Oral zinc for the prevention of hyperbilirubinaemia in neonates

  • Review
  • Intervention

Authors


Abstract

Background

Between 6% and 15% of neonates develop hyperbilirubinaemia requiring treatment. Successful management of neonatal hyperbilirubinaemia relies on prevention and early treatment, with phototherapy being the mainstay of treatment. Oral zinc has been reported to decrease the serum total bilirubin (STB), presumably by decreasing the enterohepatic circulation.

Objectives

To determine the effect of oral zinc supplementation compared to placebo or no treatment on the incidence of hyperbilirubinaemia in neonates during the first week of life and to assess the safety of oral zinc in enrolled neonates.

Search methods

We searched CENTRAL (The Cochrane Library 2014, Issue 1), MEDLINE (1966 to November 30, 2014), and EMBASE (1990 to November 30, 2014).

Selection criteria

Randomised controlled trials were eligible for inclusion if they enrolled neonates (term and preterm) to whom oral zinc, in a dose of 10 to 20 mg/day, was initiated within the first 96 hours of life, for any duration until day seven, compared with no treatment or placebo.

Data collection and analysis

We used the standard methods of The Cochrane Collaboration and its Neonatal Review Group for data collection and analysis.

Main results

Only one study met the criteria of inclusion in the review. This study compared oral zinc with placebo. Oral zinc was administered in a dose of 5 mL twice daily from day 2 to day 7 postpartum. The drug was administered into the mouth of the infant by the plastic measure provided with the bottle or with a spoon. Incidence of hyperbilirubinaemia, defined as serum total bilirubin (STB) ≥ 15 mg/dL, was similar between groups (N = 286; risk ratio (RR) 0.94, 95% confidence interval (CI) 0.58 to 1.52). Mean STB levels, mg/dL, at 72 ± 12 hours were comparable in both the groups (N = 286; mean difference (MD) -0.20; 95% CI -1.03 to 0.63). Although the duration of phototherapy in the zinc group was significantly shorter compared to the placebo group (N = 286; MD -12.80, 95% CI -16.93 to -8.67), the incidence of need for phototherapy was comparable across both the groups (N = 286; RR 1.20; 95% CI 0.66 to 2.18). Incidences of side effects like vomiting (N = 286; RR 0.65, 95% CI 0.19 to 2.25), diarrhoea (N = 286; RR 2.92, 95% CI 0.31 to 27.71), and rash (N = 286; RR 2.92, 95% CI 0.12 to 71.03) were found to be rare and statistically comparable between groups.

Authors' conclusions

The limited evidence available has not shown that oral zinc supplementation given to infants up to one week old reduces the incidence of hyperbilirubinaemia or need for phototherapy.

Résumé scientifique

Zinc par voie orale dans la prévention de l'hyperbilirubinémie chez le nouveau-né

Contexte

Entre 6 % et 15 % des nouveau-nés développeront une hyperbilirubinémie nécessitant un traitement. La prise en charge réussie de l'hyperbilirubinémie néonatale repose sur la prévention et le traitement précoce, la photothérapie étant le pilier du traitement. Il a été rapporté que le zinc par voie orale diminuait la bilirubine sérique totale (BST), supposément en diminuant la circulation entérohépatique.

Objectifs

Déterminer l'effet de la supplémentation en zinc par voie orale, comparativement à un placebo ou à l'absence de traitement, sur l'incidence de l'hyperbilirubinémie chez le nouveau-né pendant la première semaine de vie et évaluer la sécurité du zinc oral chez les nouveau-nés participants.

Stratégie de recherche documentaire

Nous avons interrogé CENTRAL (Bibliothèque Cochrane 2014, numéro 1), MEDLINE (de 1966 au 30 novembre 2014) et EMBASE (de 1990 au 30 novembre 2014).

Critères de sélection

Les essais contrôlés randomisés étaient admissibles pour inclusion s'ils portaient sur des nouveau-nés (prématurés et à terme) chez qui le zinc par voie orale, à une dose de 10 à 20 mg/jour, était débuté dans les 96 premières heures de vie, pour toute durée jusqu'à sept jours, et comparé à l'absence de traitement ou un placebo.

Recueil et analyse des données

Nous avons utilisé les méthodes standard de la Collaboration Cochrane et de son groupe thématique sur la néonatologie pour la collecte et l'analyse de données.

Résultats principaux

Une seule étude satisfaisait aux critères d'inclusion de la revue. Elle comparait le zinc par voie orale à un placebo. Le zinc oral était administré à une dose de 5 ml deux fois par jour, du jour 2 au jour 7 post-partum. Le médicament était administré dans la bouche de l'enfant en utilisant le doseur en matière plastique fourni avec le flacon ou une cuillère. L'incidence de l'hyperbilirubinémie, définie comme une bilirubine sérique totale (BST) ≥ 15 mg/dl, était similaire entre les groupes (N = 286 ; risque relatif (RR) de 0,94 ; intervalle de confiance (IC) à 95 % de 0,58 à 1,52). Les concentrations moyennes de BST, en mg/dl, à 72 ± 12 heures étaient comparables dans les deux groupes (N = 286 ; différence moyenne (DM) -0,20 ; IC à 95 % de -1,03 à 0,63). Bien que la durée de la photothérapie ait été significativement plus courte dans le groupe zinc que le groupe placebo (N = 286 ; DM -12,80 ; IC à 95 % de -16,93 à -8,67), l'incidence du recours à la photothérapie était comparable entre les deux groupes (N = 286 ; RR 1,20 ; IC à 95 % de 0,66 à 2,18). Les effets secondaires comme les vomissements (N = 286 ; RR 0,65 ; IC à 95 % de 0,19 à 2,25), les diarrhées (N = 286 ; RR 2,92 ; IC à 95 % de 0,31 à 27,71) et les éruptions cutanées (N = 286 ; RR 2,92 ; IC à 95 % de 0,12 à 71,03) étaient rares et leur incidence était statistiquement comparable entre les groupes.

