Thomas Jefferson University
Jefferson Digital Commons
Department of Obstetrics and Gynecology
Department of Obstetrics and Gynecology
Relationship between maternal methadone dose at
delivery and neonatal abstinence syndrome.
Neil S., Seligman
Thomas Jefferson University, email@example.com
Christopher V. Almario
Thomas Jefferson University
Edward J. Hayes
Thomas Jefferson University
Kevin C. Dysart
Thomas Jefferson University
Thomas Jefferson University
See next page for additional authors
This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas
Jefferson University'sAcademic & Instructional Support & Resources Department (AISR). The Commons is a showcase for Jefferson books and
journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital
Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article
has been accepted for inclusion in Department of Obstetrics and Gynecology Faculty Papers by an authorized administrator of the Jefferson Digital
Commons. For more information, please contact: JeffersonDigitalCommons@jefferson.edu.
Seligman, Neil S.,; Almario, Christopher V.; Hayes, Edward J.; Dysart, Kevin C.; Berghella,
Vincenzo; and Baxter, Jason K., "Relationship between maternal methadone dose at delivery and
neonatal abstinence syndrome." (2010).Department of Obstetrics and Gynecology Faculty Papers.
Neil S., Seligman; Christopher V. Almario; Edward J. Hayes; Kevin C. Dysart; Vincenzo Berghella; and Jason
This article is available at Jefferson Digital Commons:http://jdc.jefferson.edu/obgynfp/16
As submitted to:
Journal of Pediatrics
And later published as:
“RELATIONSHIP BETWEEN MATERNAL METHADONE
DOSE AT DELIVERY
AND NEONATAL ABSTINENCE SYNDROME”
Volume 157, Issue 3, 2010, Pages 428-433+433.e1
Neil S. Seligman, MD1; Christopher V. Almario, MD1; Edward J. Hayes, MD MSCP1;
Kevin C. Dysart, MD2; Vincenzo Berghella, MD1; Jason K. Baxter, MD MSCP1
1 Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Jefferson
Medical College of Thomas Jefferson University, Philadelphia, PA
2 Department of Pediatrics, Jefferson Medical College of Thomas Jefferson University/Nemours
Foundation, Philadelphia, PA
Neil S. Seligman, MD
Thomas Jefferson University
Department of Obstetrics and Gynecology
834 Chestnut Street, Suite 400
Philadelphia, PA 19107
Phone: (215) 955-7996
Running Foot: Methadone and neonatal abstinence syndrome
No correlation was found between maternal methadone dose and rate of neonatal abstinence
syndrome among 388 neonates exposed to doses up to 340 mg/day.
OBJECTIVE: To estimate the relationship between maternal methadone dose and the incidence
of neonatal abstinence syndrome (NAS).
METHODS: We performed a retrospective cohort study of pregnant women treated with
methadone for opiate addiction who delivered a live-born neonate between 1996 and 2006. Four
dose groups, based on total daily methadone dose, were compared (≤80mg/d, 81–120mg/d, 121–
160mg/d, and >160mg/d). The primary outcome was treatment for NAS. Symptoms of NAS
were objectively measured using the Finnegan scoring system and treatment was initiated for a
score of >24 during the prior 24 hours.
RESULTS: 330 women treated with methadone and their 388 offspring were included.
Average methadone dose at delivery was 116.6 ±49.7mg/d (range 20-340mg/d). Overall, 68% of
infants were treated for NAS. Among infants exposed to methadone doses of ≤80mg/d, 81–
120mg/d, 121–160mg/d, and >160 mg/d, treatment for NAS was initiated for 68%, 63%, 70%,
and 73% of neonates, respectively (p=0.48). The rate of maternal illicit opiate abuse at delivery
was 26%, 28%, 19%, and 11%, respectively (p=0.04).
CONCLUSION: No correlation was found between maternal methadone dose and rate of NAS.
