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Methadone assays in pregnant women and progeny
Methadone assaysin pregnant women and progeny GEORGE
BLINICK,
CHARLES
E.
EULOGIO
Data
INTURRISI,
JEREZ,
ROBERT
C.
New York,
M.D.
New
on the
PH.D.
M.D.
WALLACH,
M.D.
York
of methadone
in maternal plasma and urine of pregnant women to levels of amniotic fluid, cord blood, fetal urines, and breast findings do not demonstrate a simple relationship between levels in the neonate and the intensity of the withdrawal syndrome. The effects drug abuse and other as yet unknown factors may influence the severity of signs in the neonate. concentration
on methadone in relationship milk are presented. These methadone
of multiple withdrawal
Methods
T H E c L I N I c A L aspects of methadone maintenance treatment’ of heroin addiction in pregnant women and their offspring have been described.‘-* These observations demonstrated that mothers maintained on methadone do have normal menstruation, ovulation, pregnancy, and delivery. In the neonate the chief problems are those of “the withdrawal syndrome” and prematurity. The placental transfer of many drugs during pregnancy and labor has been reported and summarized.” The present study was undertaken to assess whether methadone crosses the placental barrier a11 d can he found in fetal fluids.
From the Department of Obstetrics and Gynecology, Beth Israel Medical Center, and Mount Sinai School of Medicine of the City University of New York, and the Department Pharmacology, Cornell University Medical College. Supported by the Charles M. Singer Funds. Dr. Inturrisi DA-00297. Received Revised Accepted
supported
H. Silver by NIMH
for publication August August
July
of
and Herbert Grant
No.
8, 1974.
material
Results
23, 1974. 29,
and
The specimens were collected from random patients enrolled in methadone maintenance programs with occasional exceptions of street methadone patients as noted in the tables. Many patients are delivered at Beth Israel Hospital but have had prenatal care elsewhere--or not at all. Inturrisi and Verebely6v i have recently described a specific and sensitive method for the quantitative determination of methadone in samples of adult, fetal, and newborn biologic fluids. No modification of original procedure was necessary for any of these analyses in pregnancy. The method involves the preparation of the sample by a multistep solvent extraction procedure followed by quantitative analysis by the use of gas-liquid chromatography. The maternal population is similar to the population described in previous publications. For labor and delivery, regional anesthesia was used in these patients to exclude any drug confusion. At the present time, concentration gradients involving the placenta and placental permeability were not investigated.8* 9
Amniotic fluid. Samples of amniotic fluid were collected by amniocentesis or the vaginal collection of clear amniotic fluid at the time of rupture of membranes concurrently with a sample of maternal plasma. The concentration of methadone in the am-
1974.
Reprint requests: George Blinick, M.D., Department of Obstetrics and Gynecology, Beth Israel Medrcal Center, 10 Nathan D. Perlman Place, New York, New York 10003.
617
618
Blinick
March 1, I975 Am. J. Obstet. Gynecol.
et al.
Table I. The concentration maintenance subjects
~~~m~-;;~~Subject
of methadone
in the amniotic
fluid
(AF)
and plasma (Pl)
from methadone
Age (yr.)
Parity
R. S. C. R B. G. D. G. Y. E. ;.cq.
23 24 20 26 26 19 21
0030 3013 1001 2002 0010 2002 1011
40 40 14" 40 18* 31 38
w. L. c. v. v. P.
22 23 21
0120 1001 onon
40 40 40
6 I’TCt 5 PTC 1 PTC 3 PTC N.P.f 95 PTC
90 80 80 90 30 a0 90
0.22 0.14 0.28 0.25 0.07 0.39 0.16
0.38 0.14 0.48 0.36 0.18 0.25 0.31
0.58 1.00 0.59 0.70 0.39 0.51 1.56
5 PTC 20 PTC 7 PTD
100 100 50
0.26 0.10 0.20
0.39 0.22 0.25
0.67 0.45 0.80
Average *Voluntary termination of pregnancy. tPTC, prior to conception; PTD, prior $Methadone and heroin on street.
to delivery.
Table II. The concentration of methadone from methadone maintenance subjects*
Age (yr.)
Subject D. M. D. w. R. v. H. C. M. L’. R. R.
