Neonatal medicine
Neonatal medicine
The article should have been published within the past 5 years in a peer-reviewed professional journal. (The features of a peer-reviewed journal are listed below). Library and research resources are provided in the Course Menu. Review the attached handouts before you begin the process:
1) How to Review a Journal Article,
2) Sample Format for Reviewing Journal Articles and
3) the Journal Article Review rubric, which will be used for grading.
Note that a Journal Article Review is not a summary of the article, but includes the following components: An abstract
1. What is the purpose of this article? (this section includes a brief summary of the article)
2. Why is it important to investigate or examine the subject of the article?
3. How are the authors carrying out the task? Are their methods and comments appropriate and adequate to the task?
4. What do they claim to have found out? Are the findings clearly stated?
How to Review a Journal Article:
Suggestions for First-Time Reviewers and Reminders for Seasoned Experts
Guidelines for Reviewing
Here are some things you should consider as you examine a manuscript and write your
review:
Look for the “intellectual plot-line” of the article. You can do this from first skimming
through the manuscript and then giving it a once-over read. As you do this, ask the major
questions that are central to the review process:
1. What is the purpose of this article?
2. Why is it important to investigate or examine the subject of the article?
3. How are the authors carrying out the task? Are their methods and comments
appropriate and adequate to the task?
4. What do they claim to have found out? Are the findings clearly stated?
5. How does this advance knowledge in the field?
How well do the authors place their findings or comments within the context of ongoing
scholarly inquiry about this topic? Look at the organization of the article. Can you find
answers to the above questions quickly and easily? Can you trace the logic consistently
from the opening paragraphs to the conclusion?
Then go back to the opening paragraphs of the article. Is the groundwork adequately and
clearly laid to guide readers into the topic that is being addressed? Is it clear what the
authors are talking about? Do they make the case that this is an important area for inquiry
or examination?
An early section of many articles is usually a review of the existing literature on this topic.
Do the authors present a convincing line of argument here—or does it appear that they
are just name-dropping (citing sources that may be important, without a clear underlying
logic for how they may be important)? Do the authors focus on ideas, or merely on
discrete facts or findings? Have they given sufficient attention to theory—the cumulative
attempts at prior explanations for the questions they are investigating? In short: How well
do the authors set the stage for the problem or issue that they are reporting?
In the case of a research article, the section presenting research results is surely the heart
of the article—though not its soul (which the reader should find in the opening
paragraphs and in the discussion section). Reviewers might consider four questions here:
1. Does the results section tell a story—taking the reader from the research questions
posed earlier to their answers in the data? Is the logic clear?
2. Are the tables and figures clear and succinct? Can they be “read” easily for major
findings by themselves, or should there be additional information provided? Are
the authors’ tables consistent with the format of currently accepted norms
regarding data presentation? Are the tables and/or figures necessary?
3. Do the authors present too many tables or figures in the form of undigested
findings? Are all of them necessary in order to tell the story of this research
2
inquiry; or can some be combined? Remember that tables and figures are very
expensive and can take up a lot of space. Also remember that undigested data
obscure rather than advance the cumulative development of knowledge in a field.
4. Are the results presented both statistically and substantively meaningful? Have the
authors stayed within the bounds of the results their data will support?
The writing style is important. Consider the three guidelines for successful
communication—to be clear, concise, and correct — and whether the authors have
achieved it:
1. Is the writing clear? Do the authors communicate their ideas using direct,
straightforward, and unambiguous words and phrases? Have they avoided jargon
(statistical or conceptual) that would interfere with the communication of their
procedures or ideas? Have they clearly and satisfactorily explained the key
concepts relevant to the article?
2. Is the writing concise? Are too many words or paragraphs or sections used to
present what could be communicated more simply?
3. Is the writing correct? Many writers have only a rudimentary grasp of grammar
and punctuation, and that results in meandering commas, clauses in complex
sentences that are struggling to find their verbs, and adjectives or even nouns that
remain quite ambiguous about their antecedents in the sentence. Does the article
have a foreign accent, i.e., is it clear that a native speaker of English did not write
it? These are not merely technical issues of grammar to be somehow dealt with by
a copy-editor down the line. Rather they involve the successful communication of
a set of ideas to an audience; and this is the basis of scholarship today.
Your evaluation to the editor: Should this paper be (a) rejected for this journal? or (b)
does it show sufficient promise for revision, in ways that you have clearly demonstrated in
your review, to encourage the authors to invest significant time and energy in revision for
this journal? Your bottom-line advice to the editor is crucial. Make a decision; state it
clearly in your remarks to the editor in the space provided. Remember that not all of the
articles submitted to a journal will be published.
