Oral anti‐diabetic pharmacological therapies for the treatment of women with gestational diabetes

Julie Brown; Ruth Martis; Brenda Hughes; Janet Rowan; Caroline A Crowther

doi:10.1002/14651858.CD011967.pub2

Cochrane Database of Systematic Reviews

Tratamientos farmacológicos con antidiabéticos orales para el tratamiento de las pacientes con diabetes gestacional

Información

DOI:

https://doi.org/10.1002/14651858.CD011967.pub2 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

25 enero 2017see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Embarazo y parto

Copyright:

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Julie Brown

Correspondencia a: Liggins Institute, The University of Auckland, Auckland, New Zealand

[email protected]
Ruth Martis

Liggins Institute, The University of Auckland, Auckland, New Zealand
Brenda Hughes

Pharmacy, Auckland City Hospital, Auckland, New Zealand
Janet Rowan

National Women's Health, Auckland, New Zealand
Caroline A Crowther

Liggins Institute, The University of Auckland, Auckland, New Zealand

ARCH: Australian Research Centre for Health of Women and Babies, Robinson Research Institute, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Adelaide, Australia

Contributions of authors

Julie Brown guarantees this review.

Julie Brown wrote the first version of this protocol and review. She contributed to data extraction and data entry.

Ruth Martis has provided comments on drafts of this review.

Brenda Hughes has provided input from a pharmacological perspective on drafts of this review.

Janet Rowan has provided input from a clinical perspective on drafts of this review.

Caroline Crowther has provided clinical and methodological feedback on drafts of this review.

Sources of support

Internal sources

An internal University department grant, New Zealand.

An internal University of Auckland department grant from the Liggins Institute has been awarded to Julie Brown to help with the preparation of several Cochrane systematic reviews as part of an overview of systematic reviews for the treatment of women with gestational diabetes. This current protocol/review will be one of the included reviews.
Liggins Institute, New Zealand.

Support for infrastructure to support the preparation of this protocol is from the Liggins Institute, University of Auckland, New Zealand.

External sources

National Institute for Health Research (NIHR), UK.

NIHR Cochrane Programme Grant Project: 13/89/05 – Pregnancy and childbirth systematic reviews to support clinical guidelines

Declarations of interest

Julie Brown has received a NZD 15,000 internal University grant to assist with the preparation of a Cochrane overview of treatment for gestational diabetes. This is one of the reviews that has been supported. The funds have contributed to a research assistant's time. The funding body gains no financial interest from the publication of the review and has not influenced the content.

Ruth Martis: none known

Brenda Hughes: none known

Janet Rowan: none known

Caroline A Crowther: none known

Acknowledgements

We acknowledge the valuable contributions of Nisreen Alwan, Jane West and Derek Tuffnall who were the authors of the original review Treatments for gestational diabetes (Alwan 2009).

We acknowledge the contribution of Tineke Crawford who assisted in data extraction and data entry.

We acknowledge the contribution of the authors of the other two reviews that were split from this original review in the preparation of the core background sections of the new review protocols.

Lifestyle interventions for the treatment of women with gestational diabetes ‐ Julie Brown, Nisreen Alwan, Stephen Brown, Christopher McKinlay, Diane Farrar, Jane West, Caroline Crowther.

Insulin for the treatment of women with gestational diabetes ‐ Julie Brown, Luke Greskowiak, Michelle Downie, Kate Williamson, Caroline Crowther.

We acknowledge the support from the Cochrane Pregnancy and Childbirth editorial team in Liverpool, the Australian and New Zealand Satellite of Cochrane Pregnancy and Childbirth and the Liggins Institute, University of Auckland, New Zealand.

As part of the pre‐publication editorial process, this review has been commented on by four peers (an editor and three referees who are external to the editorial team) and the Group's Statistical Adviser.

This project was supported by the National Institute for Health Research, via Cochrane Infrastructure and Cochrane Programme Grant funding to Cochrane Pregnancy and Childbirth. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

Version history

Published

Title

Stage

Authors

Version

2017 Jan 25

Oral anti‐diabetic pharmacological therapies for the treatment of women with gestational diabetes

Review

Julie Brown, Ruth Martis, Brenda Hughes, Janet Rowan, Caroline A Crowther

https://doi.org/10.1002/14651858.CD011967.pub2

2015 Nov 24

Oral anti‐diabetic pharmacological therapies for the treatment of women with gestational diabetes

Protocol

Julie Brown, Ruth Martis, Brenda Hughes, Janet Rowan, Caroline A Crowther

https://doi.org/10.1002/14651858.CD011967

Differences between protocol and review

The following differences are noted between the published protocol and the full review.

Objectives

Review: To evaluate the effects of oral anti‐diabetic pharmacological therapies for treating women with GDM.
Protocol: To evaluate the effectiveness of oral agents in treating women with gestational diabetes for improving maternal and fetal health and well‐being.

Types of interventions

In this section we have clarified that the ‘anti‐diabetic agents’ are in fact pharmacological therapies.