A. S. G. L. S. P. S. D. J. B. H. D.
0010 0000 2002 0120 0030 0000 0000 2002 0000 0010 0000 0000
5: 23 21 25 19 21 23 23 38
in the urn bilical cord plasma (CP)
Duration methadone (m0.j N.P. 9 PTD 3 PTC 5 PTC 6 PTC 7 PTD N.P. 9 PTC 1 PTD 24 PTD 5 PTD 24 PTD
Gestation (wk.) 40 40 40 40 40 40 38 38 38 38-40 41 40
Parity
and maternal plasma (MP) Methadone
of
(pg/ml.) Ratio CP/MP
MP 40 80 90 100 90 50 40 80 80 55 80 80
0.04 0.08 0.10 0.09 0.25 0.12 0.03 0.07 0.05 0.07 0.06 0.14
0.05 0.13 0.17 0.11 0.38 0.22 0.08 0.21 0.09 0.11 0.16 0.26
0.80 0.62 0.59 0.82 0.66 0.55 0.37 0.33 0.56 0.64 0.38 0.54
Average *Footnotes
as in Table
/
2;
of methadone
1 Parity
1 G.$at$n
FE?
23 21
0000
37 40
R. F. C. U. R. P. M. R.
21 23 21 23 23 24 21 38
0010 1011 0000 0010 0000 1001 0000 0000
40 40 40 38-40 41 41 38 40
R. S. A. B. H. s. J. D.
0.57
I.
Table III. The concentration maintenance subjects
Subject
0.73
ffZzZjf
(~~~;ayJ
79 PTD PTD 24 3 18 24 5 12 1 24
in the breast milk
PTD PTD PI-D PTD PTD PTD PTD PTD
(Mk)
1 dgry
and plasma (Pl)
I-
ffi$
from methadone
MethaZ:i{‘T>;z;l
50 10
103
0.29 0.05
0.34 0.06
0.83 0.85
40 25 30 55 80 70 80 80
4 5 5 5 3 4 5 3
0.12 0.17 0.13 0.23 0.25 0.36 0.57 0.51
0.41 0.10 0.24 0.40 0.83 0.38 1.66 0.27
0.29 1.70 0.54 0.58 0.30 0.95 0.34 1.89
Average
0.83
Volume Number
Methadone
121 5
Table IV. The
concentration
of methadone
in maternal
and
assays in pregnant
newborn
women
and progeny
619
urine
Methadone
Subject
R. R. R. w. C. B. T. M. R. A.
D. S.-B S.-A L. D. M. S. S. R. M.
Age (yr.)
Parity
Gestation (wk.)
Duration Afwr score
38 23 23
0000
40
4
0030 0030
40 40
9 8
22
0120
40
8
19 29 20
'002 0030 0000
38 32 40
8 4 9
22
0010
40
9
21 29
0010
40 38
9 9
‘122
of
methadone fmo.)
24 PTD 6 PTC 6 PTC 5 PTC 9 PTC 6 PTD 7 PTC 24 PTD 24 PTD 24 PTD
,~‘;;“;yyd
i %y
6.07 4.80 2.40 5.90 2.60
3.73 1.86
1.46 0.93
1.18
0.67
2.40 5.50
2.80 3.00
1.20
1.73
0.43
0.85 0.75 0.62
0.60 0.24 0.30
0.20 0.30
0.12
0.12
0.10
) ($jay)
49.00 9.30
1 MDUt 80 90
9.30
90
18.44 11.36 7.70 2.00 1.40 1 .oo 0.25
100 80 80 30 70 40
10
0 + t,
;y;;
0 + I;
3+ 3+ 3+ l+ l+ 2+ 2+
+
3+
t
1+
l+
*At time of delivery. tMultiple drug use.
niotic fluid from 10 women receiving a single daily oral dose of 30 to 100 mg. of methadone during pregnancy ranged from 0.07 to 0.39 pg per milliliter and from 0.14 to 0.48 pg per milliliter for this range of plasma plasma (Table I). Over methadone values, the ratio obtained when the concentration of methadone in amniotic fluid is divided by that in the plasma was on the average of 0.73. Methadone can be detected in amniotic fluid as early as the fourteenth to sixteenth weeks of gestationI” Umbilical cord plasma. A comparison of the concentration of methadone in umbilical cord plasma and that present in a concurrently collected sample of maternal plasma is given in Table II. Although the absolute value in maternal plasma varied from 0.05 to 0.38 pg per milliliter, the average ratio of methadone in cord plasma to that in maternal plasma was 0.57. These results suggest that the concentration of methadone in both amniotic fluid and cord plasma is proportional to the concentration in maternal plasma. I1 It is likely that changes in the maternal plasma levels would be reflected in an altered distribution of this drug in fetal biologic fluids. Therefore, it may be possible to control the methadone in the fetus by adjusting the maternal plasma levels without the necessity of monitoring the drug level in amniotic fluid, cord blood, and neonatal urines. Some of the factors accounting for the relatively lower levels of methadone in fetal biofluids might be the ability of placental and fetal tissues to transform methadone and the methadone-binding characteristics of fetal proteins. The contribution of these factors remains to be explored.