Some reasons to reject a manuscript:
1. The issues have already been addressed in prior studies;
2. The data have been collected in such a way as to preclude useful investigation;
3. The manuscript is not ready for publication—it is incomplete, in the improper
format, or error-ridden.
Most rejected articles do find a home in other journals. Don’t tease authors with hopes for
publication in the NECTFL Review if you feel it is not likely.
Good Reviews and Bad Reviews
A good review is supportive, constructive, thoughtful, and fair. It identifies both strengths
and weaknesses, and offers concrete suggestions for improvements. It acknowledges the
reviewer’s biases where appropriate, and justifies the reviewer’s conclusions.
3
A bad review is superficial, nasty, petty, self-serving, or arrogant. It indulges the reviewer’s
biases with no justification. It focuses exclusively on weaknesses and offers no specific
suggestions for improvement.
Adapted from “Information from Reviewers” of Foreign Language Annals, a publication of the American
Council on the Teaching of Foreign Languages (ACTFL). Retrieved from http://www.actfl.org/i4a/pages/
index.cfm?pageid=5163 on October 25, 2010. Used by permission.
original article
T h e new engl and journa l o f medicine
n engl j med 363;24 nejm.2320 org december 9, 2010
Neonatal Abstinence Syndrome after
Methadone or Buprenorphine Exposure
Hendrée E. Jones, Ph.D., Karol Kaltenbach, Ph.D., Sarah H. Heil, Ph.D.,
Susan M. Stine, M.D., Ph.D., Mara G. Coyle, M.D., Amelia M. Arria, Ph.D.,
Kevin E. O’Grady, Ph.D., Peter Selby, M.B., B.S., Peter R. Martin, M.D.,
and Gabriele Fischer, M.D.
From the Departments of Psychiatry and
Behavioral Sciences and Obstetrics and
Gynecology, Johns Hopkins University
School of Medicine, Baltimore (H.E.J.); the
Departments of Pediatrics, Psychiatry, and
Human Behavior, Jefferson Medical College,
Thomas Jefferson University, Philadelphia
(K.K.); the Departments of Psychiatry
and Psychology, University of
Vermont, Burlington (S.H.H.); the Department
of Psychiatry and Behavioral
Neurosciences, Wayne State University
School of Medicine, Detroit (S.M.S.); the
Department of Pediatrics, Warren Alpert
Medical School of Brown University, Providence,
RI (M.G.C.); the Center for Young
Adult Health and Development (A.M.A.)
and Department of Psychology (K.E.O.),
University of Maryland, College Park; the
Departments of Family and Community
Medicine and Psychiatry, University of
Toronto, Toronto (P.S.); the Departments
of Psychiatry and Pharmacology and Addiction
Center, Vanderbilt University School
of Medicine, Nashville (P.R.M.); and the
Department of Psychiatry and Psychotherapy,
Addiction Clinic, Medical University
Vienna, Vienna (G.F.). Address reprint
requests to Dr. Jones at the Center for
Addiction and Pregnancy, D-3 E., Johns
Hopkins Bayview Medical Center, 4940
Eastern Ave., Baltimore, MD 21224, or at
hjones18@jhmi.edu.
N Engl J Med 2010;363:2320-31.
Copyright © 2010 Massachusetts Medical Society.
ABSTR ACT
BACKGROUND
Methadone, a full mu-opioid agonist, is the recommended treatment for opioid
dependence during pregnancy. However, prenatal exposure to methadone is associated
with a neonatal abstinence syndrome (NAS) characterized by central nervous
system hyperirritability and autonomic nervous system dysfunction, which often requires
medication and extended hospitalization. Buprenorphine, a partial mu-opioid
agonist, is an alternative treatment for opioid dependence but has not been extensively
studied in pregnancy.
METHODS
We conducted a double-blind, double-dummy, flexible-dosing, randomized, controlled
study in which buprenorphine and methadone were compared for use in the comprehensive
care of 175 pregnant women with opioid dependency at eight international
sites. Primary outcomes were the number of neonates requiring treatment for
NAS, the peak NAS score, the total amount of morphine needed to treat NAS, the
length of the hospital stay for neonates, and neonatal head circumference.