Outcomes for use in GRADE/neonatal outcomes

We have edited ‘Neurosensory disability’ to ‘Neurosensory disability in later childhood’.

Notes

The original review, Alwan 2009 has been split into three new reviews due to the complexity of the included interventions. The following new reviews are underway.

Lifestyle interventions for the treatment of women with gestational diabetes mellitus (Brown 2015)
Oral anti‐diabetic pharmacological therapies for the treatment of women with gestational diabetes mellitus (this review)
Insulin for the treatment of women with gestational diabetes mellitus (Brown 2016)

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Female; Humans; Pregnancy;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram

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Figure 2

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

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

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Analysis 1.1

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 1 Hypertensive disorders of pregnancy.

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Analysis 1.2

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 2 Caesarean section.

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Analysis 1.3

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 3 Large‐for‐gestational age.

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Analysis 1.4

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 4 Use of additional pharmacotherapy.

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Analysis 1.5

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 5 Glycaemic control (end of treatment) (mg/dL).

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Analysis 1.6

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 6 Weight gain in pregnancy (Kg).

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Analysis 1.7

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 7 Induction of labour.

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Analysis 1.8

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 8 Perineal trauma.

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Analysis 1.9

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 9 Stillbirth.

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Analysis 1.10

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 10 Neonatal death.

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Analysis 1.11

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 11 Small‐for‐gestational age.

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Analysis 1.12

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 12 Macrosomia.

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Analysis 1.13

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 13 Birthweight (g).

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Analysis 1.14

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 14 Shoulder dystocia.

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$Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 15 Bone fracture.$

Analysis 1.15

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 15 Bone fracture.

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Analysis 1.16

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 16 Nerve palsy.

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Analysis 1.17

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 17 Gestational age at birth (weeks).

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Analysis 1.18

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 18 Neonatal hypoglycaemia.

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Analysis 1.19

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 19 Hyperbilirubinaemia.

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Analysis 1.20

Comparison 1 Oral anti‐diabetic agents versus placebo, Outcome 20 Admission to NICU.

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Analysis 2.1

Comparison 2 Metformin versus glibenclamide, Outcome 1 Hypertensive disorders of pregnancy.

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Analysis 2.2

Comparison 2 Metformin versus glibenclamide, Outcome 2 Caesarean section.

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Analysis 2.3

Comparison 2 Metformin versus glibenclamide, Outcome 3 Perinatal mortality.

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Analysis 2.4

Comparison 2 Metformin versus glibenclamide, Outcome 4 Large‐for‐gestational age.

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Analysis 2.5

Comparison 2 Metformin versus glibenclamide, Outcome 5 Death or serious morbidity composite.

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Analysis 2.6

Comparison 2 Metformin versus glibenclamide, Outcome 6 Use of additional pharmacotherapy.

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Analysis 2.7

Comparison 2 Metformin versus glibenclamide, Outcome 7 Maternal hypoglycaemia.

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Analysis 2.8

Comparison 2 Metformin versus glibenclamide, Outcome 8 Glycaemic control (mg/L; mmol/L).

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Analysis 2.9

Comparison 2 Metformin versus glibenclamide, Outcome 9 Weight gain in pregnancy (Kg).

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Analysis 2.10

Comparison 2 Metformin versus glibenclamide, Outcome 10 Induction of labour.

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Analysis 2.11

Comparison 2 Metformin versus glibenclamide, Outcome 11 Perineal trauma.

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Analysis 2.12

Comparison 2 Metformin versus glibenclamide, Outcome 12 Stillbirth.

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Analysis 2.13

Comparison 2 Metformin versus glibenclamide, Outcome 13 Macrosomia.

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Analysis 2.14

Comparison 2 Metformin versus glibenclamide, Outcome 14 Birth trauma.

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Analysis 2.15

Comparison 2 Metformin versus glibenclamide, Outcome 15 Shoulder dystocia.

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Analysis 2.16

Comparison 2 Metformin versus glibenclamide, Outcome 16 Gestational age at birth (weeks).

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Analysis 2.17

Comparison 2 Metformin versus glibenclamide, Outcome 17 Preterm birth.

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Analysis 2.18

Comparison 2 Metformin versus glibenclamide, Outcome 18 5‐minute Apgar < 7.

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Analysis 2.19

Comparison 2 Metformin versus glibenclamide, Outcome 19 Birthweight (g).

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Analysis 2.20

Comparison 2 Metformin versus glibenclamide, Outcome 20 Ponderal index.

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Analysis 2.21

Comparison 2 Metformin versus glibenclamide, Outcome 21 Neonatal hypoglycaemia.

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Analysis 2.22

Comparison 2 Metformin versus glibenclamide, Outcome 22 Respiratory distress syndrome.

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Analysis 2.23

Comparison 2 Metformin versus glibenclamide, Outcome 23 Hyperbilirubinaemia.

