Naloxone for opiate-exposed newborn infants

  • Review
  • Intervention

Authors


Abstract

Background

Naloxone, a specific opiate antagonist, is available for the treatment of newborn infants with cardiorespiratory or neurological depression that may be due to intrauterine exposure to opiate. It is unclear whether newborn infants may benefit from this therapy and whether naloxone has any harmful effects.

Objectives

To determine the effect of naloxone as a treatment for newborn infants who have been exposed in utero to opiate.

Search methods

We searched the following databases in June 2012 for new studies published since the previous search in 2007: The Cochrane Central Register of Controlled Trials (The Cochrane Library 2012, Issue 6), MEDLINE (OvidSP), MEDLINE In process & Other Non-Indexed Citations (OvidSP), EMBASE (OvidSP), CINAHL (EBSCO), Maternity and Infant Care (OvidSP) and PubMed. We searched for ongoing and completed trials in Clinical Trials.gov, metaRegister of Controlled Trials, WHO International Clinical Trials Registry Platform and the EU Clinical Trials Register. We checked the reference lists of relevant articles to identify further potentially relevant studies.

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 opiate.

Data collection and analysis

We extracted data using the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and data extraction by two review authors and synthesis of data using risk ratio, risk difference and weighted mean difference.

Main results

We included nine trials that compared the effects of naloxone versus placebo or no drug in newborn infants exposed to maternal opiate analgesia prior to delivery. None of these trials specifically recruited infants with cardiorespiratory or neurological 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. The trials did not assess the effect on the primary outcomes of this review (admission to a neonatal unit and failure to establish breastfeeding).

Authors' conclusions

The existing evidence from randomised controlled trials is insufficient to determine whether naloxone confers any important benefits to newborn infants with cardiorespiratory or neurological depression that may be due to intrauterine exposure to opiate. Given concerns about the safety of naloxone in this context it may be appropriate to limit its use to randomised controlled trials that aim resolve these uncertainties.

Résumé scientifique

Naloxone pour les nouveau-nés exposés aux opiacés

Contexte

La naloxone, un antagoniste spécifique des opiacés, est disponible pour le traitement des nouveau-nés atteints d'une dépression cardiorespiratoire ou neurologique qui peut être due à une exposition intra-utérine aux opiacés. On ignore si les nouveau-nés peuvent tirer un bénéfice de cette thérapie et si la naloxone présente des effets nocifs.

Objectifs

Déterminer l'effet de la naloxone comme traitement pour les nouveau-nés ayant été exposés in utero aux opiacés.

Stratégie de recherche documentaire

Nous avons recherché dans les bases de données suivantes, en juin 2012, de nouvelles études publiées depuis la précédente recherche en 2007 : le registre Cochrane des essais contrôlés (The Cochrane Library 2012, numéro 6), MEDLINE (OvidSP), MEDLINE In process & Other Non-Indexed Citations (OvidSP), EMBASE (OvidSP), CINAHL (EBSCO), Maternity and Infant Care (OvidSP) et PubMed. Nous avons recherché des essais en cours et achevés sur le site Clinical Trials.gov, dans le méta-registre des essais contrôlés, dans le système d'enregistrement international des essais cliniques de l'OMS (ICTRP) et dans le registre des essais cliniques de l'UE. Nous avons consulté les listes bibliographiques des articles pertinents afin d'identifier d'autres études potentiellement pertinentes.

Critères de sélection

Les essais contrôlés randomisés comparant l'administration de naloxone versus placebo, l'absence de médicament ou une autre dose de naloxone pour les nouveau-nés présentant une exposition in utero suspectée ou confirmée aux opiacés.

Recueil et analyse des données

Nous avons extrait les données à l'aide des méthodes standards du Groupe thématique Cochrane sur la néonatologie, avec une évaluation séparée de la qualité de l'essai et de l'extraction des données par deux auteurs de la revue et une synthèse des données à l'aide du rapport de risques, de la différence de risques et de la différence moyenne pondérée.

Résultats principaux

Nous avons inclus neuf essais qui comparaient les effets de la naloxone versus placebo ou l'absence de médicament chez le nouveau-né exposé à un analgésique à base d'opiacés pris par la mère avant l'accouchement. Aucun de ces essais n'a spécifiquement recruté de nouveau-nés présentant une dépression cardiorespiratoire ou neurologique. Les principaux critères de jugement rapportés étaient des mesures de la fonction respiratoire au cours des six premières heures de vie. Certaines preuves indiquent que la naloxone augmente la ventilation alvéolaire. Les essais n'ont pas évalué l'effet sur les critères de jugement principaux de cette revue (admission dans une unité néonatale et échec de l'établissement de l'allaitement).

Conclusions des auteurs

Les preuves existantes issues d'essais contrôlés randomisés sont insuffisantes pour déterminer si la naloxone apporte des bénéfices importants aux nouveau-nés atteints d'une dépression cardiorespiratoire ou neurologique qui peut être due à une exposition intra-utérine aux opiacés. En raison des inquiétudes concernant la sécurité de la naloxone dans ce contexte, il peut être approprié de limiter son utilisation aux essais contrôlés randomisés qui ont pour objectif de lever ces incertitudes.

Plain language summary

Naloxone for opiate-exposed newborn infants

When a pregnant woman uses opiate medications (for example, pethidine, morphine and similar drugs) for pain relief in labour her newborn baby's breathing or heart rate may be depressed. Naloxone, a drug that counters the effects of opiates, is often used to help 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.

Résumé simplifié

Naloxone pour les nouveau-nés exposés aux opiacés

Lorsqu'une femme enceinte utilise des médicaments opiacés (par exemple la péthidine, la morphine et des médicaments semblables) pour soulager la douleur au cours du travail, la respiration ou la fréquence cardiaque de son bébé peuvent être dégradées. La naloxone, un médicament qui contre les effets des opiacés, est souvent utilisée pour aider ces nouveau-nés. Cette revue n'a trouvé aucune preuve indiquant que la naloxone réduisait la nécessité d'une assistance respiratoire ou d'une admission dans une unité de soins néonatals pour les bébés nés après que les femmes ont utilisé des anti-douleurs à base d'opiacés durant le travail.

