmond EK. Transplacental transfer of nalbuphine in patients undergoing cesarean section. Anesth Analg 1985;64: 205). The placental transfer of meperidine after IV administration has also been documented to be rapid. Crawford et a117 demonstrated that meperidine was found in the umbilical vein within two minutes of IV administration. Rosen and Bleyer is found that the avMepcridine ami Nalbuphim,
accels of 15 bpm in 20 min
Post-treatrnent
computer did not detect a change in reactivity associated with either nalbuphine or meperidine (Table 5).
444 Giannina et al
Two
erage time to detect fetal electroencephalogram changes in an animal model after the IV administration of meperidine was 69 seconds. Because the placental transfer of both meperidine and nalbuphine have been shown to be rapid (ie, within 2 minutes), it was appropriate for us to record the FHR immediately after administration of the medication to detect an effect. Although there are multiple reports evaluating meperidine and nalbuphine in labor, the reported effects on the FHR tracings are limited to subjective visual evaluations. Frank et al 2 showed that neither nalbuphine nor meperidine affected the baseline FHR. Based on our results, we agree with their conclusions. Wilson et al 1 observed no differences in the long-term variability of the FHR tracings after the administration of nalbuphine compared with meperidine; they provided no support for their statement. Based on the findings of our study, we noted a significant change in FHR characteristics associated with the use of nalbuphine as objectively quantified by computer analysis. Finally, in a letter, a case of immediate fetal bradycardia was reported after nalbuphine was given in labor (Guillonneau M, Jacquz-Aigrain E, Decrepy A, Zeggout H. Perinatal adverse effects of nalbuphine given during parturition. Lancet 1990;335:1588). We could support no association between nalbuphine and fetal bradycardia with our findings. The main problem with all of the reports on meperidine and nalbuphine's effects on FHR tracings is that they are based on subjective interpretations of FHR tracings. The important intra- and inter-observer differences ill the assessment of intrapartum cardiotocograms has been documented in the range of 22-60%. q Several objective methods have been developed for quantifying FHR characteristics, including variability such as mathematic models ~* and computerized methods. Dawes et al u~'2° supported the objective evaluation of FHR tracings by computer analysis as a valid tool in the assessment of fetal well-being. Computer analysis has been used to evaluate the effect of magnesium sulfate and phenytoin on the FHR tracing] ~'2~ We do not know of any report using computer analysis to interpret the effects of meperidine or nalbuphine on the intrapartum FHR pattern. In our study, we saw a significant decrease in several Obstetrics & Gynecology
of t h e F H R c h a r a c t e r i s t i c s a s s o c i a t e d w i t h n a l b u p h i n e w h e n u s i n g c o m p u t e r analysis. M e p e r i d i n e d i d n o t alter a n y of t h e F H R c h a r a c t e r i s t i c s to a statistically s i g n i f i c a n t d e g r e e . W e d e m o n s t r a t e d t h e lack of an effect o n the F H R b y m e p e r i d i n e , w h i c h is in d i r e c t conflict w i t h the o p i n i o n of m a n y p h y s i c i a n s . D e s p i t e the s m a l l n u m b e r of p a t i e n t s s t u d i e d , w e b e l i e v e that the t w o g r o u p s w e r e e q u a l a n d t h a t o u r r a n d o m i z a t i o n p r o c e s s w a s effective. Also, w e a t t e m p t e d to m i n i m i z e the p o t e n t i a l effect of l a b o r o n a n y of t h e F H R t r a c i n g s b y l i m i t i n g t h e s t u d y to the e a r l y i n t r a p a r t u m p e r i o d b y e n r o l l i n g o n l y t h o s e p a t i e n t s w i t h c e r v i c a l d i l a t i o n of 4 c e n t i m e t e r s or less. A l t h o u g h w e f o u n d a statistically s i g n i f i c a n t d e c r e a s e f r o m t h e p r e - t r e a t m e n t p e r i o d in a c c e l e r a t i o n s of t e n a n d 15 b e a t s p e r m i n u t e , m i n u t e s s p e n t in e p i s o d e s of h i g h v a r i a t i o n , l o n g - a n d shortt e r m v a r i a t i o n a s s o c i a t e d w i t h t h e u s e of n a l b u p h i n e , a n d t h e p o s t - t r e a t m e n t v a l u e s for l o n g - a n d s h o r t - t e r m v a r i a t i o n w e r e still w i t h i n the n o r m a l r a n g e for t e r m fetuses. T h e d e t e r m i n a t i o n of fetal w e l l - b e i n g b y v i s u a l a n a l y s i s of F H R r e a c t i v i t y m a y n o t h a v e b e e n p o s s i b l e b e c a u s e t h e r e w a s a s i g n i f i c a n t d e c r e a s e in c o m p u t e r d e t e r m i n e d r e a c t i v i t y u s i n g a c c e l e r a t i o n s of 15 b e a t s p e r minute associated with nalbuphine. W e c o n c l u d e that at a c o m m o n l y u s e d d o s e , n a l b u p h i n e s i g n i f i c a n t l y alters i n t r a p a r t u m F H R t r a c i n g s w h e n u s e d for a n a l g e s i a in e a r l y l a b o r in u n c o m p l i c a t e d p r e g n a n c i e s at term. A t a c o m m o n l y u s e d d o s e , m e p e r i d i n e has n o s i g n i f i c a n t effect o n the F H R tracing. This c o u l d b e of v a l u e for a clinician w h e n c h o o s i n g an appropriate intrapartum analgesic without influencing t h e F H R tracing.