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Analysis 2.24

Comparison 2 Metformin versus glibenclamide, Outcome 24 Admission to NICU.

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Analysis 3.1

Comparison 3 Glibenclamide versus acarbose, Outcome 1 Caesarean section.

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Analysis 3.2

Comparison 3 Glibenclamide versus acarbose, Outcome 2 Perinatal mortality.

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Analysis 3.3

Comparison 3 Glibenclamide versus acarbose, Outcome 3 Large‐for‐gestational age.

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Analysis 3.4

Comparison 3 Glibenclamide versus acarbose, Outcome 4 Need for additional pharmacotherapy.

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Analysis 3.5

Comparison 3 Glibenclamide versus acarbose, Outcome 5 Maternal hypoglycaemia.

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Analysis 3.6

Comparison 3 Glibenclamide versus acarbose, Outcome 6 Weight gain in pregnancy (Kg).

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Analysis 3.7

Comparison 3 Glibenclamide versus acarbose, Outcome 7 Macrosomia.

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Analysis 3.8

Comparison 3 Glibenclamide versus acarbose, Outcome 8 Small‐for‐gestational age.

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Analysis 3.9

Comparison 3 Glibenclamide versus acarbose, Outcome 9 Birth trauma (not specified).

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Analysis 3.10

Comparison 3 Glibenclamide versus acarbose, Outcome 10 Gestational age at birth (weeks).

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Analysis 3.11

Comparison 3 Glibenclamide versus acarbose, Outcome 11 Preterm birth.

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Analysis 3.12

Comparison 3 Glibenclamide versus acarbose, Outcome 12 Birthweight (Kg).

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Analysis 3.13

Comparison 3 Glibenclamide versus acarbose, Outcome 13 Neonatal hypoglycaemia.

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Analysis 3.14

Comparison 3 Glibenclamide versus acarbose, Outcome 14 Respiratory distress syndrome.

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Summary of findings for the main comparison. Oral anti‐diabetic pharmacological therapies versus placebo ‐ maternal outcomes

Oral anti‐diabetic pharmacological therapies versus placebo ‐ maternal outcomes
Patient or population: women diagnosed with gestational diabetes; 24‐30 weeks' gestation; singleton pregnancy. Setting: Medical Centre, USA. Intervention: oral anti‐diabetic pharmacological therapy (glibenclamide) Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with placebo	Risk with oral anti‐diabetic pharmacological therapies	Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Hypertensive disorders of pregnancy ‐ (any type)	167 per 1000	207 per 1000 (135 to 317)	RR 1.24 (0.81 to 1.90)	375 (1 RCT)	⊕⊝⊝⊝ Very low^abc
Caearean section	360 per 1000	371 per 1000 (285 to 483)	RR 1.03 (0.79 to 1.34)	375 (1 RCT)	⊕⊝⊝⊝ Very low^abc
Development of type 2 diabetes ‐ not measured	see comment	see comment	not estimable	‐	‐	This was not a pre‐specified outcome for the included studies reporting on this comparison
Perineal trauma	5 per 1000	5 per 1000 (0 to 84)	RR 0.98 (0.06 to 15.62)	375 (1 RCT)	⊕⊝⊝⊝ Very low^abcd	Event rates were low 1/189 for anti‐diabetic pharmacological therapy and 1/186 in the control (placebo) group
Return to pre‐pregnancy weight ‐ not measured	see comment	see comment	not estimable	‐	‐	This was not a pre‐specified outcome for the included studies reporting on this comparison
Postnatal depression ‐ not measured	see comment	see comment	not estimable	‐	‐	This was not a pre‐specified outcome for the included studies reporting on this comparison
Induction of labour	188 per 1000	222 per 1000 (149 to 331)	RR 1.18 (0.79 to 1.76)	375 (1 RCT)	⊕⊝⊝⊝ Very low^abc
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^aRisk of bias ‐ we did not find a published protocol and there were more outcomes reported in the published paper than were listed in the trial registration document ‐ downgraded 1 level. ^bGeneralisability ‐ in this single study 93% of participants were Hispanic women. Results may not be generalisable to other populations ‐ downgraded 1 level. ^cImprecision ‐ evidence based on a single study ‐ downgraded 1 level. ^dImprecision ‐ wide confidence intervals crossing the line of no effect and low event rates suggestive of imprecision ‐ downgraded 1 level.