Notes de traduction

Traduit par: French Cochrane Centre 1st March, 2013
Traduction financée par: Pour la France : Ministère de la Santé. Pour le Canada : Instituts de recherche en santé du Canada, ministère de la Santé du Québec, Fonds de recherche de Québec-Santé et Institut national d'excellence en santé et en services sociaux.

Background

Description of the condition

Opioid analgesics are available, recommended and commonly used for relief of maternal pain during labour in most delivery units in middle- and high-income settings (NICE 2007; Jones 2012). Estimates suggest that about one-third to one-half of women receives opiate analgesia in labour. The extent of use in low-income settings is less certain (Redshaw 2007; Ullman 2010).

The commonly used opiates (pethidine, diamorphine, morphine, fentanyl) are highly lipid soluble and transplacental transfer to the fetus occurs rapidly. Intrauterine exposure to maternal opiates within about four hours of birth may be associated with neurological and cardiorespiratory depression and feeding-behaviour problems in newborn infants (Kumar 2003; Mercer 2007; Reynolds 2010). Concern exists that these adverse effects may delay neonatal physiological transition and postnatal adaptation and result in neonatal intensive or special care unit admission. Delay in establishment of effective breastfeeding is an important potential consequence of this maternal-infant separation (Nissen 1995; Ransjo-Arvidson 2001).

Description of the intervention

Naloxone, a specific opiate antagonist, is available for the treatment of neurological and cardiorespiratory depression in opiate-exposed newborn infants. The International Liaison Committee on Resuscitation (ILCOR) has provided guidance on the use of naloxone for 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 of naloxone recommended in 1980, 0.01 mg/kg, was later revised to 0.1 mg/kg (AAP 1990). In 2010, an ILCOR Consensus on Science and Treatment Recommendations statement updated this advice and suggested that naloxone should only be given to infants with severe respiratory depression after positive-pressure ventilation has restored a normal heart rate and colour (Kattwinkel 2010; Perlman 2010). However, despite these guidelines, surveys of policy and practice indicate that clinicians continue to administer naloxone to opiate-exposed newborn infants in the first few minutes after birth even in the absence of neurological or cardiorespiratory depression or before effective supported ventilation is established (Herschel 2000; Gill 2007).

Opiate-dependent mothers

The AAP Committee on Drugs has advised that naloxone should not be administered to infants of opiate-dependent mothers as naloxone may precipitate acute withdrawal and seizures in opiate-habituated infants (Gibbs 1989; AAP 1998). 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).

Why it is important to do this review

Naloxone should not be regarded as harmless. Concern exists that naloxone may interfere with the role of endogenous opioids in neuroendocrine programming and behaviour (Smotherman 1992; de Castro 1993; Szeto 1995). Given these questions of appropriateness of use and potential long-term effects, it is important to evaluate the available data on the use of naloxone in opiate-exposed newborn infants.

Objectives

To determine the effect of naloxone on the need for and duration of neonatal unit stay in infants of mothers who received opiate analgesia prior to delivery or of mothers who have used a prescribed or non-prescribed opiate during pregnancy.

Methods

Criteria for considering studies for this review

Types of studies

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

Types of participants

Newborn infants 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
Mother-infant separation and effect on breastfeeding
  1. Admission to neonatal intensive or special care unit.

  2. Duration of neonatal intensive or special care unit stay.

  3. Failure to establish breastfeeding by hospital discharge.

Secondary outcomes
Cardio-respiratory function, need for support, and neurobehavioural outcomes
  1. Measures of 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.

  2. Receipt of assisted ventilation (any form of mechanical ventilation including continuous positive airway pressure) in the neonatal period.

  3. Receipt of endotracheal intubation for respiratory support.

  4. Duration of assisted ventilation (days).

  5. Duration of endotracheal intubation (days).

  6. Days from birth to establish full oral feeds independently of parenteral fluids or nutrition or of enteral tube feeding.

  7. Features of opiate withdrawal, using validated behavioural assessment measures in the neonatal period.

  8. Seizures in the neonatal period.

  9. Neurodevelopmental outcomes beyond infancy assessed using validated assessment.

Search methods for identification of studies

We used the standard search strategy of the Cochrane Neonatal Review Group.

Electronic searches

We updated the searches in June 2012 to identify reports of trials available since the date of the previous searches in February 2007. The original search strategy was duplicated as far as possible. We searched the original set of databases for this review:

  • Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 6, 2012);

  • MEDLINE (OvidSP, 1946 to June week 1 2012);

  • MEDLINE In process & Other Non-Indexed Citations (OvidSP, June 15, 2012);

  • EMBASE (OvidSP, 1974 to 2012 June 15).

 In addition, we searched the following databases: 

  • CINAHL (EBSCO, inception to June 2012);

  • Maternity and Infant Care (OvidSP, 1971 to June 2012);

  • PubMed.

We limited searches to references added to the databases since January 2007 where possible. We did not apply any language restrictions. A search filter was applied in MEDLINE and PubMed (Lefebvre 2011), and in EMBASE (Lefebvre 2008) to limit retrieval to randomised controlled trials. 

We searched clinicaltrials.gov/, metaRegister of Controlled Trials (mRCT; www.controlled-trials.com/mrct/), WHO International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/en/), and the EU Clinical Trials Register (www.clinicaltrialsregister.eu/) to locate ongoing and completed trials.

The full search strategies for each database can be found in Appendix 1.

Searching other resources

We examined the references in studies identified as potentially relevant. We also searched the abstracts from the annual meetings of the Pediatric Academic Societies (1993 to 2012), the European Society for Pediatric Research (1995 to 2011), the UK Royal College of Paediatrics and Child Health (2000 to 2012) and the Perinatal Society of Australia and New Zealand (2000 to 2012). We considered trials reported only as abstracts to be eligible if sufficient information was available from the report, or from contact with the authors, to fulfil the inclusion criteria.