References 1. Wilson CM, McClean E, Moore J, Dundee JW. A double-blind comparison of intramuscular pethidine and nalbuphine in labour. Anaesthesia 1986;41:1207-13. 2. Frank M, McAteer EJ, Cattermole R, Loughnan B, Stafford LB, Hitchcock AM. Nalbuphine for obstetric analgesia. Anaesthesia 1987;42:697-703. 3. Wahab SA, Askalani AH, Amar RA, Ramadan ME, Neweigy SB, Saleh AA. Effect of some recent analgesics on labor pain and maternal and fetal blood gases and pH. lnt J Gynaecol Obstet 1988;26:75- 80. 4. Petrie RH, Yeh S, Murata Y, et al. The effect of drugs on fetal heart rate variability. Am J Obstet Gyneco! 1978;130:294-9. 5. Wilson SJ, Errick JK, Balkin J. Pharmacokinetics of nalbuphine during parturition. Am J Obstet Gynecol 1986;155:340-4. 6. Romagnoli A, Keats AS. Ceiling effect for respiratory depression by nalbuphine. Clin Pharmacol Ther 1980;27:478-85. 7. Rabinovici DY, Barkai G, Mudan M, Mashinach S. Intravenous
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pethidine and nalbuphine during labor: A prospective doubleblind comparative study. Gynecol Obstet Invest 1991;32:39 43. 8. Feinstein SJ, Lodeiro JG, Vintzileos AM, Campbell WA, Montgomery JT, Nochimson DJ. Sinusoidal fetal heart rate pattern after administration of nalbuphine hydrochloride: A case report. Am J Obstet Gynecol 1986;154:159-60. 9. Nielsen PV, Stigsby B, Nickelsen C, Nim J. Intra- and interobserver variability in the assessment of intrapartum cardiotocograms. Acta Obstet Gynecol Scand 1987;66:421-4. 10. Dawes GS, Moulden M, Redman CWG. The advantages of computer fetal heart rate analysis. J Perinat Med 1991;19:39-45. 11. Dawes GS, Visser GH, Goodman JD, Redman CW. Numerical analysis of the human fetal heart rate: The quality of ultrasound records. Am J Obstet Gynecol 1981;141:43-52. 12. Visser GH, Dawes GS, Redman CW. Numerical analysis of the normal fetal heart rate. Br J Obstet Gynaecol 1981;88:792-802. 13. Guzman ER, Conley M, Stewart R, Ivan J, Pitter M, Kappy K. Phenytoin and magnesium sulfate effects on fetal heart rate tracings assessed by computer analysis. Obstet Gynecol 1993;82:375-9. 14. Snijders RJM, McLaren R, Nicolaides KH. Computer-assisted analysis of fetal heart rate patterns at 20-41 weeks' gestation. Fetal Diagn Ther 1990;5:79-83. 15. Vintzileos AM, Egan JFX, Campbell WA, et al. Asphyxia at birth as determined by cord blood pH measurements in preterm and term gestations: Correlation with neonatal outcome. J Maternal-Fetal Med 1992;1:7-13. 16. Podlas J, Breland BD. Patient-controlled analgesia with nalbuphine during labor. Obstet Gynecol 1987;70:202-4. 17. Crawford JS, Rudofsky S. The placental transfer of pethidine. Br J Anaesth 1965;37:929-33. 18. Rosen MG, Bleyer WA. Bidirectional transfer of meperidine across the guinea pig placenta. Am J Obstet GynecoI 1968;101:918-22. 19. Parer WJ, Parer JT, Holbrook RH, Block BSB. Validity of mathematical methods of quantitating fetal heart rate variability. Am J Obstet Gynecol 1978;130:294-9. 20. Dawes GS, Houghton CRS, Redman CWG, Visser GHA. Pattern of the normal human fetal heart rate. Br J Obstet GynecoI 1982;89: 276-84. 21. Atkinson MW, Belfort MA, Saade GR, Moise KJ. The relation between magnesium sulfate therapy and fetal heart rate variability. Obstet Gynecol 1994;83:967-70.