However, higher doses of methadone were associated with decreased illicit opiate abuse at
human immunodeficiency virus (HIV)
neonatal abstinence syndrome (NAS)
urine drug screen (UDS)
receiver operating characteristic (ROC)
selective serotonin reuptake inhibitor (SSRI)
odds ratios (OR)
confidence intervals (CI)
Methadone has been employed since the early 1970s to treat opiate addiction, and it
currently remains the standard treatment for opiate addiction in pregnancy.(1) Benefits of
methadone include a reduction in cravings for heroin and drug seeking behavior, which thereby
also reduces the risk of infection with hepatitis C virus and human immunodeficiency virus
(HIV), prostitution, and criminal activity.(2) Methadone treatment also protects the fetus from
repeated episodes of withdrawal by providing steady maternal opiate levels.(3) Furthermore,
comprehensive methadone maintenance programs provide opiate-addicted women with the
opportunity to receive essential prenatal care and services that they would otherwise be
without.(4) Despite these benefits, methadone treatment is not without controversy, and much of
the debate centers on the optimal methadone dose and on its association with neonatal abstinence
One of the earliest reports of the relationship between methadone and neonatal
withdrawal was published in 1975 by Rosen et al. The authors found no consistent relationship
between maternal methadone dose and the severity of neonatal withdrawal symptoms in this
study and a subsequent study in 1976.(5)(6) In the same year, several studies reported the
opposite, showing a positive correlation between maternal methadone dose and both the severity
of neonatal withdrawal symptoms and the incidence of neonatal withdrawal requiring
pharmacologic treatment with maternal methadone doses < 20 mg/d.(7)(8)(9) Of eight published
studies, to our knowledge, which include a “low” dose group of < 30 mg/d 78% report a positive
correlation between maternal methadone and NAS.(6)(7)(8)(9)(10)(11)(12)(13) Presently,
methadone maintenance programs for pregnant women, such as ours, use significantly higher
doses to prevent withdrawal. Five out of six (83%) more recent published studies which use a
higher cutoff (< 50 mg/d or above) to define the “low” dose group report no such
association.(14)(15)(16)(17)(18)(19) Yet, despite these and other studies
(20)(21)(22)(23)(24)(25) there is still no clear answer. Much of difficulty is due to the
considerable methodological variability such as the inclusion of women undergoing withdrawal
treatment as opposed to maintenance, insufficient reporting of confounding factors (i.e.
polysubstance abuse), and differences in the definition and assessment of NAS (Table 1; online
only). With these limitations in mind, our objective was to estimate the relationship between
clinically appropriate methadone doses and NAS.
MATERIALS AND METHODS
We performed a retrospective review of the outcomes of opiate-addicted women on
methadone maintenance who delivered a live-born neonate between September 1996 and June
2006. A full description of our approach to methadone stabilization and maintenance has been
previously described elsewhere.(14) The only change in maternal management over the eleven
year study period was a small increase (20mg to 30mg) in the initial stabilization dose. There
were no changes in neonatal assessment or treatment for NAS. No distinction was made
between women who conceived while already enrolled in a methadone program and those who
became pregnant while on heroin and required initial stabilization during pregnancy.
All neonates were delivered at Thomas Jefferson University Hospital. We excluded
infants delivered < 32 weeks gestation, as signs and symptoms of prematurity can be confused
with NAS.(21) Non-viable fetuses delivered before 23 weeks gestation and stillbirths were also
excluded. Signs and symptoms of NAS were objectively assessed every eight hours for the first
72 hours of life according to the method described by Finnegan.(25) Treatment for NAS was
initiated for a cumulative score ≥ 24 during the prior 24 hours. The NAS treatment protocol at
our institution has been described elsewhere.(26) Data for a portion of the women and neonates
has been previously reported.(14)(26)
Exposure to methadone was confirmed by a UDS for methadone. For women who
instead had a drug of abuse screen (does not test for methadone), documentation in the medical
record of methadone use was necessary for inclusion in the study. The methadone dose at
delivery was defined as the total daily methadone dose at the time of delivery. To determine the
cohorts, we divided women into four dose groups approximating quartiles; ≤ 80 mg/d, 81 – 120
mg/d, 121 – 160 mg/d, and > 160 mg/d. A receiver operator characteristic (ROC) curve was
used to determine the sensitivity and specificity of various methadone dose cutoffs for predicting
NAS ensuring the appropriateness of these dose groups.