Data collection and analysis

We used the standard methods of the Cochrane Neonatal Review Group.

Selection of studies

Two review authors independently screened the title and abstract of all studies identified by the above search strategy. We assessed the full text of any potentially eligible reports and excluded those studies that did not meet all of the inclusion criteria. We discussed any disagreements until consensus was achieved.

Data extraction and management

We used a data collection form to extract relevant information from each included study. Two review authors extracted the data separately. We discussed any disagreements with the third review author until we reached consensus.

Assessment of risk of bias in included studies

We used the criteria and standard methods of the Cochrane Neonatal Review Group to assess the methodological quality of any included trials. We evaluated and reported the following issues in the 'Risk of bias' tables:

  1. Sequence generation: we categorised the method used to generate the allocation sequence as:

    1. low risk (any random process, e.g. random number table; computer random number generator);

    2. high risk (any non-random process, e.g. odd or even date of birth; patient case-record number);

    3. unclear.

  2. Allocation concealment: we categorised the method used to conceal the allocation sequence as:

    1. low risk (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

    2. high risk (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);

    3. unclear.

  3. Blinding: we assessed blinding separately for different outcomes and categorised the methods as low, high or unclear risk for:

    1. participants;

    2. clinicians and caregivers;

    3. outcome assessors.

  4. Incomplete outcome data: we described the completeness of data including attrition and exclusions from the analysis for each outcome and any reasons for attrition or exclusion where reported. We assessed whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorised completeness as:

    1. low risk (< 20% missing data);

    2. high risk (> 20% missing data);

    3. unclear.

Measures of treatment effect

We calculated risk ratio (RR) and risk difference (RD) for dichotomous data and weighted mean difference (WMD) for continuous data, with respective 95% confidence intervals (CI).

Dealing with missing data

We requested outcome data from the trial investigators when these were unavailable in the report.

Assessment of heterogeneity

We examined the treatment effects of individual trials and heterogeneity between trial results by inspecting the forest plots if more than one trial was included in a meta-analysis. We calculated the I2 statistic for statistical heterogeneity. We explored the possible causes (e.g. differences in study design, participants, interventions, or completeness of outcome assessments) in sensitivity analyses if substantial (I2 > 50%) heterogeneity was detected.

Assessment of reporting biases

We intended to conduct a funnel-plot analysis if there were data from more than five trials included in a meta-analysis.

Data synthesis

We used a fixed-effect model for meta-analyses.

Subgroup analysis and investigation of heterogeneity

We planned the following subgroup analyses:

  1. dose of naloxone < 0.1 mg/kg body weight;

  2. dose of naloxone ≥ 0.1 mg/kg body weight.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Included studies

We included nine trials in the review and these are described in the table 'Characteristics of included studies'. Two of these studies were reported in the same article (Dick 1978a; Dick 1978b).

A total of 316 infants participated in the included trials. All were undertaken in the 1970s or early 1980s. The participants were term newborn infants whose mothers had received pethidine (meperidine) for pain relief up to six hours prior to delivery. None of the trials specifically restricted participation to infants with cardiorespiratory or neurological depression following opiate exposure. In most trials, the intervention appears to have been given in the first five minutes after birth. In two trials, naloxone was given later; at 30 minutes (Gerhardt 1977) 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 to 0.07 mg/kg with the exception of one study in which a total dose of 0.2 mg was given (Wiener 1977b). The outcomes most commonly assessed were measures of respiratory effort such as Apgar scores, blood gases values, or other measures of alveolar ventilation.

None of the trials examined the effects of naloxone in infants of mothers who had used a prescribed or non-prescribed narcotic during pregnancy.

Excluded studies

We excluded two studies (Martin 1972; Brice 1979b; Characteristics of excluded studies).

Risk of bias in included studies

All of the trials were small and none presented a sample size calculation.

Allocation

Most reports did not provide any details of measures to ensure allocation concealment.

Blinding

Caregivers or assessors were likely to have been blinded in five of the trials. Three trials reported the outcome assessors were unblinded and in one trial it is unclear whether outcome assessors were blinded.

Incomplete outcome data

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.

Effects of interventions

Primary outcomes  

  1. Admission to neonatal intensive or special care unit: not reported.

  2. Duration of neonatal intensive or special care unit stay: not reported.

  3. Failure to establish breastfeeding by hospital discharge: not reported.

Secondary outcomes  

  1. Measures of respiratory function: eight of the trials presented data on measures of respiratory function measured within the first six hours after birth. There were no statistically significant differences in the Apgar score (Bonta 1979), ventilation rate (Evans 1976), time to sustained respiration (Brice 1979a), minute ventilation (Gerhardt 1977) or blood gas parameters (Dick 1978a; Dick 1978b; Bonta 1979). Four trials assessed measures of alveolar ventilation (Evans 1976; Wiener 1977a; Wiener 1977b; Brice 1979a). 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 (analyses 01.01 to 01.03; Figure 1). 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 intramuscularly compared with intravenously in the other studies.

    Figure 1.

    Forest plot of comparison: 1 Naloxone versus placebo or no drug, outcome: 1.1 Expired carbon dioxide output (mL/kg/min).

  2. Receipt of assisted ventilation in the neonatal period: not reported.

  3. Receipt of endotracheal intubation for respiratory support: not reported.

  4. Duration of assisted ventilation: not reported.

  5. Duration of endotracheal intubation: not reported.

  6. Days from birth to establish full oral feeds independently of parenteral fluids or nutrition or of enteral tube feeding: not reported.

  7. Features of opiate withdrawal: 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 intramuscular naloxone versus placebo. Wiener 1977a stated that there were no 'important differences' in habituation to auditory stimulus between infants who received intravenous naloxone versus placebo.