RESULTS
Treatment was discontinued by 16 of the 89 women in the methadone group (18%)
and 28 of the 86 women in the buprenorphine group (33%). A comparison of the
131 neonates whose mothers were followed to the end of pregnancy according to
treatment group (with 58 exposed to buprenorphine and 73 exposed to methadone)
showed that the former group required significantly less morphine (mean dose, 1.1 mg
vs. 10.4 mg; P<0.0091), had a significantly shorter hospital stay (10.0 days vs. 17.5 days,
P<0.0091), and had a significantly shorter duration of treatment for the neonatal
abstinence syndrome (4.1 days vs. 9.9 days, P<0.003125) (P values calculated in accordance
with prespecified thresholds for significance). There were no significant
differences between groups in other primary or secondary outcomes or in the rates
of maternal or neonatal adverse events.
CONCLUSIONS
These results are consistent with the use of buprenorphine as an acceptable treatment
for opioid dependence in pregnant women. (Funded by the National Institute
on Drug Abuse; ClinicalTrials.gov number, NCT00271219.)
The New England Journal of Medicine
Downloaded from nejm.org on July 1, 2014. For personal use only. No other uses without permission.
Copyright © 2010 Massachusetts Medical Society. All rights reserved.
Methadone, Buprenorphine, and Neonatal Abstinence Syndrome
n engl j med 363;24 nejm.org december 9, 2010 2321
Opioid dependence during pregnancy
is compounded by multiple risk factors
contributing to adverse maternal, neonatal,
and long-term developmental consequences.
1-6 Improved treatment options should reduce
the public health and medical costs associated
with the treatment of neonates exposed to opioids,
which in 2009 was estimated at $70.6 million to
$112.6 million in the United States alone.7 Just as
the use of methadone in nonpregnant patients
with opioid dependence improves patient outcomes,
8 its use as part of a comprehensive approach
to the care of pregnant women improves
maternal and neonatal outcomes, as compared
with no treatment and with medication-assisted
withdrawal.4,9,10 However, exposure to methadone
in utero can result in a neonatal abstinence syndrome
(NAS) characterized by hyperirritability of
the central nervous system and dysfunction in the
autonomic nervous system, gastrointestinal tract,
and respiratory system.11 When left untreated,
NAS can result in serious illness (e.g., diarrhea,
feeding difficulties, weight loss, and seizures)
and death.11 Methadone-associated NAS often requires
prolonged hospitalization, pharmacologic
intervention, and monitoring.
Buprenorphine, a partial mu-opioid agonist
and kappa-opioid antagonist, effectively treats
opioid dependence.12 Its low intrinsic receptor
efficacy results in a less-than-maximal opioid
effect13 and a diminished risk of overdose, as compared
with methadone. In nonpregnant adults,
the effects of abrupt withdrawal of buprenorphine
are minimal relative to the effects of
withdrawal of full mu-opioid agonists.14,15 Buprenorphine’s
pharmacologic advantages led to
prospective open-label and controlled studies of
its use in prenatal treatment,16-19 and the results
of some of these studies suggested that neonates
exposed to buprenorphine might be less likely to
require treatment for NAS than those exposed to
methadone.20 Recent studies of methadone and
buprenorphine have had inconsistent results with
respect to NAS outcomes.21-26 Given the calls to
increase representation of pregnant women in
medication research,27 we conducted the Maternal
Opioid Treatment: Human Experimental Research
(MOTHER) project, a multicenter, randomized,
controlled trial comparing buprenorphine with
methadone for the treatment of opioid-dependent
pregnant patients.28
Methods
Study Sites and Participants
Between May 4, 2005, and October 31, 2008,
opioid-dependent women between the ages of 18
and 41 years with a singleton pregnancy between
6 and 30 weeks of gestation (calculated on the
basis of the last menstrual period and confirmed
by ultrasonographic results) were screened and
recruited at eight international sites — six in the
United States and one each in Austria and Canada.
Seven sites contributed randomized data; one
site screened participants but did not complete
randomization.
Women were eligible for participation in the
study if they had no medical or other conditions
contraindicating participation, were not subject
to pending legal action that might prevent their
participation, had no disorders related to the use
of benzodiazepines or alcohol, and did not plan
to give birth outside the hospital at the study site
(Fig. 1). Study referral sources included community
providers, self-referral, and the site’s treatment
program.28-30
Screening for eligibility consisted of a comprehensive
battery of tests (see Fig. 1 in the Supplementary
Appendix, available with the full text of
this article at NEJM.org). The screening tests
were performed either at the time of treatment
initiation (in the case of patients who were new
to treatment) or after a patient’s request for a
change in her established treatment (e.g., in the
case of patients who were already being treated
with a mu-opioid agonist and who agreed to
randomization). Patients who were not eligible
for participation in the study were so informed
and transferred to standard care available at the
site’s clinic or at a local community clinic.
