Relationship between maternal methadone dose at delivery and neonatal abstinence syndrome.
ABSTRACT To estimate the relationship between maternal methadone dose and the incidence of neonatal abstinence syndrome (NAS).
We performed a retrospective cohort study of pregnant women treated with methadone for opiate addiction who delivered live-born neonates between 1996 and 2006. Four dose groups, on the basis of total daily methadone dose, were compared (<or=80 mg/d, 81-120 mg/d, 121-160 mg/d, and >160 mg/d). The primary outcome was treatment for NAS. Symptoms of NAS were objectively measured with the Finnegan scoring system, and treatment was initiated for a score>24 during the prior 24 hours.
A total of 330 women treated with methadone and their 388 offspring were included. Average methadone dose at delivery was 117+/-50 mg/d (range, 20-340 mg/d). Overall, 68% of infants were treated for NAS. Of infants exposed to methadone doses<or=80 mg/d, 81-120 mg/d, 121-160 mg/d, and >160 mg/d, treatment for NAS was initiated for 68%, 63%, 70%, and 73% of neonates, respectively (P=.48). The rate of maternal illicit opiate abuse at delivery was 26%, 28%, 19%, and 11%, respectively (P=.04).
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 delivery.
- [Show abstract] [Hide abstract]
ABSTRACT: Background Neonatal abstinence syndrome (NAS) is experienced by infants who were exposed to opioids such as morphine, methadone, codeine, and heroin in utero. The aim of the study was to investigate the effect of laser acupuncture therapy in neonates with NAS due to maternal substitution therapy. Patients and Method This is a prospective, randomised, observer blinded, mono-centric study performed at the division of neonatology at the university teaching hospital, Graz. Laser acupuncture was performed with a III b laser. Laser acupuncture therapy following a standardised protocol based on the five ear points of the NADA-protocol combined with body acupuncture (Large Intestine 4, Heart 7, Kidney 3, Liver 3), bilaterally. Results Since the start of the pilot study (2008–5/2012) we evaluated 20 neonates with NAS due to maternal substitution therapy. Conclusion Neonates with NAS due to maternal substitution therapy undergoing a combined laser acupuncture therapy of the ear and the body, require a statistically significant shorter oral morphine therapy than neonates with NAS without laser acupuncture therapy (IG = 28,4 days vs. CG = 39,8 days, p < 0,05).Deutsche Zeitschrift für Akupunktur 01/2014; 57(3):12–17.
- Medical Acupuncture 09/2011; 23(3):175-186.
Article: Neonatal Abstinence Syndrome.[Show abstract] [Hide abstract]
ABSTRACT: Neonatal abstinence syndrome (NAS) is a result of the sudden discontinuation of fetal exposure to substances that were used or abused by the mother during pregnancy. Withdrawal from licit or illicit substances is becoming more common among neonates in both developed and developing countries. NAS continues to be an important clinical entity throughout much of the world. NAS leads to a constellation of signs and symptoms involving multiple systems. The pathophysiology of NAS is not completely understood. Urine or meconium confirmation may assist the diagnosis and management of NAS. The Finnegan scoring system is commonly used to assess the severity of NAS; scoring can be helpful for initiating, monitoring, and terminating treatment in neonates. Nonpharmacological care is the initial treatment option, and pharmacological treatment is required if an improvement is not observed after nonpharmacological measures or if the infant develops severe withdrawal. Morphine is the most commonly used drug in the treatment of NAS secondary to opioids. An algorithmic approach to the management of infants with NAS is suggested. Breastfeeding is not contraindicated in NAS, unless the mother is taking street drugs, is involved in polydrug abuse, or is infected with HIV. Future studies are required to assess the long-term effects of NAS on children after prenatal exposure.Pediatrics 07/2014; · 5.30 Impact Factor
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
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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