Address reprint requests to: Edwin R. Guzman, MD St. Peter's Medical Center MOB Fourth Floor 254 Easton Avenue New Brunswick, NJ 08901
Received January 11, 1995. Received in revisedform May 4, 1995. Accepted May 8, 1995. Copyright © 1995 by The American College of Obstetricians and Gynecologists.
G i a n n i n a et al
Meperidineand Nalbuphine
445
For many years, meperidine has been the traditional drug of choice for intrapartum analgesia. Despite its efficacy in relieving intrapartum pain, meperidine has been associated with multiple adverse effects, including nausea and vomiting ~ as well as maternal and neonatal respiratory depression. 2'~ In addition, meperidine has
From the Division of Maternal Fetal Medicine, Department of Ob stetrics, Gynecology, and Reproductive Sciences, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, St. Peter's Medical Center, New Brunswick, New Jersey.
VOL. 86, NO. 3, SEPTEMBER 1995
been associated with a decrease in fetal heart rate (FHR) variability. 4 Recently, the narcotic agonist-antagonist class of medications (ie, nalbuphine) showed promise in obstetric analgesia because of fewer reported side effects, such as limited respiratory depression, s'6 and less nausea and vomitingJ "2"5; Because nalbuphine has a limited sideeffect profile, would there also be less of an affect on the FHR? There have been anecdotal reports on nalbuphine's effects on FHR tracings, including a sinusoidal pattern, s Wilson et al 5 reported no difference in the long-term variability of FHR tracings after administration of nalbuphine compared with meperidine. The assessment of intrapartum FHR tracings, especially FHR variability, is of p a r a m o u n t importance in m o d e r n obstetrics for evaluating fetal acid-base status. The inaccuracy of visual analysis of FHR tracings is well documented, with marked intra- and interobserver differences in the assessment of intrapartum cardiotocograms. 9 Because these inaccuracies exist, computer programs to evaluate FHR tracings objectively were developed to eliminate the differences in the interpretation of FHR tracings. 1° The purpose of this study was to assess prospectively the effects of meperidine versus nalbuphine on FHR tracings when used for intrapartum analgesia using computer analysis.
Materials and Methods We enrolled 36 women with uncomplicated, singleton, vertex gestations at term (37-41 weeks) who presented to the labor and delivery suite of St. Peter's Medical Center in early labor from March 1, 1994 through August 30, 1994. All patients who met enrollment criteria were offered participation in the study. All
0029-7844/95/$9.50 SSDI 0029-7844(95)00164-M
441
patients who were approached gave written, informed consent to participate in the study; no patient refused to participate. The study was approved by the St. Peter's Medical Center Institutional Review Board. Enrollment criteria for the study included an initial cervical dilation of 4 cm or less, at least three uterine contractions in a 10-minute period, and no known maternal or fetal condition that could affect the FHR tracing. Before entry into the study, all fetuses had to exhibit a reactive FHR tracing (two accelerations of 15 beats per minute lasting at least 15 seconds in a 20minute period). Reactivity of the FHR tracings was determined visually by the house staff. Exclusion criteria included the following: premature rupture of membranes (PROM), meconium-stained fluid, pregnancy-induced hypertension, fetal bradycardia, fetal tachycardia, fetal arrhythmias or