Naloxone for opiate-exposed newborn infants

McGuire W, Fowlie PW

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs

Dates

Date edited: 11/07/2007
Date of last substantive update: 18/06/2002
Date of last minor update: 14/03/2007
Date next stage expected 14/03/2009
Protocol first published: Issue 1, 2002
Review first published: Issue 4, 2002

Contact reviewer

Dr William McGuire
Associate Professor of Neonatology
Department of Paediatrics and Child Health
Australian National University Medical School
Canberra Hospital Campus
Canberra
ACT 2606 AUSTRALIA
Telephone 1: +61 2 62442222
Facsimile: +61 2 62443112
E-mail: william.mcguire@act.gov.au

Contribution of reviewers

Peter Fowlie (PF) and William McGuire (WM) developed the protocol for this review.
WM screened the title and abstract of all studies identified by the search strategy.
PF and WM screened the full text of the report of each study identified as of potential relevance.
PF and WM extracted the data separately, compared data, and resolved differences by consensus.
PF and WM completed the final review.

Internal sources of support

Tayside Institute of Child Health, Ninewells Hospital and Medical School, Dundee, UK
Tayside University Hospitals Trust, Dundee, UK

External sources of support

None

What's new

This review updates "Naloxone for narcotic-exposed newborn infants", published in the Cochrane Database of Systematic Reviews, The Cochrane Library, Issue 4, 2002 (McGuire 2002).

Our electronic search was updated in February 2007. No new trials that fulfilled eligibility criteria were identified.

We re-categorised studies that were previously listed as "studies awaiting assessment". Four of these were abstracts presenting data that was also presented in included substantive publications. These are now listed as secondary publications. One study was excluded.

Dates

Date review re-formatted: / /
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis

When a pregnant woman uses opiates (for example, morphine and similar drugs) for pain relief in labour her newborn baby's breathing may be depressed. Naloxone, a drug that counters the effects of opiates, is often used to help resuscitate such newborns. This review did not find any evidence that naloxone reduces the need for assisted breathing or admission to neonatal care units for babies born after women used opiate-based pain relief in labour. More research is needed on the effects of naloxone on babies when the mother has been using opiates during pregnancy.

Abstract

Background

Naloxone, a specific opiate antagonist, is available for the management of newborn infants with respiratory depression that may be due to intrauterine exposure to opiate. However, it is unclear which groups of newborn infants may benefit from this therapy, and whether naloxone has any harmful effects.

Objectives

To determine the effect of naloxone on the need for or duration of ventilatory support or neonatal unit admission in newborn infants who have been exposed in-utero to narcotics.

Search strategy

Selection criteria

Randomised controlled trials comparing the administration of naloxone versus placebo, or no drug, or another dose of naloxone, to newborn infants with suspected or confirmed in-utero exposure to narcotics.

Data collection & analysis

Data were extracted using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author and synthesis of data using relative risk, risk difference and weighted mean difference.

Main results

Nine trials that compared the effects of naloxone versus placebo or no drug in newborn infants exposed to maternal opiate analgesia prior to delivery were identified. None of these trials specifically recruited infants with respiratory depression. The main outcomes reported were measures of respiratory function in the first six hours of life. There is some evidence that naloxone increases alveolar ventilation. However, no data on the pre-specified primary outcomes of this review were noted (the need for assisted mechanical ventilation or admission to a neonatal unit).

Reviewers' conclusions

Background

Intrauterine exposure to maternal opiates may be associated with respiratory and behavioral problems in newborn infants (Gerhardt 1977a; Bonta 1979). Naloxone, a specific opiate antagonist, is available for the treatment of respiratory depression in opiate-exposed newborn infants. The International Liaison Committee on Resuscitation has provided guidance on the use of naloxone in the resuscitation of newborn infants (Niermeyer 2001). The advice follows the long-standing recommendation of the American Academy of Pediatrics (AAP) Committee on Drugs that naloxone should not be used routinely in opiate-exposed newborn infants, but should be "reserved for adjunctive therapy in selected infants who have not initiated or established independent respiration following ventilation, are significantly depressed, and have a high probability of being narcotized" (AAP 1980). These recommendations refer to infants of mothers who have received opiate for analgesia up to four hours prior to delivery. The dose recommended in 1980, 0.01 mg/kg administered via an intravenous or endotracheal route, was later revised to 0.1 mg/kg (AAP 1990). More recently the Neonatal Resuscitation Program (NRP) has further refined this advice, suggesting that naloxone should only be given to infants with 1. severe respiratory depression after positive-pressure ventilation has restored a normal heart rate and colour, and 2. a history of maternal opiate administration within the past four hours (NRP 2000).