  8. Seizures in the neonatal period: not reported.

  9. Neurodevelopmental outcomes beyond infancy assessed using validated assessment: not reported.

Subgroup analyses

  1. Dose of naloxone < 0.1 mg/kg body weight: all of the included trials used this dose.

  2. Dose of naloxone ≥ 0.1 mg/kg body weight: none of the included trials used this dose.

Discussion

Summary of main results

We identified nine small trials that compared naloxone versus placebo or no drug for treating newborn infants who had been exposed to maternal opiate analgesia prior to delivery. The trials evaluated the effect of naloxone on infants exposed to opiate analgesia in labour. None examined the use of naloxone in infants who had been exposed to opiate in utero during pregnancy, for example due to maternal opiate-dependence.

None of the included trials provided any data on any of the primary outcomes of this review, that is maternal separation (need for neonatal unit admission) and effect on breastfeeding. With regard to secondary outcome measures, most trials only reported measures of respiratory function and neurological behaviour in the first 48 hours after birth. We did not find any data on the incidence of seizures in the neonatal period, or long-term neurodevelopmental outcomes.

Overall completeness and applicability of evidence

The trials provided some evidence that infants who received naloxone had higher indices of 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 since the infants recruited to the trials did not appear to have been selected because of cardiorespiratory depression. Infants with low Apgar scores up to five minutes were not eligible for inclusion in two trials (Bonta 1979; Welles 1984). There are no trial data that assess whether treatment with naloxone affects the need for, or the duration of, mechanical respiratory support including positive-pressure ventilation. All of the included trials were conducted over 25 years ago. The evidence is likely to be of limited relevance in the clinical context for which naloxone is recommended by the ILCOR, that is, for opiate-exposed newborn infants with respiratory depression despite appropriate ventilation (Niermeyer 2001; Kattwinkel 2010; Perlman 2010).

Quality of the evidence

All of the trials were small and had various methodological weaknesses including uncertain allocation concealment that may have biased their findings and the findings of this review (Figure 2). Ascertainment or surveillance biases may also be present since caregivers and clinicians in some of the trials were aware of the allocated intervention. Although follow-up assessment was complete in the trials, none assessed outcomes beyond the first few days after birth.

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Authors' conclusions

Implications for practice

The available trial data do not provide any evidence that administration of naloxone to infants exposed in utero to opiate during delivery affects any important outcomes.

Implications for research

Clinicians and service-users may consider it appropriate to undertake a randomised controlled trial to determine if naloxone confers any important benefits to newborn infants with cardiorespiratory or neurological 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 admission to a neonatal unit for ongoing respiratory support. In view of the concerns that naloxone may interfere with the role of endogenous opioids in neuroendocrine programming and on behaviour (Smotherman 1992; de Castro 1993; Szeto 1995), follow-up assessment beyond infancy should determine neurodevelopmental outcomes.

Acknowledgements

This review was funded by the UK National Institute for Health Research (NIHR) under its Programme Grants for Applied Research funding scheme (RP-PG-0609-10107). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the UK Department of Health.

Melissa Harden, Information Specialist, provided invaluable assistance in devising and running the electronic search.

Data and analyses

Download statistical data

Comparison 1. Naloxone versus placebo or no drug
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Expired carbon dioxide output (mL/kg/min)3 Mean Difference (IV, Fixed, 95% CI)Subtotals only
1.1 At 15 minutes150Mean Difference (IV, Fixed, 95% CI)1.30 [0.15, 2.45]
1.2 At 30 minutes3108Mean Difference (IV, Fixed, 95% CI)0.90 [0.39, 1.40]
1.3 At 90 minutes150Mean Difference (IV, Fixed, 95% CI)0.50 [-0.17, 1.17]
1.4 At 4 hours258Mean Difference (IV, Fixed, 95% CI)0.86 [0.12, 1.59]
2 Alveolar carbon dioxide tension (kPa)4 Mean Difference (IV, Fixed, 95% CI)Subtotals only
2.1 At 10 minutes144Mean Difference (IV, Fixed, 95% CI)-0.60 [-1.01, -0.19]
2.2 At 30 minutes3102Mean Difference (IV, Fixed, 95% CI)-0.87 [-1.16, -0.59]
2.3 At about 35 minutes120Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.90, 0.70]
2.4 At 4 hours258Mean Difference (IV, Fixed, 95% CI)-0.87 [-1.25, -0.50]
3 Alveolar ventilation (mL/kg/minute)4 Mean Difference (IV, Fixed, 95% CI)Subtotals only
3.1 At 10 minutes144Mean Difference (IV, Fixed, 95% CI)13.0 [-16.88, 42.88]
3.2 At 15 minutes150Mean Difference (IV, Fixed, 95% CI)16.0 [-8.53, 40.53]
3.3 At 30 minutes4152Mean Difference (IV, Fixed, 95% CI)36.03 [21.92, 50.14]
3.4 At 90 minutes150Mean Difference (IV, Fixed, 95% CI)14.0 [-6.30, 34.30]
3.5 At 4 hours258Mean Difference (IV, Fixed, 95% CI)55.30 [33.92, 76.69]
Analysis 1.1.

Comparison 1 Naloxone versus placebo or no drug, Outcome 1 Expired carbon dioxide output (mL/kg/min).

Analysis 1.2.

Comparison 1 Naloxone versus placebo or no drug, Outcome 2 Alveolar carbon dioxide tension (kPa).

Analysis 1.3.

Comparison 1 Naloxone versus placebo or no drug, Outcome 3 Alveolar ventilation (mL/kg/minute).

Appendices

Appendix 1. Electronic search strategy

Cochrane Central Register of Controlled Trials (CENTRAL)

Wiley onlinelibrary.wiley.com/

Issue 6 of 12, June 2012 

Searched on 18th June 2012. 8 records were retrieved.