Summary of findings for the main comparison. Oral anti‐diabetic pharmacological therapies versus placebo ‐ maternal outcomes

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Summary of findings 2. Oral anti‐diabetic pharmacological therapies versus placebo ‐ neonatal outcomes

Oral anti‐diabetic pharmacological therapies versus placebo ‐ neonatal outcomes
Patient or population: infants of women diagnosed with gestational diabetes Setting: Medical Centre, USA Intervention: oral anti‐diabetic pharmacological therapies (glibenclamide) Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with placebo	Risk with oral anti‐diabetic pharmacological therapies	Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Large‐for‐gestational age	118 per 1000	105 per 1000 (60 to 187)	RR 0.89 (0.51 to 1.58)	375 (1 RCT)	⊕⊝⊝⊝ Very low^abc
Perinatal mortality	see comment	see comment	not estimable	‐	‐	None of the included studies pre‐specified this outcome
Death or serious morbidity composite ‐ not reported	see comment	see comment	not estimable	‐	‐	None of the included studies pre‐specified this outcome
Neonatal hypoglycaemia	11 per 1000	21 per 1000 (4 to 114)	RR 1.97 (0.36 to 10.62)	375 (1 RCT)	⊕⊝⊝⊝ Very low^abcd	Event rates were low with 4/189 for oral anti‐diabetic pharmacological therapy and 2/186 for placebo group
Adiposity (neonate, child, adult) ‐ not measured	see comment	see comment	not estimable	‐	‐	None of the included studies pre‐specified this outcome
Diabetes (child, adult) ‐ not measured	see comment	see comment	not estimable	‐	‐	None of the included studies pre‐specified this outcome
Neurosensory disability in later childhood ‐ not measured	see comment	see comment	not estimable	‐	‐	None of the included studies pre‐specified this outcome
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^aRisk of bias ‐ we did not find a published protocol and there were more outcomes reported in the published paper than were listed in the trial registration document ‐ downgraded 1 level. ^bThis single trial comprised 93% Hispanic women. The results may not be generalisable ‐ downgraded 1 level. ^cImprecision ‐ evidence was based on a single trial only ‐ downgraded 1 level. ^dImprecison ‐ wide confidence intervals crossing the line of no effect and low event rates ‐ downgraded 1 level.

Summary of findings 2. Oral anti‐diabetic pharmacological therapies versus placebo ‐ neonatal outcomes

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Summary of findings 3. Metformin versus glibenclamide ‐ maternal outcomes

Metformin versus glibenclamide ‐ maternal outcomes
Patient or population: women diagnosed with gestational diabetes Setting: trials conducted in Brazil, India and the USA Intervention: metformin Comparison: glibenclamide
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with glibenclamide	Risk with metformin	Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Hypertensive disorders of pregnancy	88 per 1000	62 per 1000 (33 to 114)	RR 0.70 (0.38 to 1.30)	508 (3 RCTs)	⊕⊕⊕⊝ Moderate^a
Caesarean section	392 per 1000	470 per 1000 (325 to 674)	RR 1.20 (0.83 to 1.72)	554 (4 RCTs)	⊕⊕⊝⊝ Low^bc
Development of type 2 diabetes ‐ not measured	see comment	see comment	not estimable	‐	‐	None of the included studies for this comparison had pre‐specified development of type 2 diabetes as an outcome
Perineal trauma	6 per 1000	11 per 1000 (1 to 81)	RR 1.67 (0.22 to 12.52)	308 (2 RCTs)	⊕⊕⊝⊝ Low^ad	Note low event rates (2/154 for metformin and 1/154 for glibenclamide
Return to pre‐pregnancy weight ‐ not measured	see comment	see comment	not estimable	‐	‐	None of the included studies for this comparison had return to pre‐pregnancy weight as a pre‐specified outcome
Postnatal depression ‐ not measured	see comment	see comment	not estimable	‐	‐	None of the included studies for this comparison had postnatal depression as a pre‐specified outcome
Induction of labour	613 per 1000	496 per 1000 (374 to 655)	RR 0.81 (0.61 to 1.07)	159 (1 RCT)	⊕⊕⊝⊝ Low^ae
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^aRisk of bias ‐ all studies were open label ‐ downgraded 1 level. ^bRisk of bias ‐ 3 of the 4 studies were open label and 3 of 4 studies were unclear for blinding of outcome assessors. 2 studies reported additional outcomes that were not pre‐specified ‐ downgraded 1 level. ^cInconsistency ‐ heterogeneity was high, I² = 61% downgraded 1 level. ^dImprecision ‐ wide confidence intervals along with low event rates suggest imprecision ‐ downgraded 1 level. ^eImprecision ‐ evidence was based on a single trial ‐ downgraded 1 level.

Summary of findings 3. Metformin versus glibenclamide ‐ maternal outcomes

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Summary of findings 4. Metformin versus glibenclamide ‐ neonatal outcomes