The AAP Committee on Drugs has advised that naloxone should not be administered to infants of opiate-dependent mothers (AAP 1998), as naloxone may precipitate acute withdrawal and seizures in opiate-habituated infants (Gibbs 1989). However, there are few data on significant adverse events due to naloxone in infants of opiate-dependent mothers, and some authors have recommended a small dose of naloxone (0.01 mg/kg) as a part of the resuscitation of such infants (Maas 1990).

There is evidence that, in current neonatal practice, naloxone is administered to many more newborn infants than recommended by the AAP Committee on Drugs (Herschel 2000). Herschel and colleagues caution that naloxone should not be regarded as harmless, and cite concerns that naloxone may interfere with the role of endogenous opioids in neuroendocrine programming and on behaviour (Szeto 1995; Smotherman 1992; de Castro 1993). Given these questions of appropriateness of use and potential longer-term effects, it is important to evaluate the available data on the use of naloxone in opiate-exposed newborn infants.

Objectives

1. To determine the effect of naloxone on the need for and duration of respiratory support or neonatal unit admission in infants of mothers who received opiate analgesia prior to delivery.

2. To determine the effect of naloxone on the need for and duration of respiratory support or neonatal unit admission in infants of mothers who have used a prescribed or non-prescribed opiate during pregnancy,

Pre-specified subgroup analyses:
1. Dose of naloxone less than 0.1 mg/kg body weight
2. Dose of naloxone equal to or greater than 0.1 mg/kg body weight

Criteria for considering studies for this review

Types of studies

Controlled trials utilizing either random or quasi-random patient allocation.

Types of participants

Newborn infants, cared for in a hospital setting, with suspected or confirmed exposure to opiates, either
1. As maternal pain relief prior to delivery
2. As a result of use during pregnancy

Types of interventions

Trials comparing naloxone with placebo or no drug, or comparing more than one dose of naloxone, as part of the management of newborn infants

Types of outcome measures

Primary outcomes:
1. Need for assisted ventilation (any form of mechanical ventilation including continuous positive airway pressure) in the neonatal period
2. Duration of assisted ventilation (days)
3. Admission to neonatal intensive care unit or special care baby unit in the neonatal period
4. Duration of neonatal intensive care unit or special care baby unit admission (days)

Secondary outcomes:
1. Time, from birth, to establish full oral feeds, independently of parenteral fluids or nutrition or of enteral tube feeding
2. Features of opiate withdrawal, using validated behavioral assessment measures in the neonatal period
3. Seizures in the neonatal period
4. Neurodevelopmental outcomes during infancy and beyond using validated assessment tools
5. Measures reflecting respiratory function, such as Apgar score, or arterial blood pH or arterial or alveolar carbon dioxide tension measured within the first six hours after birth

Search strategy for identification of studies

The standard search strategy of the Cochrane Neonatal Review Group was used. This included electronic searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2007), MEDLINE (1966 - February 2007) and EMBASE (1988 - February 2007). No language restriction was applied. References in studies identified as potentially relevant, in previous reviews, and in standard textbooks of neonatal medicine were examined. In 2002, the manufacturer of Narcan (DuPont Pharmaceuticals Company, Wilmington, Delaware 19880) provided a list of published studies, but did not provide any further data than those already found from other sources.

The search strategy involved the following keywords, using the search fields of abstract, MeSH subject heading, exploded subject heading, publication type, registry number word, subject heading word, text word, and title: "Infant-Newborn"/ all subheadings, OR infan*, OR neonat*, OR newborn, AND explode "naloxone"/ all subheadings, OR naloxone, OR narcan, OR explode "naltrexone"/ all subheadings, OR explode "narcotic antagonists"/ all subheadings, OR narcotic near3 antagonist, OR opiate near3 antagonist.

Methods of the review

1. The first review author screened the title and abstract of studies identified by the above search strategy. Both review authors re-screened the full text of the report of each study identified as of potential relevance. Only studies meeting all of the pre-specified inclusion criteria were included. The review authors resolved any disagreement by discussion until consensus was achieved.