#1    MeSH descriptor Infant, Newborn explode all trees (11587)

#2    MeSH descriptor Premature Birth, this term only (256)

#3    (neonat* or neo NEXT nat*):ti,ab (7180)

#4    (newborn* or new NEXT born* or newly NEXT born*):ti,ab (3515)

#5    (preterm or preterms or pre NEXT term or pre NEXT terms):ti,ab (4596)

#6    (preemie* or premie or premies):ti,ab (13)

#7    (prematur* NEAR/3 (birth* or born or deliver*)):ti,ab (569)

#8    (low NEAR/3 (birthweight* or birth NEXT weight*)):ti,ab (2132)

#9    (lbw or vlbw or elbw):ti,ab (676)

#10  infan*:ti,ab (15933)

#11  (baby or babies):ti,ab (2647)

#12  (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11) (25692)

#13  MeSH descriptor Naloxone explode all trees (1412)

#14  naloxone:ti,ab (1378)

#15  narcan:ti,ab (4)

#16  MeSH descriptor Narcotic Antagonists, this term only (773)

#17  ((narcotic or opiate or opioid) NEAR/3 antagonist*):ti,ab (701)

#18  (#13 OR #14 OR #15 OR #16 OR #17) (2301)

#19  (#12 AND #18) (66)

#20  (#12 AND #18), from 2007 to 2012 (8)

Line #20 shows the number of hits in CENTRAL only.

MEDLINE

OvidSP http://ovidsp.ovid.com/

1946 to June Week 1 2012 

Searched on 18 June 2012. 50 records were retrieved. The Cochrane highly sensitive search strategy for identifying randomised trials in MEDLINE (sensitivity-maximising version) was used to limit retrieval to clinical trials (lines 19-29).(Lefebvre 2011)

 

1     exp Infant, Newborn/ (465,198)

2     Premature Birth/ (4515)

3     (neonat$ or neo nat$).ti,ab. (169,877)

4     (newborn$ or new born$ or newly born$).ti,ab. (117,264)

5     (preterm or preterms or pre term or pre terms).ti,ab. (37,614)

6     (preemie$ or premie or premies).ti,ab. (95)

7     (prematur$ adj3 (birth$ or born or deliver$)).ti,ab. (10,057)

8     (low adj3 (birthweight$ or birth weight$)).ti,ab. (21,501)

9     (lbw or vlbw or elbw).ti,ab. (4342)

10     infan$.ti,ab. (292,199)

11     (baby or babies).ti,ab. (45,426)

12     or/1-11 (743,233)

13     exp Naloxone/ (21,647)

14     naloxone.ti,ab,rn. (22,762)

15     narcan.ti,ab,rn. (53)

16     Narcotic Antagonists/ (9514)

17     ((narcotic or opiate or opioid) adj3 antagonist$).ti,ab. (10,032)

18     or/13-17 (31,443)

19     randomized controlled trial.pt. (329,386)

20     controlled clinical trial.pt. (84,300)

21     randomized.ab. (233,146)

22     placebo.ab. (131,984)

23     drug therapy.fs. (1,540,302)

24     randomly.ab. (168,067)

25     trial.ab. (241,338)

26     groups.ab. (1,104,185)

27     or/19-26 (2,861,506)

28     exp animals/ not humans/ (3,732,613)

29     27 not 28 (2,429,876)

30     12 and 18 and 29 (192)

31     (2007$ or 2008$ or 2009$ or 2010$ or 2011$ or 2012$).ed. (4,122,936)

32     30 and 31 (50)

  

MEDLINE In-Process & Other Non-Indexed Citations

OvidSP ovidsp.ovid.com/

June 15, 2012 

Searched on 18 June 2012. 16 records were retrieved.

 

1     exp Infant, Newborn/ (0)

2     Premature Birth/ (0)

3     (neonat$ or neo nat$).ti,ab. (5414)

4     (newborn$ or new born$ or newly born$).ti,ab. (3154)

5     (preterm or preterms or pre term or pre terms).ti,ab. (1633)

6     (preemie$ or premie or premies).ti,ab. (2)

7     (prematur$ adj3 (birth$ or born or deliver$)).ti,ab. (320)

8     (low adj3 (birthweight$ or birth weight$)).ti,ab. (765)

9     (lbw or vlbw or elbw).ti,ab. (193)

10     infan$.ti,ab. (9274)

11     (baby or babies).ti,ab. (1838)

12     or/1-11 (16650)

13     exp Naloxone/ (0)

14     naloxone.ti,ab,rn. (336)

15     narcan.ti,ab,rn. (1)

16     Narcotic Antagonists/ (0)

17     ((narcotic or opiate or opioid) adj3 antagonist$).ti,ab. (215)

18     or/13-17 (451)

19     12 and 18 (16)

EMBASE

OvidSP http://ovidsp.ovid.com/

1974 to 2012 June 15 

Searched on 18 June 2012. 35 records were retrieved. A search strategy developed by Lefebvre et al. to identify randomised trials in EMBASE was used to limit retrieval to clinical trials (lines 23-37). (Lefebvre 2008

 

1     exp infant/ (504,798)

2     newborn/ (468,937)

3     prematurity/ (64,713)

4     premature labor/ (23,169)

5     exp low birth weight/ (33,807)

6     (neonat$ or neo nat$).ti,ab. (215,584)

7     (newborn$ or new born$ or newly born$).ti,ab. (145,479)

8     (preterm or preterms or pre term or pre terms).ti,ab. (49,475)

9     (preemie$ or premie or premies).ti,ab. (121)

10     (prematur$ adj3 (birth$ or born or deliver$)).ti,ab. (13,359)

11     (low adj3 (birthweight$ or birth weight$)).ti,ab. (26,452)

12     (lbw or vlbw or elbw).ti,ab. (5518)

13     infan$.ti,ab. (357,113)

14     (baby or babies).ti,ab. (59,494)

15     or/1-14 (1,124,362)

16     naloxone/ (35,742)

17     naltrexone/ (10,356)