All statistical tests were performed with SPSS 17.0 (SPSS Inc., Chicago, IL). The χ2 test,
analysis of variance test, and Kruskal-Wallis test were used to analyze categorical, normally
distributed continuous, and non-normally distributed continuous variables, respectively. A p
value < .05 was considered statistically significant. Several women delivered twice during the
study period. To adjust for potential confounding and clustering due to women who had more
than one pregnancy during the study period, a generalized estimating equation model was used.
For women who delivered after 2000, the database was expanded to include additional
variables. The additional information gathered included non-opiate illicit drug abuse at delivery
as determined by urine drug screen (UDS), selective serotonin reuptake inhibitor use, alcohol use
(by self report), and others. Due to the difference in the amount of variables, two separate
multivariate models were fit. The first was termed "limited" in time as it included a larger set of
variables which were recorded only for women who delivered between January 2000 and June
2006. The second was deemed “extended" in time as it included fewer variables, but data was
available for all women who delivered during the entire 10 year study period (September 1996
and June 2006). For both the “limited” and "extended" adjustments, variables with p < 0.2 found
through univariate analysis were included as covariates in the generalized estimating equation
model to calculate adjusted odds ratios (OR) with 95% confidence intervals (CI). This study was
approved by the Thomas Jefferson University Institutional Review Board. Informed consent
was not required for this study.
We analyzed outcomes of 330 opiate-addicted women on methadone treatment who had
386 pregnancies from September 1996 to June 2006. Two women had twins, thus our study
included 388 neonates. The gestational age at birth was < 32 weeks for 19 neonates (range 27-31
weeks) excluded from the study. Maternal demographic characteristics are presented in Table 2.
Only race differed among dose groups (p = .04). Caucasian women were on higher mean doses
of methadone (122.9 ± 50.7 mg/d) when compared to non-Caucasian women (103.5 ± 44.9 mg/d,
p < .001). Psychiatric medications were prescribed to 27% of women in the methadone
maintenance program and 23% of those women were taking more than one psychiatric
medication (data available for 288 pregnancies). The proportion of women in each dose group
using prescription psychiatric drugs was not significantly different (p = .39) but prescription
benzodiazepine use (mainly clonazepam) was more common among women on higher doses (p =
Table 3 presents details of the methadone maintenance program and rates of illicit
substance abuse at the time of delivery. Overall, the average methadone dose at delivery was
116.6 mg/d (range 20-340 mg/d). Timing of methadone stabilization (before or during
pregnancy) and rate of re-stabilization (due to non-compliance) was known for 288 pregnancies.
Women who conceived on methadone had a higher mean methadone dose at delivery compared
to those who were stabilized during pregnancy (135.3 ± 55.5 mg/d vs. 118.5 ± 48.7 mg/d; p =
.01) and a greater proportion of women who conceived on methadone were in higher dose
groups. Admissions for re-stabilization were less likely in the higher dose groups as was illicit
opiate abuse. Of the 77 women with known prescription psychiatric medication use, 27 (35%)
used illicit drugs at delivery compared to 42 (20%) of the 211 not taking prescription psychiatric
medications (p = .008). Women who were initially stabilized on methadone during pregnancy
had lower rate of illicit drug abuse at delivery (66 [34%] vs. 26 [28%]; p = .36) and illicit opiate
abuse at delivery (11 [12%] vs. 36 [18%]; p = .17) but the difference did not reach statistical
Neonates had an average gestational age at delivery of 37.7 ± 2.2 weeks. . The rate of
preterm birth (≥ 32 weeks and < 37 weeks) was 27% (106/388). The mean birth weight and head
circumference were 2808 ± 544 g and 32.5 ± 2.1 cm, respectively. No significant differences
were found between gestational age at delivery, birth weight, head circumference, and rate of
preterm birth among neonates exposed to maternal methadone doses of ≤ 80 mg/d, 81 – 120
mg/d, 121 – 160 mg/d, and > 160 mg/d (all p > .31).