2. The criteria and standard methods of the Cochrane Neonatal Review Group were used to assess the methodological quality of the included trials. Quality of the trials included was evaluated in terms of allocation concealment, blinding of parents or caregivers and assessors to intervention, and completeness of assessment in all randomised individuals.

3. A data collection form was used to aid extraction of relevant information and data from each included study. Each review author extracted the data separately, compared data, and resolved differences by consensus.

4. The standard method of the Cochrane Neonatal Review Group was used to synthesize the data. Effects are expressed as relative risk and 95% confidence interval and risk difference and 95% confidence interval for categorical data and weighted mean difference and 95% confidence interval for continuous data. A fixed effect model was used for meta-analysis. Heterogeneity between trial results was examined using the I² test for dichotomous outcomes and ANOVA for continuous outcomes.

Description of studies

Overall, 10 studies that appeared to be relevant were identified in the first round of screening. Nine studies were included and these are detailed in the table, Characteristics of Included Studies. Two of these studies were reported in the same article (Dick 1978a; Dick 1978b).

Two studies (Brice 1979b; Martin 1972) were excluded and are detailed in the table, Characteristics of Excluded Studies.

All of the included studies were undertaken in the 1970's or early 1980's. These studies recruited term infants whose mothers had received pethidine (meperidine) for pain relief, up to six hours prior to delivery. None of the trials specifically recruited infants with respiratory depression following narcotic exposure. In most trials, the intervention appears to have been given in the first five minutes after birth. In two trials, naloxone was given at 30 minutes (Gerhardt 1977a) or at one hour (Welles 1984) after birth. Naloxone was administered via the intramuscular route in four trials, and in the other five via the umbilical venous route. The dose of naloxone used ranged from 0.01 mg/kg to 0.04 mg/kg, with the exception of one study where a total dose of 0.2 mg was given (Wiener 1977b). The outcomes assessed were usually measures of respiratory effort such as Apgar scores, blood gases values, or other measures of alveolar ventilation.

No trials that examined the effects of naloxone in infants of mothers who had used a prescribed or non-prescribed narcotic during pregnancy were identified.

Methodological quality of included studies

Quality assessments are included in the table, Characteristics of Included Studies. All of the trials were small and none presented a power or sample size calculation. Most reports did not provide any details of measures to ensure allocation concealment. Therefore, it is unclear if the assignment of infants to naloxone or no drug could be predicted. In most trials the intervention was not blind to the caregivers or assessors. All of the trials appear to have achieved complete or near-complete follow up of infants recruited, although none of the trials undertook follow up beyond the first three days after birth.

Results

None of the included trials provided any data on any of the pre-defined primary outcomes of this review: need for assisted ventilation or neonatal unit admission. With regard to secondary outcome measures, we did not find any data on time to establishment of oral feeding, seizures in the neonatal period, or neurodevelopmental outcomes.

Five of the trials presented data on validated behavioral assessments in the neonatal period. The studies that reported the Scanlon Behavioural Score (Bonta 1979; Brice 1979a) and the Brazelton Neonatal Behavioural Assessment Score (Brice 1979a; Welles 1984) did not find any statistically significant differences. One trial reported the Broussard Neonatal Perception Inventory at 72 hours and found statistically significantly "less optimal behaviour" in the naloxone group (Welles 1984). However, standard deviations were not reported in any of these studies. Wiener 1977b found that the time taken to habituate to a sound-specific stimulus within the first 48 hours was statistically significantly lower in infants who received intra-muscular naloxone versus placebo. Wiener 1977a stated that there were not any "important differences" in habituation to auditory stimulus between infants who received intra-venous naloxone versus placebo. The data were not presented in the published report, but the investigator is now attempting to retrieve these data (personal communication: Dr. Paul Wiener, University College of Wales, Cardiff, UK).

Eight of the trials presented data on measures of respiratory function measured within the first six hours of life. There were not any statistically significant differences in the Apgar score (Bonta 1979), ventilation rate (Evans 1976), time to sustained respiration (Brice 1979a), minute ventilation (Gerhardt 1977a), or blood gas parameters (Bonta 1979; Dick 1978a; Dick 1978b).

