Divon et al.

enhance fetal breathing movements (e.g., by maternal glucose administration). 12

Studies are presently under way to investigate the effects of asphyxia and drug administration on "respi­ratory sinus arrhythmia" in the human fetus.

REFERENCES 1. Martin CB. Physiology and clinical use of fetal heart rate

variability. Clin Perinatol 1982;9(2):339-52. 2. Davies CTM, Neilson JMM. Sinus arrhythmia in man at

rest. J Appl Physiol 1967;22(5):947-55. 3. Divon MY, Sarna Z, Vilenski A, Zimmer EZ, Peretz BA,

Paldi E. Comprehensive fetal monitoring by microcom­puter-a clinical approach. Com put Bioi Med 1984; 14(2): 151-7. . .

4. Yeh SY, Forsythe A, Hon EH. Quantification of fetal heart beat-to-beat interval differences. Obstet Gynecol1973;41: 355-63.

5. Timor-Tritsch I, Zador I, Hertz RH, Rosen MG. Human fetal respiratory arrhythmia. AM j 0BSTET GYNECOL 1977;127:662-6.

6. Wheeler T, Gennser G, Lindvall R, Murrillis AJ. Changes

February l, 1985 Am J Obstet Gynecol

in fetal heart rate associated with fetal breathing and fetal movement. Br J Obstet Gynaecol1980;87:1068-79.

7. Botts RSGM, Johgsma HW, Braat AJHM, Martin CB, deHaan J. Human fetal breathing movements and heart rate variability. Proceedings of the Fifth Conference on Fetal Breathing, Nijmegen, Holland, 1978:45.

8. Dawes GS, Visser GHA, Goodman JDS, Levine DH. Nu­merical analysis of human fetal heart rate: modulation by breathing and movement. AMJ 0BSTET GYNECOL 1981; 140:535-44. .

9. Manning FA, Lange IA, Morrison I, Harman CR. Deter­mination of fetal health methods for antepartum and in~ trapartum fetal assessment. Curr Probl Obstet Gynecol 1983;7(4):1-63.

~0. Melcher A. Respiratory sinus arrhythmia in man: a study in heart rate regulating mechanisms. Acta Physiol Scand Suppl 1976;435: 1-31.

11. Akselrod S, Gordon G, Ubel FA, Shannon, DC, Barger AC, Cohen RJ. Power spectrum analysis of heart rate fluc­tuation: a quantitative probe of beat-to-beat cardiovas­cular control. Science 1981;213:220-2.

12. Lewis PJ, Trudinger BJ, Mangez J. Effect of maternal glucose ingestion on fetal breathing and body movements in late pregnancy. Br J Obstet Gynaecol1978;85:86-9.·

Disposition of meperidine and normeperidine following

multiple doses during labor

I. Mother

Betty R. Kuhnert, Ph.D., Elliot H. Philipson, M.D., Paul M. Kuhnert, Ph.D., and Carol D. Syracuse, B.S.

Cleveland, Ohio

Normeperidine, the active meperidine metabolite, has been implicated in adverse neonatal effects that may occur following administration of meperidine to parturients. However, recent studies· have suggested that normeperidine levels are not high enough to have adverse effects following single low doses of meperidine. It is not clear what occurs following multiple injections. Therefore the purpose of this study was to quantitate plasma levels of meperidine and normeperidine in the mother following multiple doses of meperidine over long time periods and to determine the half-life of normeperidine. Twelve mothers who received multiple intravenous doses of meperidine were studied. The results show that both meperidine and normeperidine accumulate in maternal plasma following multiple injections and that the half-life of normeperidine averages 20.6 hours. The data suggest that maximum exposure of the fetus to both meperidine and normeperidine would result from multiple doses to the mother because of a continued diffusion gradient from mother to fetus. (AM J OBSTET GYNECOL 1985;151 :406-9.)

Key words: Mother, pregnancy, drugs, meperidine

From the Department of Obstetrics and Gynecology and the Perinatal Clinical Research Center, Cleveland Metropolitan General Hos­pital/Case Western Reserve University.