Indices of NAS according to maternal methadone dose are included in Table 4. Overall,
262 (62%) neonates required treatment for NAS. There was no significant difference in the
incidence of NAS, maximum NAS score, length of neonatal treatment, or maximum dose of
neonatal opium solution between difference dose groups. Among women who had more than
one pregnancy during the study period, there was a trend toward higher mean methadone doses
in the subsequent pregnancy (119 ±51.7 mg/d 1st pregnancy versus 134 ±58.2 mg/d 2nd
pregnancy; p = .18) however, there was no difference in the rate of NAS (64% 1st pregnancy
versus 62% 2nd pregnancy; p = .83). Even after adjusting for confounding by significant
variables (p <0.2) and the effect clustering due to multiple pregnancies by the same woman, no
correlation was found between methadone dose and NAS (Table 5; online only). Additionally,
no methadone dose defined a cutoff significantly predictive of NAS using a ROC curve (area
.52; p = .52 [95% CI .46-.58]). In the < 80 mg/d dose group, only 7 women had a methadone
dose at delivery that was < 30 mg/d. In this subgroup, four (57%) neonates were treated for NAS
for 7, 30, 31, and 54 days. Compared to women on higher doses, there was no significant
difference in the rate of NAS (p= 1.0). The Figure depicts the stable rate of NAS against the
reduction in illicit opiate abuse at delivery which is most apparent in the three highest dose
The rate of NAS was compared between methadone dose groups for selected
subpopulations of women (Table 4). NAS was more common among neonates born to women
who were initially stabilized on methadone during pregnancy but the difference was not
statistically significant (p = .18). There was no difference in the incidence of NAS between
methadone dose groups for either neonates born to women who conceived on methadone or
those who were born to women initially stabilized on methadone during pregnancy. Likewise,
these was no difference in the incidence of NAS between dose groups for the subpopulations of
women abusing illicit opiates at delivery, women whose UDS was negative for illicit opiate
abuse at delivery, women who delivered prematurely, and those who delivered at term.
Lastly, we also investigated other variables predictive of NAS (Table 6; online only).
Through a univariate analysis, preterm birth, tobacco use, and illicit opiate and cocaine abuse at
delivery increased the risk for NAS (Table 5; online only). However, after adjusting for
confounding, only preterm birth (adjusted OR 3.0, 95% CI 1.4 – 6.1) remained predictive of
NAS. Tobacco use had a trend towards increased risk for NAS (adjusted OR 2.2, 95% CI 0.98 –
The incidence of NAS in our population was 68% and is well within the literature's
reported range of 30% to 81%.(9)(22) Even among neonates born to women prescribed the
lowest methadone dose, NAS required treatment in more than half of neonates. In our
population, the incidence of NAS requiring pharmacologic treatment does not reflect maternal
methadone use in a dose dependent fashion. Furthermore, higher doses of methadone were
associated with decreased maternal illicit opiate abuse at delivery.
There is strong physiologic evidence to support our policy of liberal dose increases to
decrease maternal withdrawal symptoms. First, physiologic changes throughout pregnancy alter
the pharmacokinetics and pharmacodynamics of methadone. Plasma volume is increased leading
to an increased volume of distribution. The fraction of oral methadone absorbed is decreased,
the half life of methadone decreased (27) secondary to increased hepatic clearance (28)(29), and
protein binding is decreased.(30) Additionally, there is a high degree of inter-individual
variability in methadone metabolism. Maternal symptomatology more closely reflects serum
trough level than dose.(31)(32)
The concentration of methadone crossing the placenta determined by gestational age-
dependent passive diffusion, P-glycoprotein efflux, and metabolism by placental aromatase.
(33)(34)(35)(36) The fetal concentration is then modified by hepatic metabolism, a process
which is also gestational age dependent. Ultimately, the expression of opioid withdrawal is
dependent on the final neonatal methadone concentration and its interplay with the central
nervous system (also gestational age dependent ). Even the exact relationship between
neonatal methadone levels at birth is unclear (17)(22)(24)(37)(38) and total opioid exposure
(methadone plus other illicit opiate abuse) should be factored in as a confounder. Given the
complex relationship between the mechanisms that determine neonatal dose and expression of
NAS, it unlikely an individual woman’s methadone dose will reliably predict neonatal outcome.