Four trials assessed measures of alveolar ventilation (Brice 1979a; Evans 1976; Wiener 1977a; Wiener 1977b). There was evidence that, at 30 minutes and four hours post intervention, the expired carbon dioxide output and alveolar ventilation rate were statistically significantly higher, and the alveolar carbon dioxide tension lower, in the naloxone group (comparison 01, outcomes 01- 03). We detected statistical heterogeneity in these meta-analyses, in each case arising from one study (Wiener 1977b). This study used a larger dose of naloxone, and naloxone was given intra-muscularly compared with intra-venously in the other studies.

The planned subgroup analysis according to naloxone dose (less than, or equal to or greater than 0.1 mg/kg body weight) could not be performed because no eligible trials using a naloxone dose in the higher range were found.

Discussion

Nine trials that compared naloxone versus placebo or no drug for newborn infants exposed to maternal narcotic analgesia prior to delivery were identified. No studies that examined the use of naloxone in infants who had been exposed to narcotic in utero during pregnancy, for example due to maternal opiate-dependence were found.

No data were reported on clinically important outcomes such as the need for or duration of assisted ventilation or neonatal unit admission, the pre-defined primary outcomes for this review. The infants recruited to the trials did not appear to have been selected because of respiratory depression, although this is not stated explicitly in any of the reports. Infants with low Apgar scores at one minute or five minutes were not eligible for inclusion in two trials (Bonta 1979; Welles 1984). Therefore the findings of the trials are of limited relevance in the clinical context for which naloxone has been recommended by the American Academy of Pediatrics Committee on Drugs (AAP 1980), the Neonatal Resuscitation Program (NRP 2000), and the International Liaison Committee on Resuscitation (Niermeyer 2001), that is, for narcotic-exposed newborn infants with severe respiratory depression despite appropriate ventilation (NRP 2000).

There was some evidence that infants who received naloxone had increased alveolar ventilation, higher expired carbon dioxide levels and lower alveolar carbon dioxide tensions than control infants. However, the clinical significance of these findings is unclear. Similarly, although there is some evidence from one study that naloxone results in a shorter time to habituate to auditory stimuli (Wiener 1977b), the clinical relevance of this finding is unknown. No data were reported on clinically important neurological or behavioral outcomes in the neonatal period, or on any longer term outcomes.

Reviewers' conclusions

Implications for practice

The currently available data from nine randomised controlled trials do not provide any evidence that routine administration of naloxone to infants exposed to in-utero opiate during delivery affects any clinically important outcomes. No data from trials that recruited opiate-exposed newborn infants with respiratory depression were found.

Implications for research

There is a need for a randomised controlled trial to determine if naloxone confers any clinically important benefits to newborn infants with respiratory depression that may be due to intrauterine exposure to opiate. This trial should assess outcomes that are relevant to the infant, family, and caregivers, such as the need for assisted mechanical ventilation or admission to a neonatal unit. In view of the concerns that naloxone may interfere with the role of endogenous opioids in neuroendocrine programming and on behaviour (Szeto 1995; Smotherman 1992; de Castro 1993), follow up assessment beyond infancy will be required to determine neurodevelopmental outcomes.

Acknowledgements

We thank S Walker at DuPont Pharmaceuticals Limited for searching the company database of trials on the use of naloxone in newborn infants.