Metformin versus glibenclamide ‐ neonatal outcomes
Patient or population: Infants of women diagnosed with gestational diabetes Setting: trials conducted in Brazil, India and the USA Intervention: metformin Comparison: glibenclamide
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with glibenclamide	Risk with metformin	Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Large‐for‐gestational age	193 per 1000	129 per 1000 (46 to 354)	RR 0.67 (0.24 to 1.83)	246 (2 RCTs)	⊕⊕⊝⊝ Low^ab
Perinatal mortality	6 per 1000	5 per 1000 (0 to 83)	RR 0.92 (0.06 to 14.55)	359 (2 RCTs)	⊕⊝⊝⊝ Very low^c	Note that event rates were very low. 1 study had no event of perinatal death in either the metformin nor the glibenclamide group. The second study had 1 death in each group
Death or serious morbidity composite	350 per 1000	189 per 1000 (109 to 329)	RR 0.54 (0.31 to 0.94)	159 (1 RCT)	⊕⊕⊝⊝ Low^d
Neonatal hypoglycaemia	48 per 1000	41 per 1000 (20 to 84)	RR 0.86 (0.42 to 1.77)	554 (4 RCTs)	⊕⊕⊝⊝ Low^ae
Adiposity ‐ not measured	see comment	see comment	not estimable	‐	‐	None of the included trials for this comparison had pre‐specified adiposity as a trial outcome
Diabetes ‐ not measured	see comment	see comment	not estimable	‐	‐	None of the included trials for this comparison had pre‐specified diabetes as a trial outcome
Neurosensory disability in later childhood ‐ not measured	see comment	see comment	not estimable	‐	‐	None of the included trials for this comparison had pre‐specified neurosensory disability as a trial outcome
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^aRisk of bias ‐ allocation concealment was unclear in 1 study. 1 study was open label ‐ downgraded 1 level. ^bInconsistency ‐ heterogeneity was I²= 54%, which could not be explained by the diagnostic criteria used ‐ downgraded 1 level. ^cRisk of bias ‐ includes open label study/studies with no evidence of blinding of participants or researchers ‐ downgraded 1 level. ^dImprecision ‐ evidence based on a single small study ‐ downgraded 1 level. ^eImprecision ‐ event rates low (< 30) ‐ downgraded 1 level.

Summary of findings 4. Metformin versus glibenclamide ‐ neonatal outcomes

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Summary of findings 5. Glibenclamide versus acarbose ‐ maternal outcomes

Glibenclamide versus acarbose ‐ maternal outcomes
Patient or population: women diagnosed with gestational diabetes; 11 to 33 weeks' gestation; singleton pregnancy Setting: Maternity hospital, Brazil Intervention: Glibenclamide Comparison: Acarbose
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with acarbose	Risk with other oral anti‐diabetic agent	Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Hypertensive disorders of pregnancy ‐ not reported	see comment	see comment	not estimable	‐	‐	No data were reported for this outcome
Caesarean section	526 per 1000	500 per 1000 (279 to 895)	RR 0.95 (0.53 to 1.70)	43 (1 RCT)	⊕⊕⊝⊝ Low^ab
Development of type 2 diabetes ‐ not reported	see comment	see comment	not estimable	‐	‐	No data were reported for this outcome
Perineal trauma ‐ not reported	see comment	see comment	not estimable	‐	‐	No data were reported for this outcome
Return to pre‐pregnancy weight ‐ not reported	see comment	see comment	not estimable	‐	‐	No data were reported for this outcome
Postnatal depression ‐ not reported	see comment	see comment	not estimable	‐	‐	No data were reported for this outcome
Induction of labour ‐ not reported	see comment	see comment	not estimable	‐	‐	No data were reported for this outcome
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^aMethod of randomisation was unclear and the study was open‐label ‐ downgraded ‐1 level. ^bEvidence based on a single small study ‐ downgraded ‐1 level.

Summary of findings 5. Glibenclamide versus acarbose ‐ maternal outcomes

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Summary of findings 6. Glibenclamide versus acarbose ‐ neonatal outcomes

Glibenclamide versus acarbose ‐ neonatal outcomes
Patient or population: women with gestational diabetes Setting: maternity hospital, Brazil Intervention: glibenclamide Comparison: acarbose
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with acarbose	Risk with glibenclamide	Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Large‐for‐gestational age	105 per 1000	251 per 1000 (57 to 1000)	RR 2.38 (0.54 to 10.46)	43 (1 RCT)	⊕⊕⊝⊝ Low^ab
Perinatal mortality	see comment	see comment	not estimable	43 (1 RCT)	⊕⊕⊝⊝ Low^ab	No events were reported in either group
Death or serious morbidity composite ‐ not reported	see comment	see comment	not estimable	‐	‐	No data were reported for this outcome
Neonatal hypoglycaemia	53/1000	333/1000 (46 to 1000)	RR 6.33 (0.87 to 46.32)	43 (1 RCT)	⊕⊕⊝⊝ Low^ab	Low event rates and sample size (8/24 in glibenclamide group and 1/19 in acarbose group)
Adiposity ‐ not reported	see comment	see comment	not estimable	‐	‐	No data were reported for this outcome
Diabetes ‐ not reported	see comment	see comment	not estimable	‐	‐	No data were reported for this outcome
Neurosensory disability in later childhood ‐ not reported	see comment	see comment	not estimable	‐	‐	No data were reported for this outcome
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^aRisk of bias ‐ evidence of selective reporting ‐ downgraded 1 level. ^bImprecision ‐ evidence based on a single small study with wide confidence intervals ‐ downgraded 1 level.