Most of the women in our study had one or more exposures to tobacco, alcohol, other
illicit drugs or prescription medications thought to confound the expression and severity of
withdrawal. Both Tobacco and benzodiazepines (prescription or illicit) worsen methadone
withdrawal. (14)(20)(26)(39)(40)(41)(42)(43) Likewise, abruption discontinuation of cocaine at
birth results in a neonatal toxicity with symptoms that overlap with methadone
withdrawal.(39)(44) The effect of each of these exposures was adjusted for in the statistical
analysis (Tables 5 and 6).
Neonatal withdrawal from selective serotonin reuptake inhibitors (SSRIs) is a well
recognized syndrome (45)(46) that occurs in 22-31.5% of exposed neonates.(47) The signs and
symptoms of SSRI withdrawal overlap considerably with opioid withdrawal and can be
measured with the Finnegan scoring system.(47) Additionally, SSRIs may increase methadone
concentrations through inhibition of the CYP450 system.(48) While it is possible that SSRI
withdrawal confounded the assessment of NAS this effect would have caused a small but equal
increase in the incidence of NAS in each group since there was no significant difference in SSRI
use. Other studies have also shown that SSRI use does not increase the odds of receiving
treatment for NAS (11) or affect the length of treatment.(26)
A significant strength of our study is the large population size. The majority of studies
reporting an association between maternal methadone dose and NAS were small studies that
included only 70 infants or less.(9)(10)(12)(16)(21)(22) Also, our population includes women
prescribed the highest reported doses used in pregnancy. The lowest dose group, < 80 mg/d,
may be considered as such compared to studies that used a cutoff of < 30 mg/d. Since our
methadone stabilization protocol uses an initial stabilization dose of either 20 or 30 mg/d and the
median methadone dose after initial hospital stabilization was 65 mg/d (range 15-250 mg/d)(26
unpublished data) a “very low” dose group (i.e. < 30 mg/d) would be impractical. Furthermore,
the large population size and wide dose range included in our study allowed us to compare the
rate of NAS between four near-equal sized dose groups inclusive of all previously published cut-
offs, as opposed to just comparing "high" and "low" dose groups as many previous studies have
Another important strength of our research was the choice to use NAS requiring
pharmacologic treatment, based on Finnegan score, as the primary outcome. The use of an
objective outcome is especially important since, as in most studies, the neonatologists were not
blinded to maternal methadone dose. Instead, other studies chose to use presence or severity of
withdrawal symptoms (8)(9)(24) or used NAS requiring pharmacologic treatment measured by
novel scoring systems. We contend that NAS requiring treatment determined by a recognized
NAS scoring system (Finnegan , Lipsitz , Rivers ) is the most appropriate outcome
measure for studying neonatal withdrawal due to in utero methadone exposure. Most neonates
experience at least some symptoms of withdrawal but neonates that do not require treatment are
discharged home after three days as opposed to an average of 30 days when treatment is
necessary.(26) Readmission after 72 hours for withdrawal or dehydration is a possibility that
was not analyzed. However, of the approximately 30% of neonates who are discharged without
treatment for NAS and whose mothers are following up at the Family Center methadone
treatment program, readmission is rare according to the neonatologists (Dysart) at our hospital.
This study evaluated the outcomes of neonates delivered over an 11 year period.