decelerations, chorioamnionitis, fetal growth restriction, abnormal placentation, maternal fever or infection, and any known fetal chromosomal or structural abnormality. Patients enrolled in the study had not received any medications (ie, narcotics, sedatives, etc) that could have potentially affected the FHR within 2 weeks of enrollment. Per standard protocol, all patients received an intravenous (IV) infusion of lactated Ringer's solution at 125 mL/hour. In addition, all patients were monitored with an external tocodynamometer as well as with continuous electronic fetal monitoring using the HewlettPackard Series 50IX M1350 Fetal Monitor (HewlettPackard, Boeblingen, Germany). After enrollment, additional recordings of the FHR were obtained over a continuous 60-minute period using a Sonicaid FM7 fetal monitor (Oxford/Sonicaid, Oxon, UK), which was interfaced with an Oxford computer (Oxford/Sonicaid) through its RS 232 port. Details of the FHR recordings were obtained as described elsewhere.l~ ~3 An FHR tracing signal loss of less than 10% over a 1-hour period was deemed acceptable. Upon requesting analgesia, all patients were again examined vaginally by the same initial examiner, then randomly assigned to receive either IV meperidine 50 mg or nalbuphine 10 mg (both are commonly used dosages). 7 The randomization was performed by a computergenerated random-number table with the Epilnfo program (USD Inc., Stone Mountain, GA). The medications were then randomly assigned with the Epilnfo program and placed into sequentially numbered, sealed envelopes. On a patient's request for analgesia, we opened each envelope in sequential order and administered the enclosed medication. The patients received no other medications during the study period. Immediately after receiving the assigned analgesic, another continuous 60-minute recording of the FHR was obtained by making simultaneous recordings with both the Hewlett-
442 Giannina et al
Mepcridille arid NtflbuFhiHc
Table 1. Comparison of Maternal and Neonatal Characteristics Between Meperidine and Nalbuphine Groups Characteristic Maternal age (y) Maternal weight (lb) Gestational age (wk) Birth weight (g) Initial cervical dilation (cm) Pre-treatment cervical dilation (cm) Umbilical artery pH at birth
Meperidine (N = 14)
Nalbuphine (N = 14)
20.5 (16-30) 25 (17-37) 150 (129 210) 163 (124-210) 40.1 (38.0-41.3) 39.9 (37.4-41.8) 3370 (2760-3870) 3320(2840-3750) 3 (2-4) 2 (1-4) 4 (2-5) 4 (2-5) 7.27 (7.18-7.37)
7.27 (7.22-7.35)
Data are presented as median (range). Comparisons between groups were not statistically significant.
Packard and Sonicaid monitors, as described previously. With the computer, we analyzed the entire 60-minute pre- and post-treatment periods for both the meperidine and nalbuphine groups. Also, to determine FHR reactivity objectively in the pre- and posttreatment periods, we searched for 20-minute epochs in which there were two computer-identified accelerations of ten or 15 beats per minute and of at least 15-seconds duration. Using the normal reference ranges for long-term variation and accelerations of ten beats per minute for a 15-second duration reported by Snijders et al, 14 we determined that the study would require 28 patients to achieve a power of 90% to detect a change from values at the 50th percentile to values below the fifth percentile at an alpha error of 0.05. Statistical analysis was performed using the Mann-Whitney U, Wilcoxon signedrank, X2, and Fisher exact tests when appropriate. Statistical significance was set at P < .05.
