Disposition of meperidine and normeperidine following

multiple doses during labor

II. Fetus and neonate

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

Cleveland, Ohio

It has been suggested that continued diffusion gradients from mother to fetus would exist and that both

meperidine and normeperidine would accumulate in the fetus following multiple doses of meperidine to the

mother during labor. However, no pharmacokinetic data are available. Therefore, the purpose of this

study was to document the disposition of meperidine and normeperidine in the fetus and neonate following

multiple doses of meperidine to the mother over long time periods. Twelve infants were studied. The results

show surprisingly high concentrations of both meperidine and normeperidine in fetal blood at delivery.

In addition, the amount of normeperidine increased with time in umbilical cord blood, the ratio of

normeperidine to meperidine increased with time, and the umbilical artery-to-vein ratio of meperidine (but

not normeperidine) was greater than one following long drug-to-delivery intervals. The data also suggest

that with long drug-to-delivery intervals the levels of normeperidine may become clinically important

and that the elimination of both compounds by the neonate is prolonged. The study suggests that multiple

doses to the mother over long time periods result in maximum accumulation of both meperidine and

normeperidine in fetal tissues. (AM J OBSTET GYNECOL 1985;151 :41 0-5.)

Key words: Fetus, drugs, meperidine

Infants born 2 to 3 hours following meperidine ad­ministration to the mother have repeatedly been shown to have the highest incidence of respiratory depres­sion. 1"3 • Since no relationship could be demonstrated between cord blood meperidine levels and this time interval,I· 4 it was hypothesized that normeperidine, the pharmacologically active metabolite of meperidine,5

was responsible. However, normeperidine levels are too low to explain any respiratory depression in the neonate following single low doses of meperidine.6- 13

Furthermore, fetal tissue uptake of meperidine, but not normeperidine, reaches a maximum approxi­mately 2 to 3 hours following its administration to the mother6 • 9• 10 ; in contrast, normeperidine levels are high­est with longer time intervals. 10· 11 Thus, following single doses and short drug-to-delivery intervals, depression in the newborn appears to be related more to the total

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 October 21, 1983; revised july 31, 1984; accepted September 19, 1984.

Reprint requests: Betty R. Kuhnert, Ph.D., Department of Obstetrics and Gynecology, Cleveland Metropolitan General Hospital, 3195 Scranton Road, Cleveland, OH 44109.

410

amount of meperidine transferred to the fetus prior to delivery than to the presence of normeperidine.

However, normeperidine may be clinically relevant if meperidine is given to the mother as multiple doses with long drug-to-delivery intervals. 10 This is supported by the accumulation of normeperidine in maternal plasma, particularly following multiple doses. 14 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. Fur­thermore, neonatal clearance of normeperidine is much slower than in the adult,"· 9• 15- 17 and normeperi­dine is not completely antagonized by naloxone. 18

Therefore the purpose of this study was to document the disposition of meperidine and normeperidine in fetal and neonatal plasma and urine following multiple doses of meperidine during labor.

Material and methods

Patients. Twelve neonates whose mothers received multiple low doses of meperidine during labor were studied. Meperidine was administered intravenously to the mothers as needed for pain relief. The clinical char­acteristics of the mothers, the timing and amount of analgesia, and the informed consent procedures have been reported previously. 14

Volume 151 Number3

Sample collection and data analysis. Cord blood samples were collected from 11 of the infants as de­scribed.6· 15 Blood samples were collected from five of the neonates every 24 hours for 72 hours. Neonatal urine samples were also collected as described.6 The goal for each neonate was to obtain six consecutive 12-hour samples. However, neonatal collections were stopped because of skin irritation associated with the collection bags in six of the infants. Data from urine samples are expressed as micrograms of drug excreted. Meperidine was extracted from plasma and urine as previously described. 14

Semilogarithmic plots showing the disappearance of meperidine and normeperidine in neonatal plasma were obtained by plotting concentrations of drugs in plasma against time since birth. Plasma half-lives were estimated. Fetal/maternal ratios were calculated by di­viding the amount of meperidine or normeperidine in !he cord vein at birth by the amount in the maternal vein at birth. Ratios of cord artery to cord vein were calculated by dividing the level of drug in the cord artery by the level found in the cord vein. Normeper­idine/meperidine ratios were calculated by dividing the amount of normeperidine in a given sample by the amount of meperidine in the same sample.