Although practice changes over time, save for a marginal difference in the initial methadone
stabilization dose (20 mg/d (14) versus 30 mg/d (26), there were no other changes in either
maternal or neonatal management during that interval. Another limitation is the expansion of the
type and amount of data included in the database. Consistency in the data collected over the two
periods was verified by carefully comparing the data dictionaries from both periods. We did not
consider the effect of breastfeeding, as such data was unavailable. The importance of
breastfeeding in preventing NAS remains controversial.(11)(16)(40)(51) The concentration of
methadone in breast milk is low (52) and although the absolute concentration is dose dependent,
is unlikely to be sufficient to prevent withdrawal.(53)
The best measure of the adequacy of methadone treatment is cessation of illicit opiate
abuse. In our study, only 11% of women taking > 160 mg/d of methadone also abused illicit
opiates at the time of delivery versus 27% of women who took ≤ 120 mg/d. McCarthy et al
noted similar findings, as only 11% of infants from their high dose methadone group (≥ 100
mg/d) were positive for illicit drugs compared to 27% of infants from their low dose group (<
100 mg/d).(18) The benefits of methadone maintenance include cessation of illegal activities,
avoidance of infectious diseases, and participating in prenatal care. Therefore, preventing
continued drug abuse by providing therapeutic doses would seem far more important than using
low methadone doses to theoretically reduce the incidence of NAS, which when treated
appropriately has not been demonstrated to have any untoward effects.(3)
Our findings provide compelling evidence that no correlation exists between maternal
methadone dose and rate of NAS. Reducing maternal methadone doses to theoretically lower the
risk for NAS appears unwarranted. Instead, the goal of the clinician should be to administer
doses of methadone that adequately control maternal withdrawal symptoms and reduce drug
cravings. In the future, a randomized, double blinded study to validate our results in which in
one group women are restricted to a certain dose while the ones in the other group aren’t would
be ideal. There may be ethical concerns over restricting dose and possibly subjecting both the
mother and fetus to withdrawal as this would constitute detoxification. In our opinion, an
adequately powered prospective trial with both the physician prescribing methadone and the
pediatrician blinded to dose, an objective measurement of NAS, and controlling for known
confounders would probably be a viable alternative.
1. National Consensus Development Panel on Effective Medical Treatment of Opiate
Addiction. Effective medical treatment of opiate addiction. JAMA 1998; 280:1936-43.
2. Wilbourne P, Wallerstedt C, Dorato V, Curet LB. Clinical management of methadone
dependence during pregnancy. J Perinat Neonatal Nurs 2001; 14:26-45.
3. Kaltenbach K, Berghella V, Finnegan L. Opioid dependence during pregnancy. effects and
management. Obstet Gynecol Clin North Am 1998; 25:139-51.
4. Finnegan LP. Treatment issues for opioid-dependent women during the perinatal period. J
Psychoactive Drugs 1991; 23:191-201.
5. Rosen TS and Pippenger CE. Disposition of methadone and its relationship to severity of
withdrawal and the newborn. Addict Dis. 1975;2(1-2):169-78.
6. Rosen TS and Pippenger CE. Pharmacologic observations on the neonatal withdrawal
syndrome. J Pediatr 1976; 88:1044-8.
7. Madden JD, Chappel JN, Zuspan F, Gumpel J, Mejia A, Davis R. Observation and treatment
of neonatal narcotic withdrawal. Am J Obstet Gynecol 1977; 127:199-201.
8. Ostrea EM, Chavez CJ, Strauss ME. A study of factors that influence the severity of
neonatal narcotic withdrawal. J Pediatr 1976; 88:642-5.
9. Strauss ME, Andresko M, Stryker JC, Wardell JN. Relationship of neonatal withdrawal to
maternal methadone dose. Am J Drug Alcohol Abuse 1976; 3:339-45.
10. Dashe JS, Sheffield JS, Olscher DA, Todd SJ, Jackson GL, Wendel GD. Relationship
between maternal methadone dosage and neonatal withdrawal. Obstet Gynecol 2002;
11. Dryden C, Young D, Hepburn M, Mactier H. Maternal methadone use in pregnancy: factors
associated with the development of neonatal abstinence syndrome and implications for
healthcare resources. BJOG. 2009;116:665-71.
12. Malpas TJ, Darlow BA, Lennox R, Horwood LJ. Maternal methadone dosage and neonatal
withdrawal. Aust N Z J Obstet Gynaecol 1995; 35:175-7.
13. Shaw NJ and McIvor L. Neonatal abstinence syndrome after maternal methadone treatment.
Arch Dis Child Fetal Neonatal Ed 1994; 71:F203-5.
14. Berghella V, Lim PJ, Hill MK, Cherpes J, Chennat J, Kaltenbach K. Maternal methadone
dose and neonatal withdrawal. Am J Obstet Gynecol 2003; 189:312-7.