Conclusions des auteurs

Les données limitées disponibles n'ont pas démontré que la supplémentation en zinc par voie orale chez le nourrisson âgé jusqu'à une semaine réduisait l'incidence de l'hyperbilirubinémie ou le besoin de photothérapie.

Resumen

Zinc oral para la prevención de la hiperbilirrubinemia en los recién nacidos

Antecedentes

Entre el 6% y el 15% de los recién nacidos desarrolla hiperbilirrubinemia que requiere tratamiento. El tratamiento exitoso de la hiperbilirrubinemia neonatal depende de la prevención y el tratamiento inicial; la fototerapia es la base del tratamiento. Se ha informado que el zinc oral reduce la bilirrubina sérica total (BST), probablemente al disminuir la circulación enterohepática.

Objetivos

Determinar el efecto de la administración oral de suplementos de zinc, en comparación con placebo o ningún tratamiento, sobre la incidencia de hiperbilirrubinemia en los recién nacidos durante la primera semana de vida y evaluar la seguridad del zinc oral en los recién nacidos reclutados.

Métodos de búsqueda

Se hicieron búsquedas en CENTRAL (The Cochrane Library 2014, número 1), MEDLINE (1966 hasta 30 noviembre, 2014) y en EMBASE (1990 hasta 30 noviembre, 2014).

Criterios de selección

Los ensayos controlados aleatorios fueron elegibles para inclusión si reclutaron recién nacidos (a término y prematuros) en los que la administración de zinc oral a una dosis de 10 a 20 mg/día comenzó en las primeras 96 horas de vida, tuvo una duración de hasta siete días y se comparó con ningún tratamiento o placebo.

Obtención y análisis de los datos

Para la obtención y el análisis de los datos se utilizaron los métodos estándar de la Colaboración Cochrane y de su Grupo de Revisión de Neonatología (Neonatal Review Group).

Resultados principales

Sólo un estudio cumplió los criterios de inclusión en la revisión. Este estudio comparó el zinc oral con placebo. El zinc oral se administró a una dosis de 5 ml dos veces al día desde el segundo día hasta el séptimo después del parto. El fármaco se administró en la boca del lactante a través de la medida de plástico que se proporcionaba con el biberón o con una cuchara. La incidencia de hiperbilirrubinemia, definida como bilirrubina sérica total (BST)≥ 15 mg/dl, fue similar entre los grupos (n = 286; cociente de riesgos [CR] 0,94; intervalo de confianza [IC] del 95%: 0,58 a 1,52). Los niveles medios de BST, mg/dl, a las 72 ± 12 horas fueron comparables en ambos grupos (n = 286; diferencia de medias [DM] -0,20; IC del 95%: -1,03 a 0,63). Aunque la duración de la fototerapia en el grupo de zinc fue significativamente más corta en comparación con el grupo placebo (n = 286; DM -12,80; IC del 95%: -16,93 a -8,67), la incidencia de necesidad de fototerapia fue comparable entre ambos grupos (n = 286; CR 1,20; IC del 95%: 0,66 a 2,18). Se encontró que la incidencia de efectos secundarios como vómitos (n = 286; CR 0,65; IC del 95%: 0,19 a 2,25), diarrea (n = 286; CR 2,92; IC del 95%: 0,31 a 27,71) y erupción cutánea (n = 286; CR 2,92; IC del 95%: 0,12 a 71,03) fue poco frecuente y estadísticamente comparable entre los grupos.

Conclusiones de los autores

Las pruebas limitadas disponibles no han mostrado que la administración oral de suplementos de zinc a los neonatos de hasta una semana de edad reduzca la incidencia de hiperbilirrubinemia o la necesidad de fototerapia.

アブストラクト

新生児における高ビリルビン血症予防のための経口亜鉛

背景

新生児の6%から15%が、治療を要する高ビリルビン血症を発症する。新生児における高ビリルビン血症の管理を成功させるには、光線療法を治療の主体とした、予防および早期治療が重要である。経口亜鉛補充はビリルビンの腸肝循環量を減少させることで血清総ビリルビン(STB)濃度を低下させると報告されている。

目的

生後1週間における新生児の高ビリルビン血症の発生率に対する経口亜鉛補充の効果をプラセボまたは無治療と比較検討すること、および新生児に対する経口亜鉛補充の安全性を評価すること。

検索戦略

CENTRAL(コクラン・ライブラリ2014年1号)、MEDLINE(1966年〜2014年11月30日)およびEMBASE(1990年〜2014年11月30日)を検索した。

選択基準

新生児(正期産児および早産児)に、生後96時間以内に10〜20 mg/日で経口亜鉛補充を開始し、7日間までの任意の期間で無治療またはプラセボと比較したランダム化比較試験を組み入れた。

データ収集と分析

データの収集および解析には、コクランおよびコクランNeonatal Review Groupの標準法を用いた。

主な結果

1件の試験のみが本レビューの選択基準を満たした。この試験では経口亜鉛補充をプラセボと比較した。生後2日から生後7日まで、経口亜鉛剤5 mLを1日2回投与した。薬瓶と一緒に提供されたプラスチック製計量カップまたはスプーンで新生児の口腔内に薬剤を投与した。高ビリルビン血症の定義は血清総ビリルビン(STB)が15 mg/dL以上とし、その発生率は両群間で同程度であった(N = 286;リスク比[RR]0.94, 95%信頼区間[CI]0.58〜1.52)。72 ± 12時間目の平均STB(mg/dL)は両群間で同等であった(N = 286;平均差[MD]-0.20; 95%CI -1.03〜0.63)。亜鉛補充群ではプラセボ群と比較して光線療法の期間が有意に短縮した(N = 286; MD -12.80, 95%CI -16.93〜-8.67)が、光線療法を要した患児数は両群間で同等であった(N = 286; RR 1.20; 95%CI 0.66〜2.18)。嘔吐(N = 286; RR 0.65, 95%CI 0.19〜2.25)、下痢(N = 286; RR 2.92, 95%CI 0.31〜27.71)、発疹(N = 286; RR 2.92, 95%CI 0.12 〜71.03)などの副作用の発現はまれで、両群間で統計学的に同等であった。

著者の結論

限られたエビデンスでは、新生児に経口亜鉛補充を最長1週齢まで実施した場合、高ビリルビン血症の発生率低下や光線療法が必要な患児数の減少は示されなかった。

Plain language summary

Oral zinc for the prevention of hyperbilirubinaemia in neonates

Review question

In newborn infants less than one week old, does oral zinc salt supplementation compared to placebo or no treatment decrease the incidence of hyperbilirubinaemia (jaundice)?