Potential conflict of interest

None

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Bonta 1979	Blinding of randomisation: Yes Blinding of intervention: Yes Complete follow-up: Yes Blinding of outcome measurement: Yes	43 normal term newborn infants whose mothers had received routine narcotic analgesia within six hours of delivery. Infants delivered in breech presentation or by Caesarean section, and infants with Apgar score less then six at one minute, were excluded.	1. intra-muscular naloxone (0.02 mg/kg body weight): N= 22 2. placebo (normal saline): N= 21	Apgar score at five minutes, capillary blood gas values at one, two and four hours of life, neurobehavioral asssessment at one, four, and twenty-four hours.	Utilised sequentially numbered ampuoles to randomise between naloxone and placebo (normal saline).	A
Brice 1979a	Blinding of randomisation: Can't tell Blinding of intervention: Can't tell Complete follow-up: Yes Blinding of outcome measurement: No (Yes for Scanlon developmental assessment)	50 term newborn infants whose mothers had received intra-muscular pethidine within four hours of delivery.	1.naloxone administered via the umbilical vein (0.01 or 0.02 mg/kg body weight): N=26 2. no drug: N=24	Time to sustained respiration, expired carbon dioxide output and alveolar ventilation up to 24 hours of life, Brazelton Neonatal Behavioral Assessment Score and Scanlon behavioral score within the first 24 hours of life.	Blinding of outcome measurement for Scanlon neurobehavioral score only.	B
Dick 1978a	Blinding of randomisation: Can't tell Blinding of intervention: No Complete follow-up: Yes Blinding of outcome measurement: No	40 newborn infants, of unspecified gestation, whose mothers had been given intravenous pethidine in labour	1. naloxone, via the umbilical vein (0.02 mg/kg): N=10 2. naloxone (0.03 mg/kg) N=10 3. naloxone (0.04 mg/kg) N=10 4. no drug. N= 10	Capillary blood gas pH and partial pressure of carbon dioxide and of oxygen at 1, 5, 10, 30, 60, and 120 minutes of life.	Presumed, although not stated explicitly in the report, that naloxone was administered at birth.	B
Dick 1978b	Blinding of randomisation: Can't tell Blinding of intervention: Yes Complete follow-up: Yes Blinding of outcome measurement: Yes	30 newborn infants, of unspecified gestation, whose mothers had been given intravenous pethidine in labour.	1. naloxone, via the umbilical vein (either 0.04 mg/kg or 0.04 mg total): N= 10 2. placebo: N= 20	Capillary blood gas pH, partial pressure of carbon dioxide and of oxygen, and calculated base excess at 1, 5, 10, 30, 60, and 120 minutes of life.		B
Evans 1976	Blinding of randomisation: Can't tell Blinding of intervention: No Complete follow-up: Yes Blinding of outcome measurement: No	44 newborn infants, of gestation 38- 42 weeks, delivered spontaneously or by forceps, whose mothers had been given pethidine in labour.	1.naloxone administered via the umbilical vein at one minute of age (0.04 mg total): N=20 2. no drug: N= 24	Time to first breath, time to onset of sustained respiration, Apgar score at five minutes, alveolar carbon dioxide tension, alveolar ventilation, and ventilation rate at 10 minutes and 30 minutes of life.		B
Gerhardt 1977a	Blinding of randomisation: Can't tell Blinding of intervention: Can't tell Complete follow-up: Yes Blinding of outcome measurement: Can't tell	20 term newborn infants, born vaginally, whose mothers had received intra-venous pethidine within three hours of delivery.	1. intra-muscular naloxone at 30 minutes of life (0.01 mg/kg): N= 12 2. placebo: N= 8	Respiratory rate, tidal volume, minute ventilation, end-tidal carbon dioxide tension, and the ventilatory response to inhalation of 4% carbon dioxide.	Naloxone given at 30 minutes of age.	B
Welles 1984	Blinding of randomisation: Can't tell Blinding of intervention: No Complete follow-up: Yes Blinding of outcome measurement: Yes	27 newborn infants, of gestation 38- 42 weeks, whose mothers had received pethidine during labour. Infants with Apgar scores less than 8 at one minute, or less than 9 at five minutes were not eligible for inclusion.	1.naloxone via the intra-muscular route at about one hour of age (0.1 mg total): N= 14 2. placebo (normal saline): N= 13	Brazelton Neonatal Behavioral Assessment Score score at 12- 24 hours of life and after a further 48 hours, and the Broussard neonatal Perception Inventory after the second Brazelton assessment.	The route of administration of naloxone and placebo is presumed to be intra-muscular, but this is not stated explicitly in the paper.	B
Wiener 1977a	Blinding of randomisation: Yes Blinding of intervention: Yes Complete follow-up: Yes Blinding of outcome measurement: Yes	28 newborn infants, of gestation 38- 42 weeks, whose mothers had been given pethidine in labour.	1.naloxone administered via the umbilical vein at one minute of age (0.04 mg total): N= 10 2. normal saline placebo: N= 18	Alveolar carbon dioxide tension, carbon dioxide excretion, alveolar ventilation, feeding behavior, and habituation to a sound-specific stimulus up to 48 hours of life.	Naloxone or normal saline were "chosen blind at random".	A
Wiener 1977b	Blinding of randomisation: Yes Blinding of intervention: Yes Complete follow-up: Yes Blinding of outcome measurement: Yes	30 newborn infants, of gestation 38- 42 weeks, whose mothers had been given pethidine in labour.	1. intra-muscular naloxone at one minute of age (0.2 mg total): N= 15 2. intra-muscular normal saline placebo: N= 15	Alveolar carbon dioxide tension, carbon dioxide excretion, alveolar ventilation, feeding behavior (mean sucking frequencies and pressures, and mean milk consumption), and habituation to a sound-specific stimulus up to 48 hours of life.		A