Results Patient population. The neonatal clinical character­

istics are summarized in Table I. One neonate had Ap­gar scores of I at I minute and 7 at 5 minutes. This neonate was delivered by emergency cesarean section under general anesthesia following prolonged fetal heart rate decelerations. There was thick meconium in the amniotic fluid, and a fetal scalp blood pH value prior to birth was 7 .18. The mother had received three doses of meperidine (125 mg total) with a drug-to-de­livery interval of 426 minutes from the first dose and 207 minutes from the last. At delivery the levels of meperidine and normeperidine in the cord vein were 110 and 70.68 ng/ml, respectively. The fetal vein/ma­ternal vein ratios were 0.94 and 1.05, respectively. This infant had the highest level of normeperidine found in the study. The infant responded to a narcotic an­tagonist and was discharged after an u~eventful stay in the nursery.

A second infant had 1- and 5-minute Apgar scores of 2. This fetus demonstrated late decelerations in the second stage of labor. After a measurement of fetal scalp blood pH of 7.32 the patient continued to labor. Subsequently there was a fetal heart rate deceleration to 60 bpm and a midforceps delivery. The neonate had the umbilical cord wrapped tightly around her neck three times, was asphyxiated, and required intubation. Generalized seizures began approximately 20 minutes

Disposition of meperidine and normeperidine. II 411

Table I. Characteristics of the neonatal study population

Characteristic

No. of infants Gestational age (wk)

Birth weight (gm)*

Apgar score <7 (n) 1 min 5min

Complications (n) <37 weeks' gestation Cord entanglement Asphyxia Narcotic antagonist Large for dates Small for dates Abnormal at discharge (seizures)

*Mean ± SD (range).

Number

12 39.9 ± 1.2

(37-41) 3306 ± 501 (2320-4090)

2 1

I 2 2 I 1 I I

after delivery. The mother had received two intrave­nous doses of meperidine (50 mg total) with the first 25 mg dose at 223 minutes and the second at 208 min­utes prior to delivery. Cord vein levels at delivery were 72.96 and 14.86 ng/ml for meperidine and normeper­idine, respectively. The fetal vein/maternal vein ratios were 1.12 and 1.04, respectively. Narcotics. were not thought to be related to the infant's depression. At discharge the infant had an abnormal neurological ex­amination and was receiving pheno~arbital.

The mean, standard deviation, and range of the me­peridine and normeperidine levels in umbilical vein and artery are shown in Table II. A significant rela­tionship was observed between the first injection-to­delivery interval and cord vein normeperidine levels (r = 0. 72, p < 0.5; regression equation, Y = -2.31 + 0.13X).

Table II also shows the fetal vein/maternal vein ratios for both meperidine and normeperidine. There were three infants with meperidine fetal vein/maternal vein ratios > 1, and two of these also had normeperidine fetal vein/maternal vein ratios > 1. All three infants had clinical signs of acidosis and/or the lowest !-minute Ap­gar scores in the study. No significant relationships were found between the fetal vein/maternal vein ratios of either compound and the interval between the first ad­ministration of the drug and delivery.

The mean and range of the umbilical artery/umbil­ical vein ratio of meperidine and normeperidine are shown in Table II. The mean drug-to-delivery intervals for the mothers of these infants was 242 ± 77 minutes. Four of five infants had more meperidine in umbilical artery plasma than in umbilical vein; the one infant who did not have more had the only short drug-to­delivery interval (137 minutes). Only one of the five

412 Kuhnert et al.

1.oof 0

0 i= .80 <( 0: w z 0 a: 0

w .60 Q.; w ::E ...... w ~ 0 a: .40 w lf ? Q.; 0 I I w I I I

::E 10 : * I

0: I I

0 I b X

z .20 0 o Umbilical vein ?

* X Umbilical artery

0 0 1 Pair X

~ 200 400 700

DRUG/DELIVERY INTERVAL (min)

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

infants had more normeperidine in umbilical artery than in umbilical vein; this infant's drug-to-delivery in­terval was 298 min.