Background

Jaundice, or yellowish discolouration of the skin, can occur due to an increased amount of bilirubin pigment in the blood. It is a commonly observed and usually harmless condition in newborn infants during the first week after birth. However, in some babies, the amount of bilirubin pigment can increase to dangerous levels and necessitate treatment. Bilirubin is metabolised in the liver and is excreted via the intestine in faeces. Increased reabsorption of bilirubin from the intestine is one of the major factors inducing hyperbilirubinaemia in newborn infants. Oral zinc salt, a relatively harmless medicine, can reduce the bilirubin level in newborn infants by decreasing its reabsorption from the intestine.

Study characteristics

Researchers from Cochrane searched for all available literature up to 30 November 2014. One randomised controlled trial met our inclusion criteria.

Results

In this review, the efficacy of oral zinc salt was compared with placebo. One study enrolling 294 infants was identified. This study evaluated oral zinc salt, given in a dose of 5 mg twice daily to infants between 25 and 168 hours old. The administration of oral zinc salt did not affect the incidence of jaundice (hyperbilirubinaemia) in these infants.

Résumé simplifié

Zinc par voie orale pour la prévention de l'hyperbilirubinémie chez les nouveau-nés

Question de la revue

Chez les nouveau-nés âgés de moins d'une semaine, une supplémentation en sel de zinc par voie orale diminue-t-elle l'incidence de l'hyperbilirubinémie (jaunisse) comparativement à un placebo ou à l'absence de traitement ?

Contexte

La jaunisse, une décoloration jaunâtre de la peau, peut être provoquée par une quantité excessive de pigments de bilirubine dans le sang. C'est une pathologie fréquemment observée, et généralement inoffensive, chez le nouveau-né pendant la première semaine suivant la naissance. Cependant, chez certains bébés la quantité de pigment de bilirubine peut atteindre des niveaux dangereux et nécessiter un traitement. La bilirubine est métabolisée dans le foie et excrétée par l'intestin dans les fèces. L'augmentation de la réabsorption de la bilirubine à partir de l'intestin est l'un des principaux facteurs induisant l'hyperbilirubinémie chez les nouveau-nés. Le sel de zinc oral, un médicament relativement inoffensif, peut réduire le taux de bilirubine chez les nouveau-nés en diminuant sa réabsorption à partir de l'intestin.

Caractéristiques de l'étude

Des chercheurs de Cochrane ont consulté toute la littérature disponible jusqu'au 30 novembre 2014. Un essai contrôlé randomisé répondait à nos critères d'inclusion.

Résultats

Dans cette revue, l'efficacité du sel de zinc par voie orale a été comparée à un placebo. Une étude portant sur 294 nourrissons a été identifiée. Cette étude évaluait le sel de zinc par voie orale, administré à une dose de 5 mg deux fois par jour à des nourrissons âgés de 25 à 168 heures. L'administration de sel de zinc oral n'a pas eu d'impact sur l'incidence de la jaunisse (hyperbilirubinémie) chez ces nourrissons.

Notes de traduction

Traduction réalisée par Cochrane France

Laienverständliche Zusammenfassung

Oral verabreichtes Zink zur Vorbeugung von Hyperbilirubinämie bei Neugeborenen

Fragestellung

Verringert oral (durch den Mund) verabreichtes Zinksalz bei Neugeborenen unter einer Woche im Vergleich mit einem Placebo oder keiner Behandlung das Auftreten von Hyperbilirubinämie (Gelbsucht)?

Hintergrund

Gelbsucht, die gelbliche Verfärbung der Haut, kann aufgrund einer erhöhten Menge des Pigments Bilirubin im Blut auftreten. Sie ist ein häufig beobachteter und in der Regel harmloser Zustand bei Neugeborenen in der ersten Woche nach der Geburt. Bei manchen Babys kann die Bilirubinmenge jedoch auf gefährliche Werte ansteigen und eine Behandlung erfordern. Bilirubin wird in der Leber verstoffwechselt und über den Darm mit dem Stuhl ausgeschieden. Eine erhöhte Wiederaufnahme von Bilirubin aus dem Darm ist einer der Hauptfaktoren, der zu Hyperbilirubinämie bei Neugeborenen führt. Oral verabreichtes Zinksalz, ein relativ harmloses Medikament, kann den Bilirubinspiegel bei Neugeborenen senken, indem es seine Wiederaufnahme aus dem Darm verringert.

Studienmerkmale

Forscher des Cochrane-Netzwerks suchten nach sämtlicher verfügbarer Literatur bis zum 30. November 2014. Eine randomisierte kontrollierte Studie erfüllte unsere Einschlusskriterien.

Ergebnisse

In diesem Review wurde die Wirkung von oral verabreichtem Zinksalz mit einem Placebo verglichen. Es wurde eine Studie mit 294 Säuglingen gefunden. In dieser Studie wurde Zinksalz untersucht, das 25 bis 168 Stunden alten Säuglingen in einer Dosis von 5 mg zweimal täglich gegeben wurde. Die orale Verabreichung von Zinksalz hatte bei diesen Säuglingen keinen Einfluss auf das Auftreten von Gelbsucht (Hyperbilirubinämie).