Summary of findings 6. Glibenclamide versus acarbose ‐ neonatal outcomes

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Table 1. Examples of diagnostic criteria for gestational diabetes

Organisation/professional body	Screening and diagnostic criteria
	1‐hour oral glucose challenge test	Oral glucose tolerance test	Fasting	1 hour	2 hour	3 hour
ADA 2013^a, IADPSG 2010^a, ADIPS 2013 (Nankervis 2014)^a, WHO 2014^a	‐	75 g	≥ 5.1 mmol/L (≥ 92 mg/dL)	≥ 10 mmol/L (≥ 180 mg/dL)	≥ 8.5 mmol/L (≥ 153 mg/dL)	‐
ACOG 2013 Carpenter and Coustan^b National Diabetes Data Group^b	50 g (> 7.2 mmol/L; > 130 mg/dL)	100 g	≥ 5.3 mmol/L (≥ 95 mg/dL)	≥ 10 mmol/L (≥180 mg/dL)	≥ 8.6 mmol/L (≥ 155 mg/dL)	≥ 7.8 mmol/L (≥ 140 mg/dL)
	50 g (> 7.8 mmol/L; > 140 mg/dL)	100 g	≥ 5.8 mmol/L (≥ 105 mg/dL)	≥ 10.6 mmol/L (≥ 190 mg/dL)	≥ 9.2 mmol/L (≥ 165 mg/dL)	≥ 8.0 mmol/L (≥ 145 mg/dL)
Canadian Diabetes Association 2013 either^a or^b	50 g ‐	75 g 75 g	≥ 5.3 mmol/L (≥ 95 mg/dL) ≥ 5.1 mmol/L (≥ 92 mg/dL)	≥ 10.6 mmol/L (≥ 190 mg/dL) ≥ 10 mmol/L (≥ 180 mg/dL)	≥ 9.0 mmol/L ≥ 8.5 mmol/L (≥ 153 mg/dL)
NICE 2015	‐	75 g	≥ 5.6 mmol/L (≥ 101 mg/dL)	‐	≥ 7.8 mmol/L (≥ 140 mg/dL)	‐
NICE 2008; WHO 1999; Hoffman 1998 (ADIPS)^b	‐	75 g	≥ 7.0 mmol/L (≥ 126 mg/dL)	‐	≥ 11.1 mmol/L (≥ 200 mg/dL)	‐
New Zealand Ministry of Health 2014^a	50 g if HbA1c < 41 mmol/mol (≥ 7.8 mmol/L; ≥ 140 mg/dL)	75 g	≥ 5.5 mmol/L (≥ 99 mg/dL)	‐	≥ 9.0 mmol/L (≥ 162 mg/dL)	‐
ADA: American Diabetes Association IADPSG: International Association of the Diabetes and Pregnancy Study Groups ADIPS: Australasian Diabetes in Pregnancy Society ACOG: American College of Obstetrics and Gynecology NICE: National Institute for Health and Care Excellence ^a1 abnormal result required for diagnosis ^b2 or more abnormal results required for diagnosis

Table 1. Examples of diagnostic criteria for gestational diabetes

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Table 2. Mean maternal age (years) ± SD

Study ID	Intervention	Comparison
Bertini 2005	31.2 ± 4.5 (n = 24), glibenclamide	31.5 ± 5.8 (n = 19), acarbose
Casey 2015	31.3 ± 6, glibenclamide	31.2 ± 6, placebo
Cortez 2006	Not stated, acarbose	Not stated, placebo
De Bacco 2015	Not stated, glibenclamide	Not stated, metformin
Fenn 2015	Not stated, glibenclamide	Not stated, metformin
George 2015	33.4 ± 4.4 (n = 79), metformin	33.6 ± 4.6 (n = 80), glibenclamide
Moore 2010	31 ± 7.1 (n = 75) ‐ metformin	29.6 ± 7.8 (n = 74), glibenclamide
Myers 2014	Not stated, metformin	Not stated, standard care
Nachum 2015	Not stated, metformin	Not stated, glibenclamide
Notelovitz 1971	Chlopropramide 30.9 (n = 58) Tolbutamide 29.7 (n = 46)	Diet 32.7 (n = 56)
Silva 2012	32.6 ± 5.6 (n = 104), metformin	31.3 ± 5.4 (n = 96), glibenclamide

Table 2. Mean maternal age (years) ± SD

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Table 3. Maternal BMI kg/m2

Study ID	Intervention	Comparison	Timepoint BMI measured at
Bertini 2005	27.5 ± 5.8 (n = 24), glibenclamide	25.7 ± 4.2 (n = 19), acarbose	Not stated
Casey 2015	29.0 ± 4.8	28.9 ± 5.3	Pre‐pregnancy
Cortez 2006	Not stated	Not stated	Not stated
De Bacco 2015	Not stated	Not stated	Not stated
Fenn 2015	Not stated	Not stated	Not stated
George 2015	28.7 ± 4.4 (n = 79), metformin	28.8 ± 4.0 (n = 80), glibenclamide	Baseline
Moore 2010	32.8 ± 5.8 (n = 75), metformin	32.7 ± 7.0 (n = 74), glibenclamide	Not stated
Nachum 2015	Not stated	Not stated	Not stated
Notelovitz 1971	Not stated	Not stated	Not stated
Silva 2012	28.7 ± 5.4 (n = 104), metformin	28.6 ± 5.9 (n = 96), glibenclamide	Not stated