15. Brown HL, Britton KA, Mahaffey D, Brizendine E, Hiett AK, Turnquest MA. Methadone
maintenance in pregnancy: A reappraisal. Am J Obstet Gynecol 1998; 179:459-63.
16. Lim S, Prasad MR, Samuels P, Gardner DK, Cordero L. High-dose methadone in pregnant
women and its effect on duration of neonatal abstinence syndrome. Am J Obstet Gynecol
17. Kuschel CA, Austerberry L, Cornwell M, Couch R, Rowley RS. Can methadone
concentrations predict the severity of withdrawal in infants at risk of neonatal abstinence
syndrome? Arch Dis Child Fetal Neonatal Ed 2004; 89:F390-3.
18. McCarthy JJ, Leamon MH, Parr MS, Anania B. High-dose methadone maintenance in
pregnancy: Maternal and neonatal outcomes. Am J Obstet Gynecol 2005; 193:606-10.
19. Stimmel B, Goldberg J, Reisman A, Murphy RJ, Teets K. Fetal outcome in narcotic-
dependent women: The importance of the type of maternal narcotic used. Am J Drug
Alcohol Abuse 1982; 9:383-95.
20. Bakskad B, Sarfi M, Welle-Strand GK, Randval E. Opioid Maintenance Treatment during
Pregnancy: Occurrence and Severity of Neonatal Abstinence Syndrome. Eur Addict Res.
21. Doberczak TM, Kandall SR, Wilets I. Neonatal opiate abstinence syndrome in term and
preterm infants. J Pediatr 1991; 118:933-7.
22. Doberczak TM, Kandall SR, Friedmann P. Relationship between maternal methadone
dosage, maternal-neonatal methadone levels, and neonatal withdrawal. Obstet Gynecol
23. Hagopian GS. Wolfe HM, Sokol RJ, Ager JW, Wardell JN, Cepeda EE. Neonatal outcome
following methadone exposure in utero. J Matern Fetal Med 1996;5:348-54.
24. Harper RG, Solish G, Feingold E, Gersten-Woolf NB, Sokal MM. Maternal ingested
methadone, body fluid methadone, and the neonatal withdrawal syndrome. Am J Obstet
Gynecol 1977; 129:417-24.
25. Finnegan LP, Connaughton JF, Jr., Kron RE, Emich JP. Neonatal abstinence syndrome:
assessment and management. Addict Dis 1975; 2(1-2):141-58..
26. Seligman NS, Salva N, Hayes EJ, Dysart KC, Pequignot EC, Baxter JK. Predicting length of
treatment for neonatal abstinence syndrome in methadone-exposed neonates. Am J Obstet
Gynecol 2008; 199:396.e1,396.e7.
27. Swift Swift RM, Dudley M, Deptrillo P, Camara P, Griffiths W. Altered methadone
pharmacokinetics in pregnancy: implications for dosing. J Subst Abuse. 1989;1(4):453-60.
28. Jarvis MA, Wu-Pong S, Kniseley JS, Schnoll SH. Alterations in methadone metabolism
during late pregnancy. J Addict Dis. 1999;18(4):51-61.
29. Wolff K, Boys A, Rostami-Hodjegan A, Hay A, Raistrick D. Changes to methadone
clearance during pregnancy. Eur J Clin Pharmacol 2005; 61:763-8.
30. Pond Pond SM, Kreek MJ, Tong TG, Raghunath J, Benowitz NL. Altered methadone
pharmacokinetics in methadone-maintained pregnant women. J Pharmacol Exp Ther.
31. Drozdick J,3rd, Berghella V, Hill M, Kaltenbach K. Methadone trough levels in pregnancy.
Am J Obstet Gynecol 2002; 187:1184-8.
32. Jansson LM, Dipetro JA, Elko A, Jansson MV. Maternal vagal tone change in response to
methadone is associated with neonatal abstinence syndrome severity in exposed neonates. J
Matern Fetal Neonatal Med. 2007;20(9):677-85.
33. Deshmukh SV, Nanovskaya TN, Hankins GD, Ahmed MS. N-demethylation of levo-alpha
acetylmethadol by human placental aromatase. Biochem Pharmacol. 2004;67(5):855-92.