Anmerkungen zur Übersetzung

S. Schmidt-Wussow, freigegeben durch Cochrane Schweiz.

Laički sažetak

Cink za sprječavanje žutice (hiperbilirubinemije) u novorođenčadi

Istraživačko pitanje

Da li u novorođenčadi mlađe od jednog tjedna dodatak soli cinka koje se uzimaju na usta, u usporedbi s placebom ili bez liječenja, smanjuje pojavnost hiperbilirubinemije (žutice)?

Dosadašnje spoznaje

Žutica, ili žućkasto obojenje kože, može nastati zbog povećane količine pigmenta bilirubina u krvi. To je često i obično bezopasno stanje u novorođenčadi u prvom tjednu nakon rođenja. Međutim, u neke djece količina pigmenta bilirubina se može povećati do opasne razine što zahtijeva liječenje. Bilirubin se metabolizira u jetri i izlučuje se putem crijeva u stolici. Povećano upijanje bilirubina iz crijeva je jedan od glavnih faktora koji izazivaju hiperbilirubinemiju u novorođenčadi. Sol cinka koja se uzima na usta relativno je bezopasan lijek, a može smanjiti razinu bilirubina u novorođenčadi smanjujući njegovu reapsorpciju iz crijeva.

Obilježja studija

Istraživači Cochranea pretražili su svu literaturu dostupnu do 30. studenog 2014. Uključen je samo jedan randomizirani kontrolirani pokus koji je ispunio kriterije.

Rezultati

U ovom Cochrane sustavnom pregledu učinkovitost davanja soli cinka na usta uspoređena je s placebom. Pronađena je samo jedna studija na tu temu koja je uključila 294 novorođenčadi. Ta studija ispitala je davanje soli cinka na usta u dozi od 5 mg dva puta dnevno kod novorođenčadi stare između 25 i 168 sati. Davanje soli cinka na usta nije utjecala na pojavnost žutice (hiperbilirubinemije) u te novorođenčadi.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Albenita Hajrović
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Ringkasan bahasa mudah

Pengambilan zink secara oral untuk mencegah hiperbilirubinemia (jaundis) pada neonat (bayi baru lahir)

Persoalannya

Adakah pengambilan garam zink sebagai oral suplemen, berbanding dengan plasebo (bahan yang tidak aktif) ataupun tiada rawatan diberikan dapat mengurangkan kejadian hiperbilirubinemia (jaundis) pada bayi yang berusia kurang daripada seminggu?

Latarbelakang

Jaundis, atau kekuningan kulit,berlaku disebabkan oleh peningkatan jumlah pigmen bilirubin didalam darah. Ia adalah satu keadaan yang lazim berlaku dalam minggu pertama selepas kelahiran dan biasanya tidak berbahaya kepada bayi. Bagaimanapun, terdapat keadaan dimana, jumlah pigmen bilirubin ini meningkat kepada tahap berbahaya yang menyebabkan rawatan diperlukan. Proses metabolisma bilirubin ini berlaku di dalam hati/hepar dan kemudian disalurkan ke usus dan dikeluarkan didalam najis. Peningkatan penyerapan semula bilirubin dari usus merupakan salah satu faktor utama yang mengakibatkan hiperbilirubinemia pada bayi baru lahir. Pengambilan garam zink secara oral, boleh mengurangkan tahap bilirubin pada bayi yang baru lahir dengan mengurangkan penyerapan semula dari usus. Garam zink ini selamat digunakan sebagai ubat.

Ciri-ciri kajian

Penyelidik dari Cochrane telah mencari kesemua kajian sehingga 30 November 2014. Hanya terdapat satu kajian yang memenuhi kriteria yang ditetapkan.

Keputusan

Dalam kajian ini, keberkesanan garam zink oral telah dibandingkan dengan plasebo. Plasebo adalah bahan kajian yang tidak berbahaya tetapi dan tidak mengandungi bahan aktif yang boleh merawat keadaan yang dikaji. Seramai 294 bayi telah direkrut ke dalam kajian ini. Didalam kajian ini, garam zink oral diberikan dalam dos 5 mg dua kali sehari kepada bayi yang berusia diantara 25 hingga 168 jam. Keputusannya, pengambilan garam zink oral ini tidak mempengaruhi kejadian jaundis (hiperbilirubinemia) pada bayi-bayi ini.

Catatan terjemahan

Diterjemahkan oleh Foo Sook Lee (Penang Medical College). Disunting oleh Rosnani Zakaria (Universiti Sains Malaysia). Untuk sebarang pertanyaan mengenai terjemahan ini sila hubungi fslee@pmc.edu.my.

Resumen en términos sencillos

Zinc oral para la prevención de la hiperbilirrubinemia en los recién nacidos

Pregunta de la revisión

En los recién nacidos con menos de una semana de vida, ¿la administración oral de suplementos de sales de zinc en comparación con placebo o ningún tratamiento disminuye la incidencia de hiperbilirrubinemia (ictericia)?

Antecedentes

La ictericia, o coloración amarillenta de la piel, puede ocurrir debido al aumento en las cantidades de pigmento de bilirrubina en la sangre. Es una afección generalmente inocua que se observa con frecuencia en los recién nacidos durante la primera semana después del nacimiento. Sin embargo, en algunos neonatos la cantidad de pigmento de bilirrubina puede aumentar a niveles peligrosos y requerir tratamiento. La bilirrubina se metaboliza en el hígado y se excreta por el intestino en las heces. El aumento en la reabsorción de la bilirrubina en el intestino es uno de los factores principales que induce hiperbilirrubinemia en los recién nacidos. La sal de zinc oral, un fármaco relativamente inocuo, puede reducir el nivel de bilirrubina en los recién nacidos al reducir la reabsorción del intestino.

Características de los estudios

Los investigadores Cochrane buscaron toda la literatura disponible hasta el 30 de noviembre de 2014. Un ensayo controlado aleatorio cumplió con los criterios de inclusión.