Results Of the 36 patients enrolled, 28 women were studied. Eight patients were eliminated from the analysis because we obtained insufficient tracings for the computer to analyze. There was no statistical difference between the meperidine and nalbuphine groups with respect to the maternal and fetal characteristics listed in Tables 1 and 2. In the nalbuphine group, the one infant with a 1-minute Apgar score less than 7 had an umbilical artery pH of 7.28 at birth. Also, in both cases, the indication for the two cesarean deliveries in the nalbuphine group was arrest of dilation (Table 2). There was 11o intervention for fetal distress in either group. Using a cord artery pH value of less than 7.15 after labor as the definition of acidemia, is we found that no infant demonstrated acidemia at birth in either study group. No
Obstetrics & Gynecology
p a t i e n t in the s t u d y h a d c h o r i o a m n i o n i t i s or r e c e i v e d p r o p h y l a c t i c a n t i b i o t i c s for b e i n g a k n o w n g r o u p B s t r e p t o c o c c u s c a r r i e r d u r i n g t h e e n t i r e i n t r a p a r t u m period. T h e r e w e r e n o statistical d i f f e r e n c e s in the c o m p u t e r F H R c h a r a c t e r i s t i c s b e t w e e n the t w o g r o u p s d u r i n g the p r e - t r e a t m e n t p e r i o d . T h e m e a n p e r c e n t c o m p u t e r signal loss b e t w e e n t h e p r e - a n d p o s t - t r e a t m e n t p e r i o d s in the n a l b u p h i n e g r o u p (5.6 v e r s u s 8.7%) a n d m e p e r i d i n e g r o u p (5.5 v e r s u s 8.4%) w a s n o t s i g n i f i c a n t l y different. T h e m e d i a n t i m e i n t e r v a l b e t w e e n the start of t h e first a n d s e c o n d 6 0 - m i n u t e F H R r e c o r d i n g s w a s n o t signific a n t l y d i f f e r e n t b e t w e e n the n a l b u p h i n e g r o u p (2.4 h o u r s ] r a n g e 1.2-6.3]) a n d the m e p e r i d i n e g r o u p (1.9 h o u r s [ r a n g e 1.2-4.9]). T h e r e w a s n o d i f f e r e n c e in t h e m e a n n u m b e r of c o n t r a c t i o n s p e r h o u r b e t w e e n t h e p r e - t r e a t m e n t a n d p o s t - t r e a t m e n t p e r i o d s in the m e p e r i d i n e g r o u p (19.1 + 0.83 v e r s u s 19.5 + 0.94 c o n t r a c t i o n s p e r h o u r , P = 0.17) as w e l l as in the n a l b u p h i n e g r o u p (19.1 + 1 v e r s u s 19.7 + 0.9 c o n t r a c t i o n s p e r h o u r , P 0.15). T h e r e also w a s n o d i f f e r e n c e in the c o n t r a c t i o n f r e q u e n c y w h e n a c o m p a r i s o n w a s m a d e b e t w e e n the p o s t - t r e a t m e n t p e r i o d s of b o t h g r o u p s (P = 0.62). T h e r e w a s n o s i g n i f i c a n t d i f f e r e n c e in a n y of the computer FHR characteristics between the pret r e a t m e n t a n d p o s t - t r e a t m e n t p e r i o d s in t h e m e p e r i d i n e g r o u p (Table 3). C o m p a r e d w i t h the p r e - t r e a t m e n t p e r i o d , n a l b u p h i n e s i g n i f i c a n t l y d e c r e a s e d the n u m b e r of a c c e l e r a t i o n s of ten a n d 15 b e a t s p e r m i n u t e , a n d the m i n u t e s s p e n t in e p i s o d e s of h i g h v a r i a t i o n , l o n g - t e r m variation, and short-term variation. Nalbuphine did not
Table 2. Comparison of Selected Maternal and Neonatal Characteristics Between Meperidine and Nalbuphine Groups Characteristic
Meperidine (N = 14)
Nalbuphine (N 14)
1 (7.1%) 2 (14.3%) 5 (35.7%) 6 (42.9%)
1 (7.1~7~) 3 (21.4q~) 7 (50~7,) 3 (21.4~a)
9 (64.3~/,) 5 (35.7%)
6 (42.9'~) 8 (57.19~)
0 0
1 (7.19~) 0
Race Asian Black Hispanic White Parity Primiparous Multiparous Apgar score <-7 at 1 min <-7 at 5 min Mode of delivery Cesarean Vaginal Umbilical artery pH at birth <7.15 ~>7.15
0 14 (100%)
2 (14.3'~) 12 (85.7¢,~)
0 14 (100%)
0 14 (100~7,)
Data are presented as n (%). Comparisons between groups were not statistically significant.