34. Nanovskaya TN, Deshmukh SV, Nekhayeva IA, Zharikova OL, Hankins GD, Ahmed MS.
Methadone metabolism by the human placenta. Biochem Pharmacol. 2004;68(3):583-91.
35. Nekhayeva IA, Nanovskaya TN, Deshmukh SV, et al., Bidirectional transfer of methadone
across human placenta. Biochemical Pharmacology 2005;69(1):187-97.
36. Nanovskaya TN, Nekhayeva IA, Hankins GDV, Ahmed MS. Transfer of methadone across
the dually perfused preterm human placental lobule. Am J Obstet Gynecol. 2008;198:126e1-
37. Blinick Blinick G, Wallach RC, Jerez E. Pregnancy in narcotics addicts treated by medical
withdrawal. The methadone detoxification program.
Am J Obstet Gynecol.
38. Mack G, Thomas D, Giles W, Buchanan N. Methadone levels and neonatal withdrawal. J
Paediatr Child Health. 1991 Apr;27(2):96-100.
39. AAP American Academy of Pediatrics Committee on Drugs: Neonatal Drug Withdrawal.
40. Abdel-Latif ME, Pinner J, Clews S, Cooke F, Lui K, Oei J. Effects of breast milk on the
severity and outcome of neonatal abstinence syndrome among infants of drug-dependent
mothers. Pediatrics 2006; 117:e1163-9
41. Choo Choo RE, Huestis MA, Schroeder JR, Shin AS, Jones HE. Neonatal abstinence
syndrome in methadone-exposed infants is altered by level of prenatal tobacco exposure.
Drug Alcohol Depend. 2004;75(3):253-60.
42. Oei J and Lui K. Management of the newborn infant affected by maternal opiates and other
drugs of dependency. J Paedriatr child Health. 2007;43(1-2):9-18.
43. Sutton LR and Hinderliter SA. Diazepam abuse in pregnant women on methadone.
Implications for the neonate. Clin Pediatr (Phila). 1990;29(2):108-11.
44. Finnegan L, Kaltenbach K, Weiner S, Haney B. Neonatal cocaine exposure:
assessment of risk scale. Pediatr Res. 1990;27:10A
45. ACOG Practice Bulletin #92: Use of Psychiatric Medications During Pregnancy and
Lactation. Obstet Gynecol. 2008;111(4):1001-20.
46. Sanz EJ, Cuevas CD, Kiuru A, Bate A, Edwards R. Selective serotonin reuptake inhibitors
in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet.
47. Levinson-Castiel R, Merlob P, Linder N, Sirota L, Klinger G. Neonatal Abstinence
Syndrome After In Utero Exposure to Selective Serotonin Reuptake Inhibitors in Term
Infants. Arch Pediatr Adolesc Med. 2006;160:173-76.
48. McCance-Katz EF, Rainey PM, Smith P, Morse GD, Friedland G, Boyarsky B, Gourevitch
M, Jatlow P. Drug interactions between opioids and antiretroviral medications: interaction
between methadone, LAAM, and delavirdine. Am J Addict. 2006 Jan-Feb;15(1):23-34.
49. Lipsitz Lipsitz PJ. A proposed neonatal withdrawal score for use with newborn infants: A
pragmatic evaluation of its efficacy. Clin Pediatr. 1975;14(6):592-4.
50. Rivers RP. Neonatal opiate withdrawal. Arch Dis Child. 1986;61(12):1236-9.
51. Jansson LM, Choo R, Velez ML, Harrow C, Schroeder JR, Shakleya DM et al. Methadone
maintenance and breastfeeding in the neonatal period. Pediatrics 2008; 121:106-14.
52. Kreek MJ. Methadone disposition during the perinatal period in humans. Pharmacol
Biochem Behav. 1979;11 Suppl:7-13.
53. Begg EJ, Malpas TJ, Hackett PL, Ilett KF. Distribution of R- and S-methadone into human
milk during multiple, medium to high oral dosing. J Clin Pharmacol. 2001;52:681-5.
Seligman Download full-text
Figure. Rates of neonatal abstinence syndrome and maternal illicit opiate abuse at delivery
according to methadone dose