18     naloxone.ti,ab. (22,967)

19     narcan.ti,ab. (89)

20     narcotic antagonist/ (2331)

21     ((narcotic or opiate or opioid) adj3 antagonist$).ti,ab. (11,952)

22     16 or 17 or 18 or 19 or 20 or 21 (50,309)

23     random$.ti,ab. (743,113)

24     factorial$.ti,ab. (19,445)

25     crossover$.ti,ab. (44,206)

26     cross-over$.ti,ab. (20,134)

27     placebo$.ti,ab. (180,615)

28     (doubl$ adj blind$).ti,ab. (134,615)

29     (singl$ adj blind$).ti,ab. (12,482)

30     assign$.ti,ab. (207,848)

31     allocat$.ti,ab. (69,955)

32     volunteer$.ti,ab. (162,807)

33     Crossover Procedure/ (34,089)

34     double blind procedure/ (111,697)

35     Randomized Controlled Trial/ (325,738)

36     single blind procedure/ (15,977)

37     23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 (1,237,026)

38     15 and 22 and 37 (119)

39     animal/ (1,784,081)

40     exp animal experiment/ (1,622,232)

41     nonhuman/ (3,857,480)

42     (rat or rats or mouse or mice or hamster or hamsters or animal or animals or dog or dogs or cat or cats or bovine or sheep).ti,ab,sh. (4,684,524)

43     39 or 40 or 41 or 42 (6,628,324)

44     exp human/ (13,638,715)

45     human experiment/ (301,557)

46     44 or 45 (13,640,150)

47     43 not (43 and 46) (5,231,569)

48     38 not 47 (99)

49     (2007$ or 2008$ or 2009$ or 2010$ or 2011$ or 2012$).em. (5,769,628)

50     48 and 49 (35) 

 

CINAHL

via EBSCO www.ebsco.com/

Inception to 15 June 2012 

Searched on 25 June 2012. 33 records were retrieved.

 

S23       S21 and S22 (33)

S22       EM 200701- (1338056)

S21       S14 and S20 (69)

S20       S15 or S16 or S17 or S18 or S19 (1755)

S19       TI ( ((narcotic or opiate or opioid) N3 antagonist*) ) OR AB ( ((narcotic or opiate or opioid) N3 antagonist*) ) (296)

S18       (MH "Narcotic Antagonists") (553)

S17       TI narcan OR AB narcan (22)

S16       TI naloxone OR AB naloxone (537)

S15       (MH "Naloxone+") (1236)

S14       (S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13) (90103)

S13       TI ( baby or babies ) OR AB ( baby or babies ) (12769)

S12       TI infan* OR AB infan* (36205)

S11       TI ( lbw or vlbw or elbw ) OR AB ( lbw or vlbw or elbw ) (1111)

S10       TI ( low N3 (birthweight* or birth-weight*) ) OR AB ( low N3 (birthweight* or birth-weight*) ) (4435)

S9         TI ( prematur* N3 (birth* or born or deliver*) ) OR AB ( prematur* N3 (birth* or born or deliver*) ) (1457)

S8         TI ( preemie* or premie or premies ) OR AB ( preemie* or premie or premies ) (152)

S7         TI ( preterm or preterms or pre-term or pre-terms ) OR AB ( preterm or preterms or pre-term or pre-terms ) (8849)

S6         TI ( newborn* or new-born* or "newly born*" ) OR AB ( newborn* or new-born* or "newly born*" ) (9626)

S5         TI ( neonat* or neo-nat* ) OR AB ( neonat* or neo-nat* ) (19333)

S4         (MH "Childbirth, Premature") (2837)

S3         (MH "Infant, Premature") (9120)

S2         (MH "Infant, Low Birth Weight+") (5567)

S1         (MH "Infant, Newborn+") (56780)

Maternity and Infant Care

OvidSP ovidsp.ovid.com/

1971 to June 2012 

Searched on 18 June 2012. 50 records were retrieved.

 

1     infant.de. (7000)

2     Infant - newborn.de. (23,180)

3     Infant - premature.de. (7126)

4     infant - very premature.de. (731)

5     Infant - low birth weight.de. (2354)

6     Infant - very low birth weight.de. (2132)

7     Premature birth - aetiology.de. (725)

8     Infant - small for gestational age.de. (881)

9     (neonat$ or neo nat$).ti,ab. (27614)

10     (newborn$ or new born$ or newly born$).ti,ab. (12,931)

11     (preterm or preterms or pre term or pre terms).ti,ab. (15,364)

12     (preemie$ or premie or premies).ti,ab. (33)

13     (prematur$ adj3 (birth$ or born or deliver$)).ti,ab. (2771)

14     (low adj3 (birthweight$ or birth weight$)).ti,ab. (7467)

15     (lbw or vlbw or elbw).ti,ab. (1891)

16     infan$.ti,ab. (41,734)

17     (baby or babies).ti,ab. (21,094)

18     or/1-17 (82513)

19     Naloxone.de. (12)

20     "Naloxone - administration and dosage".de. (3)

21     Naloxone - adverse effects.de. (4)

22     Naltrexone.de. (3)

23     naloxone.ti,ab. (57)

24     narcan.ti,ab. (1)

25     ((narcotic or opiate or opioid) adj3 antagonist$).ti,ab. (13)

26     19 or 20 or 21 or 22 or 23 or 24 or 25 (66)

27     18 and 26 (50)

  

PubMed

www.ncbi.nlm.nih.gov/pubmed/

Searched on 27 June 2012 using the PubMed advanced search builder. 195 records were retrieved. The Cochrane highly sensitive search strategy for identifying randomised trials in PubMed (sensitivity-maximizing version) was used to limit retrieval to clinical trials (lines 16-27). (Lefebvre 2011)

#28            Search (#15) AND #27 (195)

#27            Search (#25) NOT #26 (2567074)

#26            Search animals [mh] NOT humans [mh] (3683980)