Characteristics of excluded studies

Study	Reason for exclusion
Brice 1979b	This report of pharmacokinetic data in infants who received either intra-venous or intra-muscular naloxone is unlikely to be a randomised comparison.
Martin 1972	This report is unlikely to be a randomised controlled trial.

References to studies

References to included studies

Bonta 1979 {published data only}

Bonta BW, Gagliardi JV, Williams V, Warshaw JB. Naloxone reversal of mild neurobehavioral depression in normal newborn infants after routine obstetric analgesia. Journal of Pediatrics 1979;94:102-5.

Brice 1979a {published data only}

Brice JE, Moreland TA, Walker CH. Effects of pethidine and its antagonists on the newborn. Archives of Disease in Childhood 1979;54:356-61.

Dick 1978a {published data only}

Dick W, Knoche E, Traub E. Clinical investigations of the influence of various naloxone doses on the newborn. Journal of Perinatal Medicine 1978;6:95-101.

Dick 1978b {published data only}

Dick W, Knoche E, Traub E. Clinical investigations of the influence of various naloxone doses on the newborn. Journal of Perinatal Medicine 1978;6:95-101.

Evans 1976 {published data only}

* Evans JM, Hogg MI, Rosen M. Reversal of narcotic depression in the neonate by naloxone. BMJ 1976;2:1098-100.

Evans JM, Hogg MIJ, Rosen M. The effect of naloxone on the depression of the early respiratory activity of neonates produced by maternal pethidine analgesia. In: Arias, Laurado and others, editor(s). Recent Progress in Anaesthesiology and Resuscitation. Excerpta Medica: Excerpta Medica, 1975:72.

Evans JM. The effect of naloxone on the early respiratory depressant effect of maternal pethidine analgesia. In: European Congress of Anaesthesiology. Madrid, 1974.

Gerhardt 1977a {published data only}

Gerhardt T, Bancalari E, Cohen H, Rocha LF, Holsinger K. Reversal of narcotic respiratory depression in the newborn with naloxone. In: American Society of Anesthesiologists Annual Meeting. Chicago, 1975.

* Gerhardt T, Bancalari E, Cohen H, Rocha LF. Use of naloxone to reverse narcotic respiratory depression in the newborn infant. Journal of Pediatrics 1977;90:1009-12.

Welles 1984 {published data only}

Welles B, Belfrage P, de Chateau P. Effects of naloxone on newborn infant behavior after maternal analgesia with pethidine during labor. Acta Obstetricia et Gynecologica Scandinavica 1984;63:617-9.

Wiener 1977a {published data only}

Wiener PC, Hogg MI, Rosen M. Effects of naloxone on pethidine-induced neonatal depression. Part 1. Intravenous naloxone. BMJ 1977;2:228-9.

Wiener 1977b {published data only}

Weiner PC, Hogg MI, Rosen M. Neonatal respiration, feeding and neurobehavioural state. Effects of intrapartum bupivacaine, pethidine and pethidine reversed by naloxone. Anaesthesia 1979;34:996-1004.

* Wiener PC, Hogg MI, Rosen M. Effects of naloxone on pethidine-induced neonatal depression. Part 2. Intramuscular naloxone. BMJ 1977;2:229-31.

References to excluded studies

Brice 1979b {published data only}

Brice JEH, Moreland TA, Parija AC, Walker CHM. Plasma naloxone levels in the newborn after intravenous or intramuscular administration. British Journal of Clinical Pharmacology 1979;8:412P- 3P.

Martin 1972 {published data only}

Martin K, Knapstein PG, Melchert F, Schafer H, Tietze KW. Klinische Erfahrungen mit dem Opiat-Antagonisten naloxone beim Neugeborenen. Tagung der Mittelrheinischen gesellschaft fur Geburtshilfe und Gynakologie 1972;143:10-11.