The proportion of normeperidine to meperidine in fetal blood increased significantly with time (Fig. 1) (r = 0.96, p < 0.01 [Y = -0.21 + 0.00214X] and r = 0.91, p < O.Ql [Y = -0.07 + 0.00126X] forum­bilical vein and artery, respectively). The mean (and range) normeperidine/meperidine ratios in umbili­cal vein and artery respectively at delivery were 0.37 ± 0.38 (0.12 to 1.43) and 0.23 ± 0.11 (0.10 to 0.37). One infant was found with more normeperidine than meperidine in the umbilical vein at delivery. This infant's twrmeperidine/meperidine ratio was 1.43 fol­lowing a drug-to-delivery interval of 702 minutes from the first dose and 216 minutes from the second of four

25 mg doses. Neonatal plasma. Representative neonatal plasma

profiles of meperidine and normeperidine concentra­tions for four of the infants are shown in Fig. 2, A to D. A fifth infant had a profile similar to that in Fig. 2, C. In all of the infants the meperidine level decreased rapidly and the level of normeperidine was higher than meperidine by the end of the second 24 hours of life. In two infants a definite increase in normeperidine level

February 1, 1985 Am J Obstet Gynecol

was seen in the first or second day (Fig. 2, A and B);

in one infant the normeperidine level remained almost constant for over 72 hours (Fig. 2, D).

The half-lives of meperidine and normeperidine are shown in Table III. In two infants the normeperidine half-life could not be calculated because of the nonlin­earity of the disappearance (see Fig. 2, A and D).

Neonatal urine. Three or more urine samples were collected from six infants during the first 72 hours of life. Complete collections from three of the infants sug­gested that 0.24% of the maternal dose is excreted by

the infant in the form of meperidine and 0.11% in the form of normeperidine. When both compounds are combined, 0.36% of the maternal dose is excreted.

Fig. 3 illustrates the excretion of meperidine and normeperidine. Most of the meperidine is excreted be­fore the first 24 hours, but both meperidine and nor­meperidine are still being excreted when the infants are discharged. Neither is excreted in a linear fashion. Meperidine excretion increases between 12 and 24 hours, whereas normeperidine increases steadily for the first 36 hours before decreasing.

Comment

Study population. The outcomes of two of the preg­nancies are relevant to the study. Of particular interest is the infant with Apgar scores of 1 and 7 at birth who responded to the narcotic antagonist. The level of me­peridine in this infant's cord vein was not exceptionally high compared to that of the rest of the study popu­lation, but the level of normeperidine was the highest noted. Furthermore, the fetal vein/maternal vein ratios were also among the highest noted. Although no con­clusions can be drawn from the case of one infant with

a high normeperidine level, it suggests that with long drug-to-delivery intervals a high level of normeperi­dine may result, which could certainly add to the effect of meperidine already present.

Also of interest is the severely asphyxiated infant whose asphyxia was not thought to be due to narcotic depression. In this case the fetal vein/maternal vein ratios were again very high even though the absolute levels of meperidine and normeperidine were low. This suggests that ion trapping of weakly basic drugs in the more acidotic fetal tissues may occur. 19' 20 It is well known that elevated concentrations of local anesthetic agents occur as a result of ion trapping in an acidotic environment, 19 and meperidine and normeperidine would be expected to behave similarly. These two cases suggest that more studies are warranted to consider the relationships between meperidine and normeperidine levels and neonatal outcome.

Umbilical cord plasma. Surprisingly high levels of both meperidine and normeperidine were found in

Volume 151 Number 3

e ..... Cl c:

100

10

A

100

10

c

B

D

C.V. DAY DAY DAY 1 2 3

Disposition of meperidine and normeperidine. II 413

• Mepend1ne

X Normepend~ne

C.V. OAY DAY DAY 1 2 3

Fig. 2. Neonatal plasma concentrations of meperidine and normeperidine.

Table II. Umbilical vein and artery drug levels at delivery

No.

Umbilical vein II

Umbilical artery 5

Umbilical artery/umbilical vein ratio 5

Fetal vein/maternal vein ratiot 11

*Mean ± SD in ng/ml (range). t Mean of ratios, not ratio of means.

some of the fetal cord plasma samples at delivery. Levels as high as 225 ng/ml of meperidine and 71 ng/ml of normeperidine were found in umbilical vein at delivery following administration of only :::;; 125 mg to the mother as multiple low doses over long time periods. This level of meperidine is as high as that seen in ma­ternal plasma shortly after an intravenous injection of 25 mg, 14 and the level of normeperidine is higher than that typically found in maternal plasma. 14 Furthermore, as reported previously, the levels of normeperidine in­crease with timet"· 11 as does the proportion of norme­peridine to meperidine. This was aptly illustrated by the infant with 702-minute drug-to-delivery interval

Meperidine*

97.81 ± 53.8 (23-225.2)

94.35 ± 32.94 (74-153)

1.08 ± 0.15 (0.84-1.22)

0.73 ± 0.28 (0.31-1.16)

N ormeperidine*

27.91 ± 17.62 (8.1-70.7)

23.59 ± 19.16 (8.1-56.7)