Each site’s local institutional review board approved
the study. All participants provided written
informed consent at the time of screening.
Buprenorphine tablets and the associated placebo
were supplied by Reckitt Benckiser Healthcare,
Hull, United Kingdom. These tablets were
distributed to U.S. study investigators by the National
Institute on Drug Abuse. Schering-Plough
distributed buprenorphine tablets and placebo to
Austrian investigators. Neither Reckitt Benckiser
Healthcare nor Schering-Plough had involvement
in the study design; data collection, analysis, or
interpretation; or manuscript preparation.
The New England Journal of Medicine
Downloaded from nejm.org on July 1, 2014. For personal use only. No other uses without permission.
Copyright © 2010 Massachusetts Medical Society. All rights reserved.
T h e new engl and journa l o f medicine
n engl j med 363;24 nejm.2322 org december 9, 2010
Study Medications and Patient Care
Before randomization, all participants received
rapid-release morphine sulfate as inpatients to
achieve medical stabilization and to ease the transition
to the double-blind medication.26,29,31 Qualifying
participants underwent randomization and
started the assigned study medication as inpatients.
A blinded, individualized dosing schedule was
used for the study medications, and a doubleblind
method was used to implement dose-unit
increases or decreases (with dose adjustments
of 2 mg for buprenorphine and 5 or 10 mg for
methadone). Dose adjustments entailed clinical
decisions based on medication adherence, the
participant’s request, urine toxicologic results,
and self-reported symptoms of withdrawal or
craving.26 Tablets of buprenorphine (Subutex,
Reckitt Benckiser) were used to avoid prenatal
exposure to naloxone. (Neither buprenorphine
175 Underwent randomization
1074 Patients were screened for eligibility
243 Did not provide consent
656 Were excluded
557 Failed to meet inclusion criteria
149 Had estimated gestational age outside
range
124 Were taking a benzodiazepine
105 Had medical reason
57 Were using alcohol
42 Had impending legal issue
19 Did not provide consent
17 Had psychological or psychiatric reason
12 Had multiple-fetus pregnancy
11 Were outside age range
10 Were undergoing detoxification
9 Were not opioid-dependent
2 Did not speak English or German
99 Were excluded for other reasons
86 Were assigned to receive
buprenorphine
89 Were assigned to receive
methadone
28 Discontinued study
26 Had voluntary reasons
20 Were dissatisfied with
medication
5 Missed 5 consecutive
dosing days
1 Withdrew
2 Had involuntary reasons
2 Were discharged for
administrative reason
16 Discontinued study
10 Had voluntary reasons
2 Were dissatisfied with
medication
4 Missed 5 consecutive
dosing days
2 Withdrew
2 Had other reason
6 Had involuntary reasons
2 Were discharged for
administrative reason
2 Lost pregnancy
1 Had medical issues
1 Was incarcerated
58 Completed the study 73 Completed the study
Figure 1. Screening, Randomization, and Rate of Treatment Completion, According to Study Group.
The New England Journal of Medicine
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Copyright © 2010 Massachusetts Medical Society. All rights reserved.
Methadone, Buprenorphine, and Neonatal Abstinence Syndrome
n engl j med 363;24 nejm.org december 9, 2010 2323
nor naloxone has been approved by the Food and
Drug Administration or the European Medicines
Agency for use during pregnancy.) A flexible
dose range of 2 to 32 mg of buprenorphine in
sublingual tablets was estimated to be equivalent
to 20 to 140 mg of methadone on the basis of
previously published data from clinical trials.32-34
Participants were required to receive daily
medications under observation in the study clinic.
They always received seven tablets (three in
the size of an 8-mg tablet and four in the size of
a 2-mg tablet) to place under the tongue for 5 minutes,
or until the tablets dissolved. Each tablet
contained buprenorphine or placebo. After receiving
these tablets, participants received liquid
containing methadone or placebo. Oral methadone
and flavor-masking concentrates were diluted
to provide the dose in a fixed volume (e.g.,
40 ml at U.S. sites and 50 ml in Vienna). Methadone
placebo was given in the same fixed volume
and included the same flavor-masking concentrates
as the active drug concentrate. All medications
were dispensed through regulated hospital
pharmacies or methadone clinics.
The study sites provided participants with
comprehensive care. To promote drug abstinence,
patients were given monetary vouchers in exchange
for providing urine samples that were
negative for opioids (other than buprenorphine
and methadone), other illicit drugs, and misuse
of prescription medications.26 On completion of
the study, participants could receive locally available
treatment.