VOL. 86, NO. 3, SEPTEMBER 1995
Table 3. Effects of Meperidine Compared With PreTreatment Periods on Computer-Analyzed Fetal Heart Rate Characteristics Characteristic
Pre-treatment
Post-treatment
Baseline EHR (bpm) Accelerations of at least 10 bpm Accelerations of at least 15 bpm Episodes of high variation (rain) Episodes of low variation (min) Long-term variation (msec) Short-term variation (msec)
138.5 (120-154)
141.5(119-157)
Median % change 2.2
13.5 (2-24)
10.5 (1-23)
22.2
5.0 (0-15)
6.0 (0-18)
20.0
19.0 (6-42)
19.0 (0-42)
0
10.5 (0 19)
6.0 (0-40)
42.9
40.1 (24.8 69.5)
43.6 (18.6-80.3)
8.7
6.5 (5.0-10.6)
7.1 (3.7-14.4)
9.2
FHR fetal heart rate; bpm - beats per minute. Data are presented as median (range), unless specified. Comparisons between groups were not statistically significant. -
alter the b a s e l i n e F H R o r t h e m i n u t e s s p e n t in e p i s o d e s of l o w v a r i a t i o n w h e n c o m p a r e d w i t h t h e p r e - t r e a t m e n t p e r i o d (Table 4). W h e n c o m p a r i n g t h e effects of n a l b u p h i n e a n d m e peridine on computer-determined FHR tracing reactivity ( d e f i n e d as h a v i n g t w o a c c e l e r a t i o n s of 15 b e a t s p e r m i n u t e a b o v e b a s e l i n e for at least 15 s e c o n d s ) , n a l b u p h i n e s i g n i f i c a n t l y d e c r e a s e d the i n c i d e n c e of r e a c t i v e F H R t r a c i n g s (93 v e r s u s 57%, P = .04), w h e r e a s m e p e r i d i n e d i d n o t (71 v e r s u s 86%). W h e n F H R r e a c t i v i t y w a s d e f i n e d as h a v i n g t w o a c c e l e r a t i o n s of ten b e a t s p e r m i n u t e a b o v e b a s e l i n e for at least 15 s e c o n d s , the
Table 4. Effects of Nalbuphine Compared With PreTreatment Periods of Computer-Analyzed Fetal Heart Rate Characteristics Characteristics
Pre-treatment
Median Post-treatment % change
Baseline FHR 135.5 (125-140) 134.5(120-149) (bpm) Accelerations of 17.0 (3-23) 4.0 (1-24) at least 10 bpm Accelerations of 10.0 (2-20) 1.5 (0 6) at least 15 bpm Episodes of high 35.5 (0-48) 10.0 (0-29) variation (min) Episodes of low 5.5 (0 22) 11.0 (0-38) variation (rain) Long-term 47.0 (23.8-72.8) 29.8 (21.2-50.3) variation (msec) Short-term 8.4 (4 12.9) 6.4 (4.4-10.9) variation (msec)
-0.74
P NS
76.50 .003 -85.0
.001
-71.8
.004
100.0
NS
-36.6
.002
23.8
.03
FHR fetal heart rate; NS = not significant; bpm = beats per minute. Data are presented as median (range), unless specified.
G i a n n i n a et al
Meperidine and Nalbuphine 443
Table 5. Comparison of Effects of Meperidine and Nalbuphine on Fetal Heart Rate Tracing Reactivity Using Computer Analysis Two accels of 10 bpm in 20 rain Medication
Pre-treatment
Meperidine 13/14 (93',;) Nalbuphine 13/14 (93~,i) accels accelerations;bpm beatsper minute. * P .04.
Pre-treatment
Post-treatment
13/14 (93';'i) 12/14 (86~~,)
10/14 (71'>~) 13/14 (93~)
12/14 (86%) 8/14 (57%)*
Discussion Despite the increasing use of epidural analgesia during labor, parenteral narcotic agents remain frequently used for intrapartum analgesia. Traditionally, meperidine has been the drug of choice in many institutions for relieving the pain of labor. Although meperidine is effective as an analgesic, it has marked adverse effects when used in labor, including maternal nausea and vomiting, ~ maternal and neonatal depression, 2"3 and FHR changes.~'4 Petrie et al 4 demonstrated a decrease in the FHR variability that began 10 minutes after administration of meperidine and recovered 30 minutes after the injection. We could not demonstrate an effect on the short- and long-term variation with the use of meperidine. Noting the adverse effects of meperidine when used intrapartum, others have evaluated the narcotic agonistantagonist agents (ie, nalbuphine) during labor] ~,5,7.~ Nalbuphine seemed to be an attractive alternative for intrapartum analgesia, particularly because of its ceiling effect on respiratory depression. The maximum respiratory depression noted with nalbuphine occurs at a dose of 30 mg per 70 kg and is easily reversed with 0.4 mg of nalaxone." Nalbuphine has been studied extensively when used in labor. Wilson et al 5 investigated the pharmacokinetics of nalbuphine in labor and found an initial distribution phase of 4-20 minutes and a terminal half-life of 2.4 _+ 0.4 hours. Wilson et al also reported that nalbuphine entered the fetal circulation with values ranging from one-third to six times the simultaneous maternal concentration. The placental transfer of nalbuphine after IV administration is believed to be more rapid than meperidine, as reported in an abstract by Dadabohoy et al (Dadabohoy ZP, Tapia DP, Zsigmond EK. Transplacental transfer of nalbuphine in patients undergoing cesarean section. Anesth Analg 1985;64: 205). The placental transfer of meperidine after IV administration has also been documented to be rapid. Crawford et a117 demonstrated that meperidine was found in the umbilical vein within two minutes of IV administration. Rosen and Bleyer is found that the avMepcridine ami Nalbuphim,
accels of 15 bpm in 20 min
Post-treatrnent
computer did not detect a change in reactivity associated with either nalbuphine or meperidine (Table 5).