Breast milk. Table III contains values for the concentration of methadone in breast milk and in maternal plasma. These samples were collected at from 3 to 10 days after birth. The daily dose of methadone ranged from 10 to 80 mg. Fur eight of the 10 subjects, the concentration of methadone in breast milk was less than the corresponding value for plasma drug level. The ratio, calculated by dividing the concentration of methadone in breast milk by the plasma concentration, averaged 0.83. The finding of methadone in breast milk raises the question of mothers motivated toward breast feeding. During intrauterine life, as we know from analysis of the amniotic fluid, these babies have been bathed in methadone. Within our experience, there have been no adverse results from breast feeding and it is permitted if desired. Fetal urine. The concentration of methadone in samples of maternal and newborn urine is presented in Table IV. The maternal urine samples were collected prior to delivery and the newborn samples were collected during the first, second, and third days after birth. The values shown in Table IV are the concentration of methadone in micrograms per milliliter and not the total daily excretion in urine. At this time the total daily excretion is under study. Nevertheless, a pattern is evident. Over a wide range of urinary methadone, the concentration of drug in the newborn urine was found to be considerably lower than the corresponding value for maternal urine. For example, on the first day after birth the methadone concentration in newborn urine was approximately 37 per cent of the maternal concentration and by the third day the aver-
620
Blinick
et al.
age value had decreased to 16 per cent of the maternal concentration. The levels of methadone in newborn urine and maternal urine are demonstrated in Table IV. Withdrawal syndrome in the newborn. The evidence for the newborn withdrawal syndrome is based on clinical signs and assessment of the behavior of the neonate; a clear definition has yet to be formulated. There is direct biochemical confirmation that many drugs such as barbiturates, meperidine, chlorpromazine, tranquilizers, and alcohol readily cross the placenta.” Placental transmission of opiates in human subjects, however, has been based on clinical observations and not on biochemical confirmation. In experimental animals, radioactive tagged opiates have been shown to be present in the body tissues and fluid of the fetus.12 A brief discussion of the withdrawal syndrome is of interest in relationship to the fetal concentration of methadone and other related factors. The observations of Shute and DavisI concerning the effect on the infant of morphine administered in labor are, like other reports, based primarily on clinical observations. They do state that in six subjects 15 mg. of morphine were administered from 2 to 6 minutes before birth. Morphine was recovered in the stool of all of the infants on the third or fourth day after delivery by biochemical methods then available. Zelson, Rubio, and Wassermanl” state that in 19 of their mothers with known heroin addiction, urines were collected from the infants during the first 24 hours of life. Ten showed detectable amounts of morphine and quinine or both, although which drug was detected is not stated. Six of the 10 infants in whom morphine and quinine were detected in the urine did not develop signs of withdrawal. The initial patients treated with methadone maintenance were hospitalized at the center for a period of 6 weeks. Those with schizophrenia, multiple-drug abuse, and excessive alcoholism were excluded. In-depth interviews with physicians, social service workers, counselors, and nurses helped to create and continue social rehabilitation in patients motivated to discontinue drugs. Useful attitudes toward working, schooling, marriage, and other myriad problems were encouraged. Continuing help and rehabilitation are desirable aspects of the program.15, IF Withdrawal symptoms in these initial patients were absent to mild. However, because of the large number of addicts treated, the program was decentralized, so that there are presently 35
March 1, 1975 Am. J. Obstct. Gynecol.