Resultados

En esta revisión la eficacia de la sal de zinc oral se comparó con placebo. Se identificó un estudio que reclutó a 294 lactantes. Este estudio evaluó la sal de zinc oral administrada a una dosis de 5 mg dos veces al día a lactantes con entre 25 y 168 horas de vida. La administración oral de la sal de zinc no afectó la incidencia de la ictericia (hiperbilirrubinemia) en estos neonatos.

Notas de traducción

La traducción y edición de las revisiones Cochrane han sido realizadas bajo la responsabilidad del Centro Cochrane Iberoamericano, gracias a la suscripción efectuada por el Ministerio de Sanidad, Servicios Sociales e Igualdad del Gobierno español. Si detecta algún problema con la traducción, por favor, contacte con Infoglobal Suport, cochrane@infoglobal-suport.com.

平易な要約

新生児における高ビリルビン血症予防のための経口亜鉛

レビューの論点

生後1週齢未満の新生児では、経口亜鉛塩補充がプラセボまたは無治療と比較して高ビリルビン血症(黄疸)の発生率を低下させるか?

背景

皮膚が黄色に変色する黄疸は、血中のビリルビン色素量が増加することで発生する。生後1週間の新生児では黄疸の発生率が高く、通常は無害である。しかし、一部の新生児ではビリルビン色素の量が危険なレベルまで増加し、治療が必要となる。ビリルビンは肝臓で代謝され、腸管を介して糞便中に排泄される。腸管からのビリルビンの再吸収増加が、新生児の高ビリルビン血症を引き起こす主な要因の一つである。経口亜鉛塩は比較的無害な薬剤で、腸管からのビリルビン再吸収を減少させることで新生児のビリルビン濃度を低下させる。

試験の特性

コクランの研究者は2014年11月30日までに入手可能な文献をすべて検索した。1件のランダム化比較試験が選択基準を満たした。

結果

本レビューでは、経口亜鉛塩の効果をプラセボと比較した。294名の新生児を対象とした1件の試験を同定した。この試験では経口亜鉛塩5 mgを生後25時間から168時間の新生児に1日2回投与して評価した。経口亜鉛塩投与は、これらの新生児における黄疸(高ビリルビン血症)の発生率に影響を及ぼさなかった。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2018.3.13]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。 
CD008432 Pub2

Background

Description of the condition

More than 60% of neonates develop jaundice during the first week of life. Mostly, in these neonates, the level of serum bilirubin lies within the physiologic range. Between 6% and 15% of neonates develop hyperbilirubinaemia (serum total bilirubin (STB) levels that have a high likelihood of requiring intervention to prevent bilirubin toxicity) (Maisels 1988; Narang 1997). The most devastating complication of neonatal hyperbilirubinaemia is bilirubin-induced encephalopathy and its chronic sequelae (Shapiro 2003). The fundamental principle for the management of neonatal hyperbilirubinaemia is prevention and early treatment. Phototherapy is commonly used and is a very effective therapy for neonatal hyperbilirubinaemia. Phototherapy causes photoisomerization of bilirubin into a water-soluble form that can be excreted by the kidneys. Phototherapy effectively decreases the STB in jaundiced newborn infants and decreases the need for exchange blood transfusion (Maisels 1992). Metalloporphyrins are a relatively new but potentially effective mode of management of neonatal hyperbilirubinaemia. Metalloporphyrins are heme analogues that inhibit heme oxygenase, the rate-limiting enzyme in the catabolism of heme to bilirubin. By preventing the formation of bilirubin, they have the potential to reduce the level of unconjugated bilirubin in neonates. However, more research is required on their safety and to compare them with other well-established treatments (Suresh 2003).

Description of the intervention

Oral zinc has been reported to decrease the STB levels in animal models (Méndez-Sánchez 2001; Vitek 2005); and in adults with Gilbert syndrome (Méndez-Sánchez 2002). However, currently little is known about the role of oral zinc salt in jaundiced neonates. In a randomised intervention trial, potential adverse effects of oral zinc salt like diarrhoea, vomiting, and rash were reported to be rare, and similar among both oral zinc and placebo groups (Rana 2011).

How the intervention might work

Studies have suggested that enterohepatic circulation (EHC) might play a significant role in the metabolism of bilirubin (Bloomer 1976). EHC may be exaggerated in the neonatal period, in part because the newborn intestinal tract is not yet colonised with bacteria that convert unconjugated bilirubin (UCB) to urobilinogens and because intestinal beta glucuronidase activity is high (Madan 2005). Various strategies have been used to bind the bilirubin in the intestinal lumen to substances that resist absorption in order to counteract the process of enhanced EHC. Products such as oral agar have been used but with inconsistent results (Odell 1983). Oral zinc salts, which flocculate at physiological pH, reduce the STB, presumably by precipitating UCB from unsaturated micellar solution of bile salts and consequently inhibit the EHC of bilirubin (Méndez-Sánchez 2001; Vitek 2005).   

Why it is important to do this review

In animal models, oral zinc has been used for hyperbilirubinaemia with inconsistent results (Méndez-Sánchez 2001; Vitek 2005). Based on available data from animal and adult human studies, it seems plausible that oral zinc salt may reduce the incidence of hyperbilirubinaemia and the need for phototherapy and exchange transfusion in jaundiced neonates. However, there are very few published reports evaluating the effectiveness of oral zinc salt in neonatal hyperbilirubinaemia. The aim of this review is to systematically assess and compile the available evidence from randomised trials on this issue.

Objectives

1. To determine the effect of oral zinc salt supplementation compared to placebo or no treatment on the incidence of hyperbilirubinaemia in neonates during the first week of life.

2. To assess the safety of oral zinc in enrolled neonates.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials in which oral zinc supplementation was compared with no treatment or placebo were included in this review.

Types of participants

All healthy term and preterm neonates were included. We excluded neonates with Rhesus isoimmunisation, major gross congenital anomaly, sepsis (receiving intravenous antibiotics), postnatal age more than four days at initiation of the intervention, and neonates who required treatment for jaundice within 24 hours of birth or required intensive care for more than 24 hours within the first seven days of life.