Supported in part by National Institutes of Health Grant No. 5M01-RR-00210.

Received for publication November 2, 1983; revised July 31, 1984; accepted September 18, 1984.

Reprint requests: Betty R. Kuhnert, Ph.D., Department of Obstetrics and Gynecology, Cleveland Metropolitan General Hospital, 3395 Scranton Road, Cleveland, OH 44109:

406

Normeperidine, the pharmacologically active me­peridine metabolite, has been implicated asthe cause of respiratory depression in infants born 2 to 3 hours following meperidine administration to the mother. 1

However, recent studies have suggested that following single doses and short drug-to-delivery intervals, depression in the newborn infant appears to be related more to the total amount of meperidine transferred to

Volume 151 Number 3

the fetus before delivery than to the presence of nor­meperidine. 2-7

Normeperidine may have a clinical effect, however, if meperidine is given to the mother as repeated injec­tions with long drug-to-delivery intervals. 6 The fact that normeperidine is excreted more slowly than meperi­dine supports this hypothesis.8• 9 Although the half-life in parturients is not well documented, normeperidine would be expected to accumulate in maternal as well as fetal plasma following multiple doses.8• 9 Thus an infant born to a mother who has received several in­jections of meperidine over long periods of time may have considerable normeperidine levels at birth.

Therefore the purpose of this study was to document the disposition of meperidine and normeperidine in maternal plasma following multiple doses of meperi­dine and to determine the half-life of normeperidine in these patients.

Material and methods

Patients. Twelve pregnant women were studied. Me­peridine was administered intravenously as needed for pain relief. Patients with liver or renal disease or his­tories of substance abuse were eliminated from the study. Others with mild pregnancy complications were included as long as meperidine administration was ap­propriate. This study was approved by the Human In­vestigation Committee of Cleveland Metropolitan Gen­::ral Hospital, and appropriate informed consent was obtained from each patient prior to inclusion in the study.

Sample collection and data analysis. Intrapartum maternal blood samples were collected at various in­tervals following meperidine injection as previously de­scribed. 10• 11 Postpartum blood samples were collected from four of the mothers every 24 hours for 72 hours.

Meperidine was extracted from plasma with the use of the technique of Mather and Tucker12 and quanti­tated by gas chromatography-mass spectrometry. 7

Semilogarithmic plots showing the disappearance of meperidine and normeperidine in maternal plasma were obtained by plotting concentrations of drugs in plasma against the time since injection of meperidine. Half-lives were estimated from the disappearance of the compounds in plasma. Normeperidine/meperidine ratios were calculated by dividing the amount of nor­meperidine in a given sample by the amount of me­peridine in the same sample. Statistics and calculations were done by means of the statistical and linear or exponential curve-fitting programs for a Hewlett Pack­ard 41 C programmable calculator.

Results

Patient population. The clinical characteristics and amount of mep~ridine administered to the mothers are shown in Table I. One cesarean section was performed

Disposition of meperidine and normeperidine. I 407

Table I. Characteristics of the maternal study population

Characteristic

No. of mothers Antenatal characteristics

Age (yr)* Nulliparous Multiparous

Intrapartum analgesia Meperidine (No. of

doses) Total dose (mg) Drug-to-delivery

interval: first dose (min)

Drug-to-delivery interval: final dose (min)

Delivery method (n) Vaginal Primary cesarean

section Complications (n)

Preeclampsia >200 lb Sickle cell disease Smoking Premature rupture of

membranes

*Mean: ± SD (range).