Evaluation for NAS
NAS assessment was performed for a minimum
period of 10 days after birth. Hospitalized neonates
were examined every 4 hours by trained
staff. Neonates discharged from the hospital before
postnatal day 10 were expected to reside
with the mother in a residential setting, where
the evaluation was continued. NAS scores were
obtained twice daily, at least 8 hours apart, with
the use of a modified Finnegan scale (called the
MOTHER NAS scale), which includes 28 items11;
19 items were used for scoring and medication
decisions. Scores on the modified scale range
from 0 to 42, with higher scores indicating
more severe withdrawal. Original NAS-item definitions,
35 as well as the morphine medication
protocol,26,36 were refined before data collection
(Fig. 2 in the Supplementary Appendix);
the study was conducted in accordance with the
protocol.
An expert rater trained a highly experienced
rater at each site; by the end of training, the site
raters were required to obtain scores that were
within 2 points of the expert rater’s scores. To
maintain consistency in the reliability of the ratings
at each site, every 6 months the expert rater
provided a video of an infant undergoing NAS
assessment. An intraclass correlation coefficient
(ICC[2,2]) for the degree of agreement37 between
the expert rater and the site rater was estimated;
the lowest coefficient exceeded 0.94, indicating
excellent agreement between the raters.
Study Outcomes and Adverse Events
The five primary neonatal outcome measures
were the number of neonates requiring treatment
for NAS, peak NAS score, total amount of morphine
needed for treatment of NAS, length of
hospital stay, and head circumference. The seven
secondary neonatal outcomes were the number
of days during which medication was given for
NAS, weight and length at birth, preterm birth
(defined as birth at <37 weeks of gestation), gestational
age at delivery, and 1-minute and 5-minute
Apgar scores. The nine secondary maternal outcomes
were cesarean section, weight gain, abnormal
fetal presentation during delivery, anesthesia
during delivery, the results of drug screening at
delivery, medical complications at delivery, study
discontinuation, amount of voucher money earned
for drug-negative tests, and number of prenatal obstetrical
visits. Adverse events for all participants
were categorized on the basis of the Medical Dictionary
for Regulatory Activities (version 10.0) system of
organ classes and predefined categories of events.
Statistical Analysis
Bonferroni’s principle was used to set the familywise
alpha level at 0.01 (nominal alpha level,
0.05 ÷ 5) for each of the five primary outcome
measures at the time of the initial study design;
an interim analysis requested by the data safety
and monitoring board resulted in a recalculation
of the alpha level on the basis of the O’Brien–
Fleming spending function, such that the end-oftrial
alpha level was 0.0091 for each primary outcome
measure. Bonferroni’s principle was also
used to set the family-wise alpha level at 0.003125
(nominal alpha level, 0.05 ÷ 16) for the secondary
outcome measures.
The New England Journal of Medicine
Downloaded from nejm.org on July 1, 2014. For personal use only. No other uses without permission.
Copyright © 2010 Massachusetts Medical Society. All rights reserved.
T h e new engl and journa l o f medicine
n engl j med 363;24 nejm.2324 org december 9, 2010
There were two fixed-effect factors in all analyses:
medication (buprenorphine vs. methadone)
and site (U.S. urban [Baltimore; Philadelphia; Detroit;
Providence, RI] vs. U.S. rural [Burlington,
VT; Nashville] vs. European [Vienna]). Pooling the
sites minimized the possibility that site heterogeneity
would adversely effect the analyses.30 Poisson
regression analyses were conducted for the
total amount of morphine needed to treat NAS,
neonatal length of stay in the hospital, number
of days of treatment for NAS, estimated gestational
age at delivery, amount of money earned
for drug-negative tests, number of prenatal obstetrical
visits, and Apgar scores at 1 minute and
5 minutes. Ordinary least-squares regression
analyses
were conducted for the peak score on the
NAS scale during the assessment period, infant
head circumference, and infant weight and length
at birth. Logistic-regression analyses were conducted
for the remaining dichotomous variables.
For medication effects, model-derived leastsquares
means are reported for normally distributed
outcome variables, model-derived exponentiated
estimated means for Poisson-distributed
outcome variables, and odds ratios for the logistic
regressions. To minimize the possibility that
the effects attributed to the assigned medication
might be due to differences in participant characteristics,
the analyses were repeated with the
inclusion of covariates selected on the basis of
their potential associations with the outcome
variables. (For details on covariates, see Table 1
in the Supplementary Appendix.)
Results
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