444 Giannina et al
Two
erage time to detect fetal electroencephalogram changes in an animal model after the IV administration of meperidine was 69 seconds. Because the placental transfer of both meperidine and nalbuphine have been shown to be rapid (ie, within 2 minutes), it was appropriate for us to record the FHR immediately after administration of the medication to detect an effect. Although there are multiple reports evaluating meperidine and nalbuphine in labor, the reported effects on the FHR tracings are limited to subjective visual evaluations. Frank et al 2 showed that neither nalbuphine nor meperidine affected the baseline FHR. Based on our results, we agree with their conclusions. Wilson et al 1 observed no differences in the long-term variability of the FHR tracings after the administration of nalbuphine compared with meperidine; they provided no support for their statement. Based on the findings of our study, we noted a significant change in FHR characteristics associated with the use of nalbuphine as objectively quantified by computer analysis. Finally, in a letter, a case of immediate fetal bradycardia was reported after nalbuphine was given in labor (Guillonneau M, Jacquz-Aigrain E, Decrepy A, Zeggout H. Perinatal adverse effects of nalbuphine given during parturition. Lancet 1990;335:1588). We could support no association between nalbuphine and fetal bradycardia with our findings. The main problem with all of the reports on meperidine and nalbuphine's effects on FHR tracings is that they are based on subjective interpretations of FHR tracings. The important intra- and inter-observer differences ill the assessment of intrapartum cardiotocograms has been documented in the range of 22-60%. q Several objective methods have been developed for quantifying FHR characteristics, including variability such as mathematic models ~* and computerized methods. Dawes et al u~'2° supported the objective evaluation of FHR tracings by computer analysis as a valid tool in the assessment of fetal well-being. Computer analysis has been used to evaluate the effect of magnesium sulfate and phenytoin on the FHR tracing] ~'2~ We do not know of any report using computer analysis to interpret the effects of meperidine or nalbuphine on the intrapartum FHR pattern. In our study, we saw a significant decrease in several Obstetrics & Gynecology
of t h e F H R c h a r a c t e r i s t i c s a s s o c i a t e d w i t h n a l b u p h i n e w h e n u s i n g c o m p u t e r analysis. M e p e r i d i n e d i d n o t alter a n y of t h e F H R c h a r a c t e r i s t i c s to a statistically s i g n i f i c a n t d e g r e e . W e d e m o n s t r a t e d t h e lack of an effect o n the F H R b y m e p e r i d i n e , w h i c h is in d i r e c t conflict w i t h the o p i n i o n of m a n y p h y s i c i a n s . D e s p i t e the s m a l l n u m b e r of p a t i e n t s s t u d i e d , w e b e l i e v e that the t w o g r o u p s w e r e e q u a l a n d t h a t o u r r a n d o m i z a t i o n p r o c e s s w a s effective. Also, w e a t t e m p t e d to m i n i m i z e the p o t e n t i a l effect of l a b o r o n a n y of t h e F H R t r a c i n g s b y l i m i t i n g t h e s t u d y to the e a r l y i n t r a p a r t u m p e r i o d b y e n r o l l i n g o n l y t h o s e p a t i e n t s w i t h c e r v i c a l d i l a t i o n of 4 c e n t i m e t e r s or less. A l t h o u g h w e f o u n d a statistically s i g n i f i c a n t d e c r e a s e f r o m t h e p r e - t r e a t m e n t p e r i o d in a c c e l e r a t i o n s of t e n a n d 15 b e a t s p e r m i n u t e , m i n u t e s s p e n t in e p i s o d e s of h i g h v a r i a t i o n , l o n g - a n d shortt e r m v a r i a t i o n a s s o c i a t e d w i t h t h e u s e of n a l b u p h i n e , a n d t h e p o s t - t r e a t m e n t v a l u e s for l o n g - a n d s h o r t - t e r m v a r i a t i o n w e r e still w i t h i n the n o r m a l r a n g e for t e r m fetuses. T h e d e t e r m i n a t i o n of fetal w e l l - b e i n g b y v i s u a l a n a l y s i s of F H R r e a c t i v i t y m a y n o t h a v e b e e n p o s s i b l e b e c a u s e t h e r e w a s a s i g n i f i c a n t d e c r e a s e in c o m p u t e r d e t e r m i n e d r e a c t i v i t y u s i n g a c c e l e r a t i o n s of 15 b e a t s p e r minute associated with nalbuphine. W e c o n c l u d e that at a c o m m o n l y u s e d d o s e , n a l b u p h i n e s i g n i f i c a n t l y alters i n t r a p a r t u m F H R t r a c i n g s w h e n u s e d for a n a l g e s i a in e a r l y l a b o r in u n c o m p l i c a t e d p r e g n a n c i e s at term. A t a c o m m o n l y u s e d d o s e , m e p e r i d i n e has n o s i g n i f i c a n t effect o n the F H R tracing. This c o u l d b e of v a l u e for a clinician w h e n c h o o s i n g an appropriate intrapartum analgesic without influencing t h e F H R tracing.