Types of interventions

Oral zinc salt, in a dose of 10 to 20 mg/day, initiated within the first 96 hours after birth for any duration until day seven, compared to no treatment or placebo.

Types of outcome measures

Primary outcomes

Incidence of hyperbilirubinaemia any time within the first seven days postpartum.

(Hyperbilirubinemia was defined as:

  • for term and near-term neonates (neonates ≥ 35 weeks' gestation): STB level that would qualify for phototherapy requirement as described in American Academy of Pediatrics 2004's guidelines or absolute STB level ≥ 15 mg/dL;

  • for preterm neonates (< 35 weeks' gestation): STB level > 1% of body weight.)

Secondary outcomes
  1. Mean STB level (mg/dL) at 72 ± 12 hours of age

  2. Proportion of neonates receiving or received phototherapy

  3. Duration of phototherapy (hours)

  4. Incidence of vomiting

  5. Incidence of diarrhoea

  6. Incidence of rash

  7. Duration of hospital stay (days)

  8. Incidence of exchange transfusion (number of babies requiring exchange transfusions regardless of the number of transfusions in a particular baby)

  9. Mortality (defined as all-cause death during the intervention or within a week of stopping the intervention)

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2014, Issue 1), MEDLINE (1966 to November 30, 2014), and EMBASE (1990 to November 30, 2014) using MeSH term infant-newborn AND text terms zinc AND hyperbilirubinaemia OR phototherapy OR jaundice. Additional search of clinical trial registries (ClinicalTrials.gov, controlled-trials.com) were done. Language restriction was not placed during electronic searches.

Searching other resources

  • Reference lists from the above, and from review articles.

  • Personal communication with primary authors from the above to retrieve unpublished data related to published articles.

Data collection and analysis

We used the standard methods of the Cochrane Neonatal Review Group for data collection and analysis.

Selection of studies

All the authors independently examined the title and abstract of each retrieved study to assess eligibility and identified the studies to be included.

Data extraction and management

Two authors (SM and AC) independently extracted data using a data extraction form. Differences were resolved after discussion among all the review authors.

Assessment of risk of bias in included studies

We used the standard methods of the Cochrane Neonatal Review Group for assessing the methodological quality of the studies. All the review authors independently assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion among all the authors.

We assessed the methodological quality of the studies using the following criteria.

Sequence generation (selection bias)

For the included study, we assessed the method of sequence generation as:

  • low risk: when sequences were generated using true randomisation process;

  • high risk: when any non-random process was used for sequence generation;

  • unclear risk: when methodology of sequence was unclear.

Allocation concealment (selection bias)

For the included study, we assessed the method of allocation concealment as:

  • low risk: when adequate methods were used for allocation concealment (e.g. consecutively numbered, sealed, opaque envelopes);

  • high risk: when allocation concealment was inadequately done;

  • unclear risk: when methodology of allocation concealment was unclear.

Blinding (performance bias and detection bias)

For the included study, we categorised the methods used to blind study participants and personnel from the knowledge of which intervention a participant received. We assessed the process of blinding separately for different outcomes and categorised the methods as:

  • low risk, high risk or unclear risk for participants;

  • low risk, high risk or unclear risk for personnel;

  • low risk, high risk or unclear risk for outcome assessors.

Incomplete outcome data (attrition bias)

For the included study, we examined the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. We categorised the method as:

  • low risk: < 20% missing data;

  • high risk: > 20% missing data;

  • unclear risk.

Selective reporting (reporting bias)

For the included study, we investigated the possibility of selective outcome reporting. We categorised the method as:

  • low risk: when all the study’s pre-specified outcomes and expected outcomes of interest were reported;

  • high risk: when not all the pre-specified outcomes were reported or one or more primary outcomes were not pre-specified;

  • unclear risk: when information provided was unclear.

Other source of bias

For the included study, we have described our concerns about other possible sources of bias. Based on potential sources of bias we described the included study as:

  • low risk;

  • high risk;

  • unclear risk.

Measures of treatment effect

For categorical data the risk ratio (RR), risk difference (RD) and number needed to treat (NNT) with 95% confidence intervals (CI) were calculated. Continuous data were analysed using mean difference (MD).

Unit of analysis issues

Unit of analysis was the individual patient. We compared neonates receiving oral zinc supplementation with neonates receiving no treatment or placebo in overall analysis.

Dealing with missing data

We contacted the original investigators with requests for any missing data.

Assessment of heterogeneity

We planned the estimation of the degree of statistical heterogeneity using the I² statistic (< 25% none, 25% to 49% low, 50% to 74% moderate, and > 75% high heterogeneity) if we had found two or more studies for inclusion in this meta analysis. However, with detailed search we could find only one study, so did not need this analysis.

Assessment of reporting biases

A comprehensive search of eligible studies including from prospective clinical trial registries and conference proceedings was done to decrease publication bias and skewing of the conclusion.

Data synthesis

Data were synthesised using fixed-effect model.

Subgroup analysis and investigation of heterogeneity

We planned to examine outcomes separately in the following subgroups, however no data were available for the comparison:

  1. term and near-term versus preterm neonate;

  2. all neonates versus neonates at risk of hyperbilirubinaemia;

  3. low dose (≤ 10 mg/day) versus high dose (11 to 20 mg/day) of oral zinc;

  4. short (< 72 hours) versus long (≥ 72 hours) duration of treatment.

Sensitivity analysis

We planned sensitivity analyses for situations where this might affect the interpretation of significant results. However, we could find only one eligible study and there were no significant missing data. Therefore, we did not need it.

Results

Description of studies

Results of the search

A total of 17 studies were retrieved from detailed literature search. Of these, only one study reported the efficacy of zinc on hyperbilirubinaemia and met inclusion criteria for the review (Rana 2011). The study was conducted at a tertiary care hospital in New Delhi, India, and included at-risk neonates (STB levels ≥ 6mg/dL at 24 ± 6 hours postpartum) born at ≥ 35 weeks gestation.