0.99 ± 0.45 (0.59-l. 76)

0.84 ± 0.15 (0. 77-1.05)

and the normeperidine/meperidine ratio of 1.43. These findings support the suggestion that accumula­tion of both compounds in fetal tissues will occur for hours following the last dose of meperidine to the mother. Furthermore, this study suggests that the levels of normeperidine cannot always be considered negli­gible as was once suggested. 21· 22

The fetal vein/maternal vein ratios of meperidine and normeperidine are similar to what has been re­ported.6· 8• 13· 15· 16 With long drug-to-delivery i~tervals, the fetal vein/maternal vein ratio for the metabolite was found to be higher than that of the parent compound, which has been reported following intravenous per-

414 Kuhnert et al.

0 w 1-

~

60

(.) 40 X w ~ ;:) a: 0 0, 20 ::I.

(2)

I (5)

D Meperidine

~ Normeperidine

(6) (6)

(4)

24 36 HOURS OF AGE

Fig. 3. Neonatal urinary excretion of meperidine and nor­meperidine.

fusion of meperidine.8 This may be expected, since the metabolite diffusing across the placenta is added to what the fetus is producing.

The umbilical artery/umbilical vein ratios also sup­port continued accumulation of both compounds with multiple doses. A ratio of 1 would mean that the fetal tissues and blood had reached equilibrium and is thought to occur about 2 hours fo!lowing a single dose. 10 In all of the infants with drug-to-delivery inter­vals >3 hours, the meperidine ratio was > 1. This sug­gests that considerable accumulation had occurred and that the diffusion gradient was now from fetal tissues back into fetal blood. (This was observed with an av­erage drug-to-delivery interval from the first dose of 4 hours and from the last dose of 2 hours.) However, the normeperidine umbilical artery/umbilical vein ratio was > 1 in only one infant, which suggests that normeper­idine was still increasing and reaching equilibrium with fetal tissues. Higher levels of normeperidine in cord artery than in cord vein have been reported previously and also demonstrate formation of the metabolite by the fetus.6• 8

Neonatal plasma. In neonatal plasma the half-lives of both compounds are prolonged. The plasma me­peridine half-lives ranging from 11 to 17 hours are in good agreement with previous reports ranging from 6.5 to 15 hours8 or 12 to 39 hours. 16 The half-lives of normeperidine (29-85 hours) were more prolonged than that found in one other study.8 Furthermore, these authors have also noted the increase in normeperidine

February 1, 1985 Am J Obstet Gynecol

Table III. Neonatal half-lives of meperidine and· normeperidine

Half-life in hours

Patient No. Meperidine N ormeperidine

I 11.36 2 11.55 28.88 3 17.33 74.52 4 14.44 84.51 5 11.55

Mean± SD 13.24 ± 2.6 62.63 ± 29.7

levels 24 to 48 hours after birth.8 These prolonged lev­els of normeperidine may have clinical significance9• 10

and may help to explain some of the adverse effects noted days after delivery. 23

Neonatal urine. In neonatal urine the prolonged ex­cretion of meperidine and the prolonged and nonlinear excretion of normeperidine are consistent with the plasma disappearance of these compounds. Further­more, the results of this study are similar to what has been reported pr.eviously following shorter drug-to-de­livery intervals. 6• 15• 24 However, this study also adds the datum that 0.36% of the maternal dose is excreted by the neonate in the forms of meperidine and norme­peridine during the first 72 hours of life.

In summary, the purpose of this study was to provide information regarding fetal and neonatal meperidine and normeperidine levels following multiple doses of meperidine to the mother over long periods of time. The results of this study show that with multiple doses the drug accumulates in fetal tissues because of the continued diffusion gradient from maternal to fetal tissues.14 Furthermore, ion trapping can occur if the fetus is acidotic. Finally, with long drug to delivery in­tervals, the levels of normeperidine may become clin­ically significant because they can account for 60% or more of the total drug present.

The clinical protocol for the administration of me­peridine during labor has changed as more has become known about the pharmacology of the drug in the in­trapartum period.25' 27 The results of this and other re­cent studies6• 10• 14 suggest that single doses are better than multiple doses for the fetus, since multiple dose regimens could lead to maximum accumulation of both meperidine and normeperidine in fetal tissues. Phar­macologically, the best time to be born following ma­ternal analgesia with meperidine would be within 1 hour or >4 hours after a single, low intravenous dose. a· lo."

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Volume 151 Number 3

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Disposition of meperidine and normeperidine. II 415

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