Number

12

22.6 ± 4.5 (17-32) 9 3

2.58 ± 0.79 (2-4)

79.04 ± 25.9 (50-125) 303 ± 190 (93-702)

150 ± 110 (51-401)

10 2

3 I 1 4 1

because of fetal distress and the second for failure to progress following premature rupture of membranes. The neonatal outcomes of these pregnancies are pre­sented in a companion paper. u

Intrapartum plasma drug levels. A disappearance curve from a typical patient resulting from three suc­cessive injections of 25 mg of meperidine at hourly intervals and the corresponding appearance curves of normeperidine are shown in Fig. I. These curves show that both meperidine and normeperidine plasma levels steadily increase with time. Plasma levels of meperidine an hour after the second or third dose were typically two to three times higher than those at I hour after the first dose. Plasma levels of normeperidine increased at variable rates in individual patients. No differences were apparent in patients with medical complications.

The mean maternal plasma meperidine and nor­meperidine levels at delivery and the normeperidine/ meperidine ratio are shown in Table II. A delivery sample was not obtained from one patient. No signif­icant correlation was observed between normeperi­dine levels and the drug-to-delivery interval. However, the proportion of normeperidine to meperidine in­creased significantly (r = 0.77, p < 0.01, Y = 0.03 + 0.000753X) with time; the high observed was 58%. Fig. 2 illustrates this relationship.

Postpartum plasma drug levels. Samples were col­lected from four mothers post partum and the mean half-life of normeperidine was estimated to be 20.55 ± 3.61 hours (range, 17.3 to 24.8 hours). At 24 hours

408 Kuhnert et al.

10,000

X Mependine • Normeperidine

1000

-E .....

"' c

z 0 j:: 100 <[ 0:: 1-z w v--.....---u z 0 u

t 25mq 25mq 25mq

15 30 60 90 120 150 lBO 210 216

TIME (MINUTES)

Fig. 1. Plasma concentrations of meperidine and normeper­idine following multiple doses of meperidine during labor.

Table II. Maternal meperidine and normeperidine levels (ng/ml) and the normeperidine/meperidine ratio at delivery

Meperidine Normeperidine Normeperidine/meperidine*

I Mean± SD

129.2 ± 57.5 33.6 ± 19.9 0.26 ± 0.17

Range

65.6-268.2 10.5-69.1 0.09-0.58

*Corresponds to an average injection-to-delivery interval of 275 min from the first dose.

post partum, plasma normeperidine levels were similar to those found at delivery, whereas meperidine levels were very low. For this reason, not enough data points were available to calculate the postpartum half-life of meperidine in these patients. However, in two of the mothers, meperidine was detectable for at least 48 hours.

Comment Intrapartum plasma drug levels. Both meperidine

and normeperidine levels in maternal plasma increase

with repeated injections. Although this is not surpris­ing, there may be implications for the fetus that may not have been considered. When a single dose of me­peridine is given, uptake of meperidine into fetal tissues occurs for 2 to 3 hours, at which point the diffusion gradient reverses and meperidine begins to be cleared

1 OOI 0 .80 i= < a: w z 0 .60 0: w a.. w :::!: .... w z 0

.40

0: w a.. w :::!: a: .20 0 z

February l, 1985 Am J Obstet Gynecol

200 400 ~00 DRUG/DELIVERY INTERVAL (min)

Fig. 2. The relationship between the normeperidine/meper­idine ratio and the drug-to-delivery interval.

from fetal tissues. 2· 5• 6 When multiple doses of meper­idine are given, uptake into fetal tissues occurs as be­fore, but the concentration gradient does not have time to reverse before the next injection. Uptake of meper­idine into fetal tissues would continue for at least 2 to 3 hours after the last dose.

With respect to normeperidine, its level also increases in maternal plasma, and the proportion of normeper­idine to meperidine increases with time. Therefore fe­tal tissue uptake of normeperidine by diffusion will continue, and fetal levels will be augmented by what is produced by fetal metabolism. Normeperidine should

accumulate in fetal tissues for many hours following the last dose of meperidine. At the highest levels, nor­meperidine may be clinically relevant, since it could add to the effects of the meperidine already present.6

Postpartum plasma drug levels. The half-life of me­peridine has consistently been reported to be approx­imately 3 to 7 hours.•· 5• 10• 14 However, several of the mothers in this study had detectable meperidine levels for as long as 48 hours. These results are in agreement with a recent study by Morrison et a!., 15 who also re­ported the presence of meperidine in maternal plasma for as long as 48 hours. The results of these two studies suggest that the postpartum half-life of meperidine in maternal plasma may have been underestimated by ear­lier investigators.