clinics in the Bernstein Institute program at Beth Israel Medical Center and 44 clinics in the New York City Methadone Maintenance Treatment Program. In addition, many private and even marginal private treatment programs are now in operation in New York City, “Rapid induction” programs with physical examination alone to exclude associated disease (such as hepatitis, infection, emphysema, etc.) have become common. It has become evident in these expanded programs that there are considerable multiple drug abuse in both pregnant and nonpregnant addicts. less severe standards for entry into the program, and less individualization and rehabilitation of patients. In particular, multiple-drug use has become common although obstetricians and pediatricians have been the last to recognize the problem as related to pregnancy and the neonate. For example, Jones and associates’7 have recently reported a characteristic syndrome of intrauterine and postnatal retardation of babies born to mothers who were chronic alcoholics. Chronic maternal barbiturate utilization has been shown to produce withdrawal syndromes in the neonate similar to those of heroin.18 This is particularly confusing because it most often occurs in the second to fourth week of life, after the infant has left the nursery to return home. The pediatric service at the hospital recorded the signs of withdrawall” in the neonate according to a modified classification described by Kahn, Neumann, and Polk.20 Assessment of these signs by this method is divided into grades 1, 2, and 3 according to clinical severity. The patients were questioned as to their history of drug use but it is probable that many were withholding drug information. In addition, the urine of all subjects was tested by thin-layer chromatography.“’ This method, while reliable for routine drug testing, cannot be used as a completely accurate indicator of drug use. Recently, according to addicts, the use of goldenseal, a herbal root, has been used to conceal the detection of heroin from the most thorough medical screening. One paroled addict said that he had been “using the herb for several years without being caught and that most of his addict companions also used it.“*? In the future, more sophisticated methods of assaying for morphine, barbiturates, amphetamines, tranquilizers, etc., will be explored by radioisotopic assay and enzymes. The results reported in Table IV suggest that an attempt to demonstrate a simple relationship between urinary methadone levels in newborn infants
Volume Numher
121 5
and the intensity of withdrawal symptoms observed in these infants may in some cases be complicated by the presence of other drugs-particularly heroin, which is immediately converted to morphine and is tested as such. For example, newborn infant No. 1, with the highest urinary methadone concentration and no known evidence of maternal multiple-drug use, was considered to have severe withdrawal symptoms. Newborn infant No. 9, whose urinary methadone concentration was tenfold lower than that of No. 1, also showed severe withdrawal symptoms. The drug screening and history revealed morphine in addition to methadone in the maternal urine of No. 9. The contribution of multiple-drug abuse to withdrawal symptoms seen in the newborn infants of women receiving methadone maintenance treatment needs further study.
Methadone
assays
in pregnant
women
and
progeny
621
Conclusions 1. Data on the concentration of methadone in maternal plasma and urine in relation to levels in amniotic fluid, cord blood, fetal urine, and breast milk are presented. These findings do not demonstrate a simple relationship between urinary methadone levels in the newborn infant and the intensity of the withdrawal syndrome. The effects of multiple-drug abuse and other factors are under continuing investigation. 2. The pattern of drug addiction currently evolving is the licit and illicit use of methadone often associated with multiple-drug abuse. The effect on the maternal-fetal unit is poorly understood, but may be responsible for the high degree of withdrawal signs currently reported.
REFERENCES
Dole, V. P., and Nyswander, M.: J. A. M. A. 193: 646, 1965. 2. Blinick, G.: Nature 219: 180, 1968. 3. Wallach, R. C., Jerez, E., and Blinick, G.: AM. J. OBSTET. GYNECOL. 105: 1226, 1969. 4. Blinick, G., Jerez, E., and Wallach, R. C.: J. A. M. A. 225: 477, 1973. 5. Moya, F., and Thorndike, V.: AM. J. OBSTET. GYNECOL. 84: 1778, 1962. 6. Inturrisi, C. E., and Verebely, K.: J. Chromatogr. 65: 361, 1972. 7. Inturrisi, C. E., and Verebely, K.: Clin. Pharmacol. Thcr. 13: 633, 1972. 8. LaDu, B. N., Mandel, H. G., and Way, E. L.: Fundamentals of Drug Metabolism and Drug Disposition, Baltimore, 1971, The Williams & Wilkins Company, p. 93. 9. Battaglia, F. Cl.: J. Pediatr. 62: 926, 1963. IO. Blinick, G., Inturrisi, C. E., Jerez, E., and Wallach, R. C.: Mt. Sinai J. Med. 41: 254, 1974. 11. Inturrisi, C. E., Blinick, G., and Lipsitz, P. J.: Pharmacologist 15: 168, 1973. 1.
12.