#25            Search (((((((#16) OR #17) OR #18) OR #19) OR #21) OR #22) OR #23) OR #24 (2997189)

#24            Search groups[Title/Abstract] (1205973)

#23            Search trial[Title/Abstract] (306478)

#22            Search randomly[Title/Abstract] (182400)

#21            Search drug therapy[MeSH Subheading] (1525535)

#19            Search placebo[Title/Abstract] (141339)

#18            Search randomized[Title/Abstract] (265625)

#17            Search controlled clinical trial[Publication Type] (83926)

#16            Search randomized controlled trial[Publication Type] (325861)

#15            Search (#1) AND #14 (847)

#14            Search ((((((#4) OR #5) OR #6) OR #11) OR #13) OR #10) OR #12 (34499)

#13            Search (opioid[Title/Abstract]) AND antagonist*[Title/Abstract] (11829)

#12            Search (opiate[Title/Abstract]) AND antagonist*[Title/Abstract] (4385)

#11            Search (narcotic[Title/Abstract]) AND antagonist*[Title/Abstract] (1057)

#10            Search "Narcotic Antagonists"[Mesh:NoExp] (9354)

#6              Search narcan (27518)

#5              Search naloxone (27515)

#4              Search "Naloxone"[Mesh] (21432)

#1              Search ((((((((((((((("Infant, Newborn"[Mesh])) OR ("Premature Birth"[Mesh])) OR (((neonat*[Title/Abstract]) OR neo nat*[Title/Abstract]) OR neo-nat*[Title/Abstract])) OR (((((newborn*[Title/Abstract]) OR new born*[Title/Abstract]) OR new-born*[Title/Abstract]) OR newly born*[Title/Abstract]) OR newly-born*[Title/Abstract])) OR ((((((preterm[Title/Abstract]) OR preterms[Title/Abstract]) OR pre term[Title/Abstract]) OR pre-term[Title/Abstract]) OR pre terms[Title/Abstract]) OR pre-terms[Title/Abstract])) OR (((preemie*[Title/Abstract]) OR premie[Title/Abstract]) OR premies[Title/Abstract])) OR ((prematur*[Title/Abstract]) AND birth*[Title/Abstract])) OR ((prematur*[Title/Abstract]) AND born[Title/Abstract])) OR ((prematur*[Title/Abstract]) AND deliver*[Title/Abstract])) OR ((low[Title/Abstract]) AND birthweight*[Title/Abstract])) OR ((low[Title/Abstract]) AND birth weight*[Title/Abstract])) OR ((low[Title/Abstract]) AND birth-weight*[Title/Abstract])) OR (((lbw[Title/Abstract]) OR vlbw[Title/Abstract]) OR elbw[Title/Abstract])) OR (infan*[Title/Abstract])) OR ((baby[Title/Abstract]) OR babies[Title/Abstract]) (768278)

 

Trial registers

 

ClinicalTrials.gov

www.clinicaltrials.gov/

 Searched on 26 June 2012. 2 studies found.

 1. Naloxone AND (infant OR infants OR newborn OR newborns OR premature OR prematurity OR neonate OR neonates OR neonatal OR preterm OR preterms OR preemie OR preemies OR premie OR premies OR birthweight OR baby OR babies) – 1 result

 2. Narcan AND (infant OR infants OR newborn OR newborns OR premature OR prematurity OR neonate OR neonates OR neonatal OR preterm OR preterms OR preemie OR preemies OR premie OR premies OR birthweight OR baby OR babies) – 1 result 

 

metaRegister of Controlled Trials (mRCT)

www.controlled-trials.com/mrct/searchform

 Searched on 26th June 2012. 6 studies found.

 1. Naloxone AND (infant OR infants OR newborn OR newborns OR premature OR prematurity OR neonate OR neonates or neonatal OR preterm OR preterms OR  preemie OR preemies  OR premie OR premies OR birthweight OR  baby OR  babies) – 5 results

2. Narcan AND (infant OR infants OR newborn OR newborns OR premature OR prematurity OR neonate OR neonates or neonatal OR preterm OR preterms OR  preemie OR preemies  OR premie OR premies OR birthweight OR  baby OR  babies) – 1 result

 

WHO International Clinical Trials Registry Platform

apps.who.int/trialsearch/AdvSearch.aspx

 Searched on 26 June 2012. 12 studies found.

 1. Naloxone in title, clinical trials in children – 4 results

2. Naloxone in intervention field, clinical trials in children – 4 results

3. Narcan in title, clinical trials in children – 0

4. Narcan in intervention field, clinical trials in children – 4 results

  

EU Clinical Trials Register

www.clinicaltrialsregister.eu/ctr-search/search

 Searched on 26th June 2012 using the advance search page. No studies were found. 

1. naloxone textword search, limited to newborn or preterm new born infants age filter – 0 results 

2. narcan textword search, limited to newborn or preterm new born infants age filter – 0 results

 

What's new

Last assessed as up-to-date: 31 July 2012.

DateEventDescription
31 July 2012New search has been performedThis updates the review "Naloxone for opiate-exposed newborn infants" (McGuire 2002).
31 July 2012New citation required but conclusions have not changed

Search updated in June 2012.
No new trials added.

Background and discussion updated.

History

Protocol first published: Issue 1, 2002
Review first published: Issue 4, 2002

DateEventDescription
10 June 2008AmendedConverted to new review format.
14 March 2007New search has been performedThis 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.
18 June 2002New citation required and conclusions have changedSubstantive amendment

Contributions of authors

Thirimon Moe-Byrne and Jennifer Brown searched and screened the studies for inclusion, assessed the methodological quality of the trials and extracted and entered the relevant information and data from each included study independently.
All authors completed the final review.

Declarations of interest

None.

Sources of support

Internal sources

  • Hull York Medical School & Centre for Reviews and Dissemination, University of York, UK.

External sources

  • NIHR Programme: Improving quality of care and outcome at preterm birth, UK.