Table 3. Maternal BMI kg/m2

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Table 4. Gestational age at trial entry

Study ID	Intervention	Comparison
Bertini 2005	Not stated	Not stated
Casey 2015	26.0 ± 2.0, glibenclamide	26.0 ± 1.0, placebo
Cortez 2006	Not stated	Not stated
De Bacco 2015	Not stated	Not stated
Fenn 2015	Not stated	Not stated
George 2015	29.3 ± 3.3 weeks' (n = 79), metformin	29.7 ± 3.7 weeks' (n = 80)
Moore 2010	27.3 ± 6.8 weeks' (n = 75), metformin	29.1 ± 5.0 weeks' (n = 74), glibenclamide
Myers 2014	Not stated	Not stated
Nachum 2015	Not stated	Not stated
Notelovitz 1971	Not stated	Not stated
Silva 2012	27.0 ± 6.4 weeks' (n = 104), metformin	25.4 ± 7.1 weeks' (n = 96), glibenclamide

Table 4. Gestational age at trial entry

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Table 5. Diagnostic criteria

Study ID	Timing	Screening	Diagnosis	Criteria
Casey 2015	24‐28 weeks'	1 hour, 50 g OGCT(≥ 7.8 mmol/L; 140 mg/dL)	2 abnormal values 3 hour, 100 g OGTT Fasting < 5.8 mmol/L (105 mg/dL) 1‐hour ≥ 10.6 mmol/L (190 mg/dL) 2‐hour ≥ 9.2 mmol/L (165 mg/dL) 3‐hour ≥ 8.1 mmol/L (145 mg/dL)	National Diabetes Data Group
Bertini 2005	11‐33 weeks'	Not stated	75 g OGTT Fasting ≥ 6.1 mmol/L (110 mg/dL); 2‐hour value ≥ 7.8 mmol/L (140 mg/dL).	WHO criteria (old)
Cortez 2006	12‐34 weeks'	Not stated	Not stated	Not stated
De Bacco 2015	Not stated	Not stated	Not stated	WHO criteria but not stated if 1999 or 2015
Fenn 2015	‐	1 hour 50 g OGCT (≥ 7.8 mmol/L; 140 mg/dL)	2 abnormal values 100 g OGTT: fasting glucose ≥ 5.3 mmol/L, 1‐hour ≥ 10 mmol/L, 2‐hour ≥ 8.6 mmol/L, 3‐hour ≥ 7.8 mmol/L	Carpenter and Coustan
George 2015	24‐28 weeks'	Not stated	2 abnormal values 100 g OGTT: fasting glucose ≥ 5.3 mmol/L, 1‐hour ≥ 10 mmol/L, 2‐hour ≥ 8.6 mmol/L, 3‐hour ≥ 7.8 mmol/L	National Diabetes Data Group (1979)
Moore 2010	11‐33 weeks'	1 hour 50 g OGCT (≥ 7.2 mmol/L; 130 mg/dL)	3 hour 100 g OGTT using criteria with 2 or more abnormal results.	Carpenter and Coustan
Myers 2014	Not stated	Not stated	Fasting blood glucose 5.1 to 5.4 mmol/L, 2 hour < 8.5 mmol/L	Not stated
Nachum 2015	11‐33 weeks'	1 hour 50 g OGCT (≥ 7.2 mmol/L; 130 mg/dL)	3 hour 100 g OGTT using criteria with 2 or more abnormal results.	Carpenter and Coustan
Notelovitz 1971	Not stated	Not stated	Not stated	Not stated
Silva 2012	Not stated	Not stated	Not stated	WHO criteria (1999)
OGCT oral glucose tolerance test; OGTT oral glucose tolerance test

Table 5. Diagnostic criteria

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Table 6. Treatment target

Study ID	Fasting	1‐hour post‐prandial	2‐hour post‐prandial
Casey 2015	< 5.3 mmol/L (95mg/dL)	‐	< 6.7mmol/L (120 mg/dL)
Bertini 2005	< 5.0 mmol/L (90 mg/dL)	‐	< 5.5 mmol/L (100 mg/dL)
Cortez 2006	< 5.3 mmol/L (95 mg/dL)	< 7.5 mmol/L (135 mg/dL)	‐
De Bacco 2015	Not stated	Not stated	Not stated
Fenn 2015	< 5.3 mmol/L (95 mg/dL)	< 7.8 mmol/L (140 mg/dL)	‐
George 2015	≤ 5.3 mmol/L (95 mg/dL)	‐	≤ 6.7 mmol/L (120 mg/dL)
Moore 2010	< 5.8 mmol/L (105 mg/dL)	‐	< 6.7 mmol/L (120 mg/dL)
Myers 2014	Not stated	Not stated	Not stated
Nachum 2015	≤ 5.3 mmol/L (95 mg/dL)	90 minutes < 7.2 mmol/L (130 mg/dL)	‐
Notelovitz 1971	‐	8.3 mmol/L* (150 mg/dL)	‐
Silva 2012	5.0 mmol/L (90 mg/dL)	< 6.7 mmol/L (120 mg/dL)	‐
Post‐prandial timing not specified