Sanner, J. H., and Woods, L. A.: J. Pharmacol. Exp. Ther. 148: 176, 1965. 13. Shute, E., and Davis, M. E.: Surg. Gynecol. Obstet. 57: 727, 1933. 14. Zelson, C., Rubio, E., and Wasserman, E.: Pediatrics 48: 178. 1971. 15. Dole, V. P., and Nyswander, M.: N. Y. State J. Med. 66: 2011. 1966. 16. Dash, R.1 N. Y. State J. Med. 74: 1418, 1974. 17. Jones, K. L., Smith, D. W., Ulleland, C. N., and Streissguth, P.: Lancet 1: 1267, 1973. 18. Desmond, M. D., Schwanecke, R. P., Wilson, G. S., Yasunaga, S., and Burgdorff, I.: J. Pediatr. 80: 190, 1972. 19. Lipsitz, P. J., and Blatman, S.: N. Y. State J. Med. 74: 994, 1974. 20. Kahn, E. J., Neumann, I,. L., and Polk, G. A.: J. Pediatr. 75: 495, 1969. 21. Dole, V. P., Crowther, A., Johnson, J., Monsalvatge, M., Biller, B., and Nelson, S. S.: N. Y. State J. Med. 72: 471, 1972. 22. New York Times, Aug. 7, p. 13, 1974.
BLINICK,
CHARLES
E.
EULOGIO
Data
INTURRISI,
JEREZ,
ROBERT
C.
New York,
M.D.
New
on the
PH.D.
M.D.
WALLACH,
M.D.
York
of methadone
in maternal plasma and urine of pregnant women to levels of amniotic fluid, cord blood, fetal urines, and breast findings do not demonstrate a simple relationship between levels in the neonate and the intensity of the withdrawal syndrome. The effects drug abuse and other as yet unknown factors may influence the severity of signs in the neonate. concentration
on methadone in relationship milk are presented. These methadone
of multiple withdrawal
Methods
T H E c L I N I c A L aspects of methadone maintenance treatment’ of heroin addiction in pregnant women and their offspring have been described.‘-* These observations demonstrated that mothers maintained on methadone do have normal menstruation, ovulation, pregnancy, and delivery. In the neonate the chief problems are those of “the withdrawal syndrome” and prematurity. The placental transfer of many drugs during pregnancy and labor has been reported and summarized.” The present study was undertaken to assess whether methadone crosses the placental barrier a11 d can he found in fetal fluids.
From the Department of Obstetrics and Gynecology, Beth Israel Medical Center, and Mount Sinai School of Medicine of the City University of New York, and the Department Pharmacology, Cornell University Medical College. Supported by the Charles M. Singer Funds. Dr. Inturrisi DA-00297. Received Revised Accepted
supported
H. Silver by NIMH
for publication August August
July
of
and Herbert Grant
No.
8, 1974.
material
Results
23, 1974. 29,
and
The specimens were collected from random patients enrolled in methadone maintenance programs with occasional exceptions of street methadone patients as noted in the tables. Many patients are delivered at Beth Israel Hospital but have had prenatal care elsewhere--or not at all. Inturrisi and Verebely6v i have recently described a specific and sensitive method for the quantitative determination of methadone in samples of adult, fetal, and newborn biologic fluids. No modification of original procedure was necessary for any of these analyses in pregnancy. The method involves the preparation of the sample by a multistep solvent extraction procedure followed by quantitative analysis by the use of gas-liquid chromatography. The maternal population is similar to the population described in previous publications. For labor and delivery, regional anesthesia was used in these patients to exclude any drug confusion. At the present time, concentration gradients involving the placenta and placental permeability were not investigated.8* 9
Amniotic fluid. Samples of amniotic fluid were collected by amniocentesis or the vaginal collection of clear amniotic fluid at the time of rupture of membranes concurrently with a sample of maternal plasma. The concentration of methadone in the am-
1974.
Reprint requests: George Blinick, M.D., Department of Obstetrics and Gynecology, Beth Israel Medrcal Center, 10 Nathan D. Perlman Place, New York, New York 10003.
617
618
Blinick
March 1, I975 Am. J. Obstet. Gynecol.
et al.
Table I. The concentration maintenance subjects
~~~m~-;;~~Subject
of methadone
in the amniotic
fluid
(AF)
and plasma (Pl)
from methadone
Age (yr.)
Parity
R. S. C. R B. G. D. G. Y. E. ;.cq.
23 24 20 26 26 19 21
0030 3013 1001 2002 0010 2002 1011
40 40 14" 40 18* 31 38
w. L. c. v. v. P.
22 23 21
0120 1001 onon
40 40 40
6 I’TCt 5 PTC 1 PTC 3 PTC N.P.f 95 PTC
90 80 80 90 30 a0 90
0.22 0.14 0.28 0.25 0.07 0.39 0.16
0.38 0.14 0.48 0.36 0.18 0.25 0.31
0.58 1.00 0.59 0.70 0.39 0.51 1.56
5 PTC 20 PTC 7 PTD
100 100 50
0.26 0.10 0.20
0.39 0.22 0.25
0.67 0.45 0.80
Average *Voluntary termination of pregnancy. tPTC, prior to conception; PTD, prior $Methadone and heroin on street.
to delivery.