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.

    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bonta 1979

MethodsRandomised controlled trial
Participants43 normal term newborn infants whose mothers had received routine narcotic analgesia within 6 hours of delivery. Infants delivered in breech presentation or by Caesarean section, and infants with Apgar score less than 6 at 1 minute, were excluded
Interventions1. Intramuscular naloxone (0.02 mg/kg body weight): n = 22
2. Placebo (normal saline): n = 21
OutcomesApgar score at 5 minutes, capillary blood gas values at 1, 2 and 4 hours of life, neurobehavioural assessment at 1, 4, and 24 hours
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom sequence generated in pharmacy to produce sequentially numbered ampoules containing either naloxone or placebo
Allocation concealment (selection bias)Low riskSequentially numbered ampoules (unable to predict whether naloxone or placebo)
Blinding (performance bias and detection bias)
All outcomes
Low riskOutcome assessors blinded (placebo-controlled)
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete ascertainment of outcomes

Brice 1979a

MethodsRandomised controlled trial
Participants50 term newborn infants whose mothers had received intramuscular pethidine within 4 hours of delivery
Interventions

1. Naloxone administered via the umbilical vein (0.01 or 0.02 mg/kg body weight): n = 26

2. No drug: n = 24

OutcomesTime 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
NotesBlinding of outcome measurement for Scanlon Behavioral Score only
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskAssessors blinded for Scanlon developmental assessment
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up

Dick 1978a

MethodsRandomised controlled trial
Participants40 newborn infants, of unspecified gestation, whose mothers had been given intravenous pethidine in labour
Interventions

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

OutcomesCapillary blood gas pH and partial pressure of carbon dioxide and of oxygen at 1, 5, 10, 30, 60 and 120 minutes of life
NotesReceived naloxone immediately after birth
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
High riskUnblinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up

Dick 1978b

MethodsRandomised controlled trial
Participants30 newborn infants, of unspecified gestation, whose mothers had been given intravenous pethidine in labour
Interventions1. Naloxone, via the umbilical vein (either 0.04 mg/kg or 0.04 mg total): n = 20
2. Placebo: n = 10
OutcomesCapillary 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
NotesReceived naloxone immediately after birth
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low risk"Double-blind"
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up

Evans 1976

MethodsRandomised controlled trial
Participants44 newborn infants, of gestation 38-42 weeks, delivered spontaneously or by forceps, whose mothers had been given pethidine in labour
Interventions

1. Naloxone administered via the umbilical vein at 1 minute of age (0.04 mg total): n = 20

2. No drug: n = 24

OutcomesTime to first breath, time to onset of sustained respiration, Apgar score at 5 minutes, alveolar carbon dioxide tension, alveolar ventilation, and ventilation rate at 10 minutes and 30 minutes of life
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
High riskUnblinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up

Gerhardt 1977

MethodsRandomised controlled trial
Participants20 term newborn infants, born vaginally, whose mothers had received intravenous pethidine within 3 hours of delivery
Interventions

1. Intramuscular naloxone at 30 minutes of life (0.01 mg/kg): n = 14

2. Placebo: n = 10

OutcomesRespiratory rate, tidal volume, minute ventilation, end-tidal carbon dioxide tension, and the ventilatory response to inhalation of 4% carbon dioxide
NotesNaloxone given at 30 minutes of age
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Random number" selection
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Placebo-controlled", but unclear whether investigators aware of which group infants allocated to
Incomplete outcome data (attrition bias)
All outcomes
Low riskNear-complete follow-up but 2 infants in each group were excluded post-randomisation because "lung compliance values changed more than 25% between the two determinations"

Welles 1984

MethodsRandomised controlled trial
Participants27 newborn infants, of gestation 38-42 weeks, whose mothers had received pethidine during labour. Infants with Apgar scores less than 8 at 1 minute, or less than 9 at 5 minutes were not eligible for inclusion
Interventions

1. Naloxone at about 1 hour of age (0.1 mg total): n = 14

2. Placebo (normal saline): n = 13

OutcomesBrazelton Neonatal Behavioral Assessment Score at 12-24 hours of life and after a further 48 hours, and the Broussard Neonatal Perception Inventory after the second Brazelton assessment
NotesThe route of administration of naloxone and placebo is presumed to be intramuscular, but this is not stated explicitly in the paper
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskOutcome assessor blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up

Wiener 1977a

MethodsRandomised controlled trial
Participants28 newborn infants, of gestation 38-42 weeks, whose mothers had been given pethidine in labour
Interventions

1. Naloxone administered via the umbilical vein at 1 minute of age (0.04 mg total): n = 10

2. Normal saline placebo: n = 18

OutcomesAlveolar carbon dioxide tension, carbon dioxide excretion, alveolar ventilation, feeding behaviour, and habituation to a sound-specific stimulus up to 48 hours of life
NotesNaloxone or normal saline were "chosen blind at random"
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom allocation in pharmacy
Allocation concealment (selection bias)Low riskCoded ampoules
Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding (placebo-controlled)
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up

Wiener 1977b

MethodsRandomised controlled trial
Participants30 newborn infants, of gestation 38-42 weeks, whose mothers had been given pethidine in labour
Interventions

1. Intramuscular naloxone at 1 minute of age (0.2 mg total): n = 15

2. Intramuscular normal saline placebo: n = 15

OutcomesAlveolar carbon dioxide tension, carbon dioxide excretion, alveolar ventilation, feeding behaviour (mean sucking frequencies and pressures, and mean milk consumption), and habituation to a sound-specific stimulus up to 48 hours of life
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom allocation in pharmacy
Allocation concealment (selection bias)Low riskCoded ampoules
Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding (placebo-controlled)
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Brice 1979bThis report of pharmacokinetic data in infants who received either intravenous or intramuscular naloxone is unlikely to be a randomised comparison
Martin 1972This report is unlikely to be a randomised controlled trial

Ancillary