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pethidine and nalbuphine during labor: A prospective doubleblind comparative study. Gynecol Obstet Invest 1991;32:39 43. 8. Feinstein SJ, Lodeiro JG, Vintzileos AM, Campbell WA, Montgomery JT, Nochimson DJ. Sinusoidal fetal heart rate pattern after administration of nalbuphine hydrochloride: A case report. Am J Obstet Gynecol 1986;154:159-60. 9. Nielsen PV, Stigsby B, Nickelsen C, Nim J. Intra- and interobserver variability in the assessment of intrapartum cardiotocograms. Acta Obstet Gynecol Scand 1987;66:421-4. 10. Dawes GS, Moulden M, Redman CWG. The advantages of computer fetal heart rate analysis. J Perinat Med 1991;19:39-45. 11. Dawes GS, Visser GH, Goodman JD, Redman CW. Numerical analysis of the human fetal heart rate: The quality of ultrasound records. Am J Obstet Gynecol 1981;141:43-52. 12. Visser GH, Dawes GS, Redman CW. Numerical analysis of the normal fetal heart rate. Br J Obstet Gynaecol 1981;88:792-802. 13. Guzman ER, Conley M, Stewart R, Ivan J, Pitter M, Kappy K. Phenytoin and magnesium sulfate effects on fetal heart rate tracings assessed by computer analysis. Obstet Gynecol 1993;82:375-9. 14. Snijders RJM, McLaren R, Nicolaides KH. Computer-assisted analysis of fetal heart rate patterns at 20-41 weeks' gestation. Fetal Diagn Ther 1990;5:79-83. 15. Vintzileos AM, Egan JFX, Campbell WA, et al. Asphyxia at birth as determined by cord blood pH measurements in preterm and term gestations: Correlation with neonatal outcome. J Maternal-Fetal Med 1992;1:7-13. 16. Podlas J, Breland BD. Patient-controlled analgesia with nalbuphine during labor. Obstet Gynecol 1987;70:202-4. 17. Crawford JS, Rudofsky S. The placental transfer of pethidine. Br J Anaesth 1965;37:929-33. 18. Rosen MG, Bleyer WA. Bidirectional transfer of meperidine across the guinea pig placenta. Am J Obstet GynecoI 1968;101:918-22. 19. Parer WJ, Parer JT, Holbrook RH, Block BSB. Validity of mathematical methods of quantitating fetal heart rate variability. Am J Obstet Gynecol 1978;130:294-9. 20. Dawes GS, Houghton CRS, Redman CWG, Visser GHA. Pattern of the normal human fetal heart rate. Br J Obstet GynecoI 1982;89: 276-84. 21. Atkinson MW, Belfort MA, Saade GR, Moise KJ. The relation between magnesium sulfate therapy and fetal heart rate variability. Obstet Gynecol 1994;83:967-70.
Address reprint requests to: Edwin R. Guzman, MD St. Peter's Medical Center MOB Fourth Floor 254 Easton Avenue New Brunswick, NJ 08901
Received January 11, 1995. Received in revisedform May 4, 1995. Accepted May 8, 1995. Copyright © 1995 by The American College of Obstetricians and Gynecologists.
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