Table II. The concentration of methadone from methadone maintenance subjects*
Age (yr.)
Subject D. M. D. w. R. v. H. C. M. L’. R. R.
A. S. G. L. S. P. S. D. J. B. H. D.
0010 0000 2002 0120 0030 0000 0000 2002 0000 0010 0000 0000
5: 23 21 25 19 21 23 23 38
in the urn bilical cord plasma (CP)
Duration methadone (m0.j N.P. 9 PTD 3 PTC 5 PTC 6 PTC 7 PTD N.P. 9 PTC 1 PTD 24 PTD 5 PTD 24 PTD
Gestation (wk.) 40 40 40 40 40 40 38 38 38 38-40 41 40
Parity
and maternal plasma (MP) Methadone
of
(pg/ml.) Ratio CP/MP
MP 40 80 90 100 90 50 40 80 80 55 80 80
0.04 0.08 0.10 0.09 0.25 0.12 0.03 0.07 0.05 0.07 0.06 0.14
0.05 0.13 0.17 0.11 0.38 0.22 0.08 0.21 0.09 0.11 0.16 0.26
0.80 0.62 0.59 0.82 0.66 0.55 0.37 0.33 0.56 0.64 0.38 0.54
Average *Footnotes
as in Table
/
2;
of methadone
1 Parity
1 G.$at$n
FE?
23 21
0000
37 40
R. F. C. U. R. P. M. R.
21 23 21 23 23 24 21 38
0010 1011 0000 0010 0000 1001 0000 0000
40 40 40 38-40 41 41 38 40
R. S. A. B. H. s. J. D.
0.57
I.
Table III. The concentration maintenance subjects
Subject
0.73
ffZzZjf
(~~~;ayJ
79 PTD PTD 24 3 18 24 5 12 1 24
in the breast milk
PTD PTD PI-D PTD PTD PTD PTD PTD
(Mk)
1 dgry
and plasma (Pl)
I-
ffi$
from methadone
MethaZ:i{‘T>;z;l
50 10
103
0.29 0.05
0.34 0.06
0.83 0.85
40 25 30 55 80 70 80 80
4 5 5 5 3 4 5 3
0.12 0.17 0.13 0.23 0.25 0.36 0.57 0.51
0.41 0.10 0.24 0.40 0.83 0.38 1.66 0.27
0.29 1.70 0.54 0.58 0.30 0.95 0.34 1.89
Average
0.83
Volume Number
Methadone
121 5
Table IV. The
concentration
of methadone
in maternal
and
assays in pregnant
newborn
women
and progeny
619
urine
Methadone
Subject
R. R. R. w. C. B. T. M. R. A.
D. S.-B S.-A L. D. M. S. S. R. M.
Age (yr.)
Parity
Gestation (wk.)
Duration Afwr score
38 23 23
0000
40
4
0030 0030
40 40
9 8
22
0120
40
8
19 29 20
'002 0030 0000
38 32 40
8 4 9
22
0010
40
9
21 29
0010
40 38
9 9
‘122
of
methadone fmo.)
24 PTD 6 PTC 6 PTC 5 PTC 9 PTC 6 PTD 7 PTC 24 PTD 24 PTD 24 PTD
,~‘;;“;yyd
i %y
6.07 4.80 2.40 5.90 2.60
3.73 1.86
1.46 0.93
1.18
0.67
2.40 5.50
2.80 3.00
1.20
1.73
0.43
0.85 0.75 0.62
0.60 0.24 0.30
0.20 0.30
0.12
0.12
0.10
) ($jay)
49.00 9.30
1 MDUt 80 90
9.30
90
18.44 11.36 7.70 2.00 1.40 1 .oo 0.25
100 80 80 30 70 40
10
0 + t,
;y;;
0 + I;
3+ 3+ 3+ l+ l+ 2+ 2+
+
3+
t
1+
l+
*At time of delivery. tMultiple drug use.