Included studies

The study conducted by Rana 2011 is a double-blind, placebo-controlled, randomised trial conducted at a tertiary care neonatal centre in New Delhi, India. All neonates born at ≥ 35 weeks' gestational age were potentially eligible for enrolment in the study. Neonates with Rhesus incompatibilities, major gross congenital anomalies, sepsis (requiring intravenous antibiotics), those who required exchange blood transfusion or phototherapy within 24 hours of birth, or those requiring intensive care for more than 24 hours were all excluded. All potentially eligible neonates were screened for STB at 24 ± 6 hours after birth. A total of 294 neonates with STB value ≥ 6 mg/dL at 24 ± 6 hours postpartum were enrolled in the study. Of these, 148 neonates received the oral zinc gluconate in a dose of 5 mL twice daily on days 2 to 7 postpartum and 146 neonates received the identical placebo syrup in a similar manner. Both zinc salt and placebo were provided in identical 60 mL bottles. The drug was administered into the mouth of the infant by the plastic measure provided with the bottle or a spoon. Eight infants were lost to follow up on day seven, so 145 children in the zinc group and 141 in the placebo group were analysed for the primary outcome.

Excluded studies

None

Risk of bias in included studies

Risk of bias in the included study was found to be low (Figure 1).

Figure 1.

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

Allocation

The random sequence generation method is well described in the study. Random sequence were generated using permuted blocks of fixed size, six each, by a statistical package. The randomisation and numbered packing of intervention drug (oral zinc or placebo) was prepared off site by staff not involved in the study. The random sequences were kept in safe custody at two places by staff not involved in the study. Risk of bias was low.

Blinding

The blinding process is well described. Oral zinc and placebo were identical in colour, taste, and appearance and packaged in bottles indistinguishable from each other. The code was kept blinded from the participants, investigators, and the statistician until the analysis was completed. Risk of bias was low.

Incomplete outcome data

The study reported complete outcome data.

Selective reporting

The study is assessed to be free of risk of selective reporting bias.

Other potential sources of bias

The zinc and placebo bottles were made available free of cost by manufacturer. As per additional information provided by authors "Zinc and placebo bottles were provided by Shalakas Pharmaceuticals Pvt.Ltd. However, they had no role in the design, conduct, analysis and reporting of the study."

Effects of interventions

Oral zinc salt supplementation compared to placebo (comparison 1)

Incidence of hyperbilirubinaemia during first week of age (outcome 1.1)

The incidence of hyperbilirubinaemia was reported in 286 neonates. There was no significant difference in the incidence of hyperbilirubinaemia among both the groups, 17.9% in oral zinc group vs 19.1% in placebo group (RR 0.94, 95% CI 0.58 to 1.52; RD -0.01, 95% CI -0.10 to 0.08).

Proportion of neonates receiving or received phototherapy (outcome 1.2)

Requirement of phototherapy within first seven days of age was reported in 286 neonates. There was no significant difference between the zinc and the placebo groups in the incidence of need for phototherapy (RR 1.20, 95% CI 0.66 to 2.18; RD -0.05, 95% CI -0.13 to 0.04).

Side effects (Incidence of vomiting, diarrhoea, and rash) (outcome 1.3 to 1.5)

Incidences of side effects were reported for 286 neonates. Events of vomiting (RR 0.65, 95% CI 0.19 to 2.25; RD 0.65, 95% CI 0.19 to 2.25), diarrhoea (RR 2.92, 95% CI 0.31 to 27.71; RD 0.01, 95% CI -0.01 to 0.04), and rash (RR 2.92, 95% CI 0.12 to 71.03; RD 0.01, 95% CI -0.01 to 0.03) were found to be rare and statistically similar between groups.

Mean STB level at 72±12 hours of age (outcome 1.6)

Mean STB levels, mg/dL, at 72 ± 12 hours were reported for 286 neonates. The mean STB levels at 72 ± 12 hours of age between the two groups were similar (MD -0.20, 95% CI -1.03 to 0.63).

Duration of phototherapy (outcome 1.7)

This outcome was reported in total of 286 neonates. The duration of phototherapy, in hours, in the zinc group was significantly shorter compared to placebo group (MD -12.80, 95% CI -16.93 to -8.67).

Other clinical outcomes: duration of hospital stay (days), incidence of exchange transfusion, mortality

These outcomes were not reported in the trial included in this review (Rana 2011).

Discussion

Summary of main results

After a detailed literature search, we could find only one study fulfilling the criteria of inclusion in this systematic review (Rana 2011). It compared oral zinc and placebo for prevention of hyperbilirubinaemia in neonates. Data suggested that oral zinc salt as compared to placebo did not decrease the incidence of hyperbilirubinaemia, or mean serum bilirubin at 72 ± 12 hours postpartum. Though duration of phototherapy was lower in the oral zinc group, the incidence of need for phototherapy was comparable across both the groups. Side effects of oral zinc were rare and comparable between groups.

Overall completeness and applicability of evidence

Prevention of enterohepatic circulation of bilirubin via enhancement of bilirubin sequestration or degradation in intestinal lumen is an exciting approach for prevention of neonatal hyperbilirubinaemia. Among compounds having this potential, zinc salts were demonstrated to be promising both in vitro and in vivo. Rana 2011, the study included in this review, compared oral zinc and placebo for prevention of hyperbilirubinaemia in at-risk neonates. Authors used oral zinc gluconate in a dose of 5 mL twice daily from day 2 to 7 following birth. Data revealed that administration of oral zinc salt did not reduce the incidence of subsequent hyperbilirubinaemia among at-risk neonates during the first week of life. Though the zinc administration was not associated with any reduction in proportion of neonates requiring phototherapy, duration of phototherapy was lower in the group supplemented with oral zinc compared to the placebo group. The mean serum total bilirubin at 72 ± 12 hours postpartum was also comparable in the oral zinc and placebo groups. The side effects (diarrhoea, vomiting, and rash) were rare and comparable between groups.