To our knowledge, the absolute half-life of norme­peridine in the puerperium has not previously been published although several studies have suggested that it is "prolonged."•· "· 15 Finding a mean half-life of >20

Volume 151 Number3

hours for these patients suggests that normeperidine would still be increasing in maternal plasma for hours after delivery of the infant.

In summary, the results of this study suggest that with multiple doses, the drug and its metabolite would continuously accumulate in the fetus because of the continued diffusion gradient from mother to fetus. This would result in maximum accumulation of both compounds in fetal tissues at birth.

REFERENCES

1. Morrison 1C, Wiser WL, Rosser Sl, et al. Metabolites of meperidine related to fetal depression. AM 1 0BSTET GY­NECOL 1973;115:1132.

2. Kuhnert BR, Kuhnert PM, Tu AL, Lin DCK. Meperidine and normeperidine levels following meperidine admin­istration during labor. II. Fetus and neonate. AM1 OBSTET GYNECOL 1979;133:909.

3. Edwards D1, Svensson CK, Visco 1P, Lalka D. Clinical pharmacokinetics of pethidine: 1982. Clin Pharmacokinet 1982;7:421.

4. Talafre ML, Rovei V, Barrier G, et al. Pharmacocinetique de Ia pethidine chez le nouveau-ne et Ia mere pendant le travail. Pharmacol Dev 1979;89:287.

5. Morselli PL, Rovei V. Placental transfer of pethidine and norpethidine and their pharmacokinetics in the newborn. Eur 1 Clin Pharmacoll980;18:25.

6. Belfrage P, Boreus LO, Hartvig P, Irestedt L, Raabe N. Neonatal depression after obstetrical analgesia with peth­idine: the role of the injection-delivery time interval and

Disposition of meperidine and normeperidine. I 409

of the plasma concentrations of pethidine and norpethi­dine. Acta Obstet Gynecol Scand 1981;60:43.

7. Kuhnert BR, Kuhnert PM, Knapp DR. Relationship be­tween cord vein normeperidine and time. AM 1 0BSTET GYNECOL 1980;137:518.

8. Dahlstrom BE, Paalzow LK, Lindberg C, Bogentoft C. Pharmacokinetics and analgesic effect of pethidine (me­peridine) and its metabolites in the rat. Drug Metab Dispos 1979;7: 108.

9. Szeto HH, Inturrisi CE, Houde R, Saal S, Cheigh1, Rei­denberg MM. Accumulation of normeperidine, an active metabolite of meperidine, in patients with renal failure or cancer. Ann Intern Med 1977;86:738.

10. Kuhnert BR, Kuhnert PM, Tu AL, Lin DCK. Meperidine and normeperidine levels following meperidine admin­istration during labor. I. Mother. AM 1 0BSTET GYNECOL 1979;133:904.

11. Kuhnert BR, Kuhnert PM, Prochaska AL, Sokol RJ. Me­peridine disposition in mother, neonate, and nonpreg­nant females. Clin Pharmacol Ther 1980;27:486.

12. Mather LE, Tucker GT. Meperidine and other basic drugs: general method for their determination in plasma. 1 Pharm Sci 1974;63:306.

13. Kuhnert BR, Kuhnert PM, Philipson EH, Syracuse CD. Disposition of meperidine and normeperidine following multiple doses during labor. II. Fetus and neonate. AM 1 0BSTET GYNECOL 1985;151:410.

14. Caldwell1, Wakile LA, Notarianni L1, et al. Maternal and neonatal disposition of pethidine in childbirth-a study using quantitative gas chromatography-mass spectrome­try. Life Sci 1978;22:589.

15. Morrison 1C, Todd EL, Lipshitz 1. et al. Meperidine metabolism in the parturient. Obstet Gynecol 1982;59: 359.