niotic fluid from 10 women receiving a single daily oral dose of 30 to 100 mg. of methadone during pregnancy ranged from 0.07 to 0.39 pg per milliliter and from 0.14 to 0.48 pg per milliliter for this range of plasma plasma (Table I). Over methadone values, the ratio obtained when the concentration of methadone in amniotic fluid is divided by that in the plasma was on the average of 0.73. Methadone can be detected in amniotic fluid as early as the fourteenth to sixteenth weeks of gestationI” Umbilical cord plasma. A comparison of the concentration of methadone in umbilical cord plasma and that present in a concurrently collected sample of maternal plasma is given in Table II. Although the absolute value in maternal plasma varied from 0.05 to 0.38 pg per milliliter, the average ratio of methadone in cord plasma to that in maternal plasma was 0.57. These results suggest that the concentration of methadone in both amniotic fluid and cord plasma is proportional to the concentration in maternal plasma. I1 It is likely that changes in the maternal plasma levels would be reflected in an altered distribution of this drug in fetal biologic fluids. Therefore, it may be possible to control the methadone in the fetus by adjusting the maternal plasma levels without the necessity of monitoring the drug level in amniotic fluid, cord blood, and neonatal urines. Some of the factors accounting for the relatively lower levels of methadone in fetal biofluids might be the ability of placental and fetal tissues to transform methadone and the methadone-binding characteristics of fetal proteins. The contribution of these factors remains to be explored.
Breast milk. Table III contains values for the concentration of methadone in breast milk and in maternal plasma. These samples were collected at from 3 to 10 days after birth. The daily dose of methadone ranged from 10 to 80 mg. Fur eight of the 10 subjects, the concentration of methadone in breast milk was less than the corresponding value for plasma drug level. The ratio, calculated by dividing the concentration of methadone in breast milk by the plasma concentration, averaged 0.83. The finding of methadone in breast milk raises the question of mothers motivated toward breast feeding. During intrauterine life, as we know from analysis of the amniotic fluid, these babies have been bathed in methadone. Within our experience, there have been no adverse results from breast feeding and it is permitted if desired. Fetal urine. The concentration of methadone in samples of maternal and newborn urine is presented in Table IV. The maternal urine samples were collected prior to delivery and the newborn samples were collected during the first, second, and third days after birth. The values shown in Table IV are the concentration of methadone in micrograms per milliliter and not the total daily excretion in urine. At this time the total daily excretion is under study. Nevertheless, a pattern is evident. Over a wide range of urinary methadone, the concentration of drug in the newborn urine was found to be considerably lower than the corresponding value for maternal urine. For example, on the first day after birth the methadone concentration in newborn urine was approximately 37 per cent of the maternal concentration and by the third day the aver-
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age value had decreased to 16 per cent of the maternal concentration. The levels of methadone in newborn urine and maternal urine are demonstrated in Table IV. Withdrawal syndrome in the newborn. The evidence for the newborn withdrawal syndrome is based on clinical signs and assessment of the behavior of the neonate; a clear definition has yet to be formulated. There is direct biochemical confirmation that many drugs such as barbiturates, meperidine, chlorpromazine, tranquilizers, and alcohol readily cross the placenta.” Placental transmission of opiates in human subjects, however, has been based on clinical observations and not on biochemical confirmation. In experimental animals, radioactive tagged opiates have been shown to be present in the body tissues and fluid of the fetus.12 A brief discussion of the withdrawal syndrome is of interest in relationship to the fetal concentration of methadone and other related factors. The observations of Shute and DavisI concerning the effect on the infant of morphine administered in labor are, like other reports, based primarily on clinical observations. They do state that in six subjects 15 mg. of morphine were administered from 2 to 6 minutes before birth. Morphine was recovered in the stool of all of the infants on the third or fourth day after delivery by biochemical methods then available. Zelson, Rubio, and Wassermanl” state that in 19 of their mothers with known heroin addiction, urines were collected from the infants during the first 24 hours of life. Ten showed detectable amounts of morphine and quinine or both, although which drug was detected is not stated. Six of the 10 infants in whom morphine and quinine were detected in the urine did not develop signs of withdrawal. The initial patients treated with methadone maintenance were hospitalized at the center for a period of 6 weeks. Those with schizophrenia, multiple-drug abuse, and excessive alcoholism were excluded. In-depth interviews with physicians, social service workers, counselors, and nurses helped to create and continue social rehabilitation in patients motivated to discontinue drugs. Useful attitudes toward working, schooling, marriage, and other myriad problems were encouraged. Continuing help and rehabilitation are desirable aspects of the program.15, IF Withdrawal symptoms in these initial patients were absent to mild. However, because of the large number of addicts treated, the program was decentralized, so that there are presently 35
March 1, 1975 Am. J. Obstct. Gynecol.