Quality of the evidence

The study included in the review is a well-conducted, double-blind, placebo-controlled, randomised trial which enrolled an adequate number of infants (Figure 1). The estimate of effect on primary outcome, the incidence of hyperbilirubinaemia during the first week of life, and reported secondary outcomes is reasonably precise.

Potential biases in the review process

Four authors of the review are also authors of the study included in this review.

Agreements and disagreements with other studies or reviews

To the best of our knowledge there is no other published review comparing the efficacy of oral zinc and placebo for prevention of hyperbilirubinaemia in neonates.

Authors' conclusions

Implications for practice

The limited evidence available has not shown that oral zinc supplementation in infants up to one week old reduces the incidence of hyperbilirubinaemia or need for phototherapy.

Implications for research

Although Rana 2011, the only available study, does not suggest any meaningful improvement in hyperbilirubinaemia with oral zinc supplementation, there is a strong rationale to use oral zinc supplementation as an agent to prevent enterohepatic circulation of bilirubin via enhancement of bilirubin sequestration or degradation in the intestinal lumen. The estimates of effect from this single study are broad enough to consider further adequately powered trials to address this issue.

Acknowledgements

The Cochrane Neonatal Review Group has been funded in part 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. HHSN267200603418C.

Data and analyses

Download statistical data

Comparison 1. Oral zinc salt supplementation compared to placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of hyperbilirubin a emia 1286Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.58, 1.52]
2 Proportion of neonates receivin g phototherapy 1286Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.45, 1.27]
3 Incidence of vomiting 1286Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.19, 2.25]
4 Incidence of diarrhoea 1286Risk Ratio (M-H, Fixed, 95% CI)2.92 [0.31, 27.71]
5 Incidence of rash 1286Risk Ratio (M-H, Fixed, 95% CI)2.92 [0.12, 71.03]
6 Mean total serum bilirubin , mg/dL, at 72 ± 12 hours of age 1286Mean Difference (IV, Fixed, 95% CI)-0.20 [-1.03, 0.63]
7 Duration of phototherapy (hours) 1286Mean Difference (IV, Fixed, 95% CI)-12.8 [-16.93, -8.67]
Analysis 1.1.

Comparison 1 Oral zinc salt supplementation compared to placebo , Outcome 1 Incidence of hyperbilirubin a emia .

Analysis 1.2.

Comparison 1 Oral zinc salt supplementation compared to placebo , Outcome 2 Proportion of neonates receivin g phototherapy .

Analysis 1.3.

Comparison 1 Oral zinc salt supplementation compared to placebo , Outcome 3 Incidence of vomiting .

Analysis 1.4.

Comparison 1 Oral zinc salt supplementation compared to placebo , Outcome 4 Incidence of diarrhoea .

Analysis 1.5.

Comparison 1 Oral zinc salt supplementation compared to placebo , Outcome 5 Incidence of rash .

Analysis 1.6.

Comparison 1 Oral zinc salt supplementation compared to placebo , Outcome 6 Mean total serum bilirubin , mg/dL, at 72 ± 12 hours of age .

Analysis 1.7.

Comparison 1 Oral zinc salt supplementation compared to placebo , Outcome 7 Duration of phototherapy (hours) .

Contributions of authors

Satish Mishra: search, data extraction, data entry, data analysis, writing and editing of the review.

Aminderjit Cheema: search, data extraction, data entry, data analysis, writing and editing of the review.

Ramesh Agarwal: reviewed manuscript.

Ashok Deorari: reviewed manuscript.

Vinod Paul: reviewed manuscript.

Declarations of interest

No conflict of interest.

Sources of support

Internal sources

  • No source of support, India.

External sources

  • 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

Differences between protocol and review

None noted.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Rana 2011

MethodsRandomised, double blind, placebo-controlled trial.
ParticipantsA total of 294 at-risk neonates, neonates with STB levels ≥ 6 mg/dL at 24 ± 6 hours postpartum, (148 intervention, 146 placebo)
InterventionsZinc gluconate (10 mg/day) or placebo was provided in identical syrup form and administered in twice- daily doses from day 2 to day 7 postpartum. The drug was administered into the mouth of the infant by the plastic measure provided with the bottle or a spoon.
Outcomes

Primary outcome: Incidence of hyperbilirubinaemia (STB ≥15 mg/dl) anytime between 25 and 168 hours of age.

Secondary outcome:

  • Mean STB level at 72±12 hours of age;

  • Proportion of infants requiring phototherapy;

  • Duration of phototherapy.

NotesThe enrolled neonates were administered the intervention drug in a dose of 5 mL twice daily on day 2 to 7 of age. Intervention drug was either zinc gluconate, 5 mg/5 mL or identical placebo syrup provided in 60 mL bottles.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Random sequence were generated using permuted blocks of fixed size, 6 each, by a statistical package."
Allocation concealment (selection bias)Low risk"The randomisation and numbered packing of intervention drug (zinc or placebo) was prepared off site by a staff not involved in the study. The random sequences were kept in safe custody at two places by staff not involved in the study."
Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Zinc and placebo were identical in colour, taste, and appearance and packaged in similar looking bottles. The code was kept blinded from the participants, investigators, and the statistician until the analysis was completed."
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The code was kept blinded from the participants, investigators, and the statistician until the analysis was completed."
Incomplete outcome data (attrition bias)
All outcomes
Low riskIn view of lack of data on day seven of age for eight neonates, who were lost to follow up, 145 children in the zinc group and 141 in the placebo group were analysed for the primary outcome.
Selective reporting (reporting bias)Low riskAuthors have reported all the clinically relevant outcomes. Risk of bias due to selective reporting is unlikely. Study protocol is available from ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT00692224).
Other biasLow riskZinc and placebo bottles were provided by a pharmaceuticals company. However, authors have stated that they did not have any role in the design, conduct, analysis and reporting of the study.