* indicates the primary reference for the study

Other references

Additional references

AAP 1980

American Academy of Pediatrics Committee on Drugs. Naloxone use in newborns. Pediatrics 1980;65:667-9.

AAP 1990

American Academy of Pediatrics Committee on Drugs. Naloxone dosage and route of administration for infants and children: addendum to emergency drug doses for infants and children. Pediatrics 1990;86:484-5.

AAP 1998

American Academy of Pediatrics Committee on Drugs. Neonatal drug withdrawal. Pediatrics 1998;101:1079-88.

de Castro 1993

de Castro RM, Cabral-Filho JE, Costa JA, Costa FB, Gallindo MA, Hecksher CA. Neonatal treatment with naloxone causes permanent hyperalgesia in rats. Brazilian Journal of Medical & Biological Research 1993;26:747-51.

Gerhardt 1977b

Gerhardt T, Bancalari E, Cohen H, Macias-Loza M. Respiratory depression at birth--value of Apgar score and ventilatory measurements in its detection. Journal of Pediatrics 1977;90:971-5.

Gibbs 1989

Gibbs J, Newson T, Williams J, Davidson DC. Naloxone hazard in infant of opioid abuser. Lancet 1989;2:159-60.

Herschel 2000

Herschel M, Khoshnood B, Lass NA. Role of naloxone in newborn resuscitation. Pediatrics 2000;106:831-4.

Maas 1990

Maas U, Kattner E, Weingart-Jesse B, Schafer A, Obladen, M. Infrequent neonatal opiate withdrawal following maternal methadone detoxification during pregnancy. Journal of Perinatal Medicine 1990;18:111-8.

Niermeyer 2001

Niermeyer S, Van Reempts P, Kattwinkel J, Wiswell T, Burchfield D, Saugstad OD et al. Resuscitation of newborns. Annals of Emergency Medicine 2001;37:S110-25.

NRP 2000

Neonatal Resuscitation Program. Textbook of Neonatal Resuscitation. 4th edition. American Academy of Pediatrics, American Heart Association, Heart and Stroke Foundation of Canada, 2000.

Smotherman 1992

Smotherman WP, Robinson SR. Prenatal experience with milk: fetal behavior and endogenous opioid systems. Neuroscience & Biobehavioral Reviews 1992;16:351-64.

Szeto 1995

Szeto HH, Soong Y, Wu DL, Cheng PY. Opioid modulation of fetal glucose homeostasis: role of receptor subtypes. Journal of Pharmacology & Experimental Therapeutics 1995;275:334-9.

Other published versions of this review

McGuire 2002

McGuire W, Fowlie PW. Naloxone for narcotic-exposed newborn infants. In: Cochrane Database of Systematic Reviews, Issue 4, 2002.

Comparisons and data

Comparison or outcome	Statistical method	Effect size
01 Naloxone versus placebo or no drug
01 Expired carbon dioxide output (ml/kg/min)	WMD (fixed), 95% CI	Subtotals only
02 Alveolar carbon dioxide tension (kPa)	WMD (fixed), 95% CI	Subtotals only
03 Alveolar ventilation (ml/kg/minute)	WMD (fixed), 95% CI	Subtotals only

01 Naloxone versus placebo or no drug

01.01 Expired carbon dioxide output (ml/kg/min)

01.01.01 At 15 minutes

01.01.02 At 30 minutes

01.01.03 At 90 minutes

01.01.04 At 4 hours

01.02 Alveolar carbon dioxide tension (kPa)

01.02.01 At 10 minutes

01.02.02 At 30 minutes

01.02.03 At about 35 minutes

01.02.04 At 4 hours

01.03 Alveolar ventilation (ml/kg/minute)

01.03.01 At 10 minutes

01.03.02 At 15 minutes

01.03.03 At 30 minutes

01.03.04 At 90 minutes

01.03.05 At 4 hours

Contact details for co-reviewers

Dr Peter W Fowlie, MSc MRCPCH
Consultant Paediatrician, Clinical Director Women & Child Health
Tayside Institute of Child Health
Ninewells Hospital and Medical School
Dundee
Scotland UK
E-mail: peter.fowlie@nhs.net

This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2007 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.