clinics in the Bernstein Institute program at Beth Israel Medical Center and 44 clinics in the New York City Methadone Maintenance Treatment Program. In addition, many private and even marginal private treatment programs are now in operation in New York City, “Rapid induction” programs with physical examination alone to exclude associated disease (such as hepatitis, infection, emphysema, etc.) have become common. It has become evident in these expanded programs that there are considerable multiple drug abuse in both pregnant and nonpregnant addicts. less severe standards for entry into the program, and less individualization and rehabilitation of patients. In particular, multiple-drug use has become common although obstetricians and pediatricians have been the last to recognize the problem as related to pregnancy and the neonate. For example, Jones and associates’7 have recently reported a characteristic syndrome of intrauterine and postnatal retardation of babies born to mothers who were chronic alcoholics. Chronic maternal barbiturate utilization has been shown to produce withdrawal syndromes in the neonate similar to those of heroin.18 This is particularly confusing because it most often occurs in the second to fourth week of life, after the infant has left the nursery to return home. The pediatric service at the hospital recorded the signs of withdrawall” in the neonate according to a modified classification described by Kahn, Neumann, and Polk.20 Assessment of these signs by this method is divided into grades 1, 2, and 3 according to clinical severity. The patients were questioned as to their history of drug use but it is probable that many were withholding drug information. In addition, the urine of all subjects was tested by thin-layer chromatography.“’ This method, while reliable for routine drug testing, cannot be used as a completely accurate indicator of drug use. Recently, according to addicts, the use of goldenseal, a herbal root, has been used to conceal the detection of heroin from the most thorough medical screening. One paroled addict said that he had been “using the herb for several years without being caught and that most of his addict companions also used it.“*? In the future, more sophisticated methods of assaying for morphine, barbiturates, amphetamines, tranquilizers, etc., will be explored by radioisotopic assay and enzymes. The results reported in Table IV suggest that an attempt to demonstrate a simple relationship between urinary methadone levels in newborn infants
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and the intensity of withdrawal symptoms observed in these infants may in some cases be complicated by the presence of other drugs-particularly heroin, which is immediately converted to morphine and is tested as such. For example, newborn infant No. 1, with the highest urinary methadone concentration and no known evidence of maternal multiple-drug use, was considered to have severe withdrawal symptoms. Newborn infant No. 9, whose urinary methadone concentration was tenfold lower than that of No. 1, also showed severe withdrawal symptoms. The drug screening and history revealed morphine in addition to methadone in the maternal urine of No. 9. The contribution of multiple-drug abuse to withdrawal symptoms seen in the newborn infants of women receiving methadone maintenance treatment needs further study.
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Conclusions 1. Data on the concentration of methadone in maternal plasma and urine in relation to levels in amniotic fluid, cord blood, fetal urine, and breast milk are presented. These findings do not demonstrate a simple relationship between urinary methadone levels in the newborn infant and the intensity of the withdrawal syndrome. The effects of multiple-drug abuse and other factors are under continuing investigation. 2. The pattern of drug addiction currently evolving is the licit and illicit use of methadone often associated with multiple-drug abuse. The effect on the maternal-fetal unit is poorly understood, but may be responsible for the high degree of withdrawal signs currently reported.
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Sanner, J. H., and Woods, L. A.: J. Pharmacol. Exp. Ther. 148: 176, 1965. 13. Shute, E., and Davis, M. E.: Surg. Gynecol. Obstet. 57: 727, 1933. 14. Zelson, C., Rubio, E., and Wasserman, E.: Pediatrics 48: 178. 1971. 15. Dole, V. P., and Nyswander, M.: N. Y. State J. Med. 66: 2011. 1966. 16. Dash, R.1 N. Y. State J. Med. 74: 1418, 1974. 17. Jones, K. L., Smith, D. W., Ulleland, C. N., and Streissguth, P.: Lancet 1: 1267, 1973. 18. Desmond, M. D., Schwanecke, R. P., Wilson, G. S., Yasunaga, S., and Burgdorff, I.: J. Pediatr. 80: 190, 1972. 19. Lipsitz, P. J., and Blatman, S.: N. Y. State J. Med. 74: 994, 1974. 20. Kahn, E. J., Neumann, I,. L., and Polk, G. A.: J. Pediatr. 75: 495, 1969. 21. Dole, V. P., Crowther, A., Johnson, J., Monsalvatge, M., Biller, B., and Nelson, S. S.: N. Y. State J. Med. 72: 471, 1972. 22. New York Times, Aug. 7, p. 13, 1974.