Table 6. Treatment target

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Comparison 1. Oral anti‐diabetic agents versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Hypertensive disorders of pregnancy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Hypertensive disorders of pregnancy (any type)	1	375	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.81, 1.90]
1.2 Pregnancy‐induced hypertension	1	375	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.71, 2.19]
1.3 Pre‐eclampsia	1	375	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.59, 2.56]
2 Caesarean section Show forest plot	1	375	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.79, 1.34]

3 Large‐for‐gestational age Show forest plot	1	375	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.51, 1.58]

4 Use of additional pharmacotherapy Show forest plot	2	434	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.42, 1.11]

4.1 Placebo	2	434	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.42, 1.11]
5 Glycaemic control (end of treatment) (mg/dL) Show forest plot	1	375	Mean Difference (IV, Fixed, 95% CI)	‐3.0 [‐5.13, ‐0.87]

6 Weight gain in pregnancy (Kg) Show forest plot	1	375	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.96, 0.96]

7 Induction of labour Show forest plot	1	375	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.79, 1.76]

8 Perineal trauma Show forest plot	1	375	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.06, 15.62]

9 Stillbirth Show forest plot	1	375	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.05, 5.38]

10 Neonatal death Show forest plot	1	375	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

11 Small‐for‐gestational age Show forest plot	1	375	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.58, 2.10]

12 Macrosomia Show forest plot	1	375	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.36, 1.41]

13 Birthweight (g) Show forest plot	1	375	Mean Difference (IV, Fixed, 95% CI)	‐33.0 [‐134.53, 68.53]

14 Shoulder dystocia Show forest plot	1	375	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.00]

15 Bone fracture Show forest plot	1	375	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.17, 3.25]

16 Nerve palsy Show forest plot	1	375	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.00]

17 Gestational age at birth (weeks) Show forest plot	1	375	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.32, 0.32]

18 Neonatal hypoglycaemia Show forest plot	1	375	Risk Ratio (M‐H, Fixed, 95% CI)	1.97 [0.36, 10.62]

19 Hyperbilirubinaemia Show forest plot	1	375	Risk Ratio (M‐H, Fixed, 95% CI)	1.97 [0.50, 7.75]

20 Admission to NICU Show forest plot	1	375	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.53, 2.53]

Comparison 1. Oral anti‐diabetic agents versus placebo

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Comparison 2. Metformin versus glibenclamide

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Hypertensive disorders of pregnancy Show forest plot	3	508	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.38, 1.30]

1.1 Pre‐eclampsia	1	149	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.11, 3.82]
1.2 Pregnancy‐induced hypertension	2	359	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.37, 1.37]
2 Caesarean section Show forest plot	4	554	Risk Ratio (M‐H, Random, 95% CI)	1.20 [0.83, 1.72]

2.1 Carpenter and Coustan criteria	2	195	Risk Ratio (M‐H, Random, 95% CI)	2.36 [0.53, 10.52]
2.2 National Diabetes Data Group criteria	1	159	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.75, 1.68]
2.3 World Health Organization (1999)	1	200	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.78, 1.15]
3 Perinatal mortality Show forest plot	2	359	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.06, 14.55]

4 Large‐for‐gestational age Show forest plot	2	246	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.24, 1.83]

4.1 Carpenter and Coustan criteria	1	46	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.38, 4.07]
4.2 World Health Organization (1999)	1	200	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.21, 0.92]
5 Death or serious morbidity composite Show forest plot	1	159	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.31, 0.94]

6 Use of additional pharmacotherapy Show forest plot	5	660	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.28, 1.57]

7 Maternal hypoglycaemia Show forest plot	3	354	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.36, 2.19]

8 Glycaemic control (mg/L; mmol/L) Show forest plot	3		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only

8.1 Fasting blood glucose	3	508	Std. Mean Difference (IV, Fixed, 95% CI)	0.19 [0.02, 0.37]
8.2 Postprandial blood glucose	3	508	Std. Mean Difference (IV, Fixed, 95% CI)	0.16 [‐0.01, 0.34]
8.3 HbA1c	1	200	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.39, 0.16]
9 Weight gain in pregnancy (Kg) Show forest plot	1	200	Mean Difference (IV, Fixed, 95% CI)	‐2.06 [‐3.98, ‐0.14]

10 Induction of labour Show forest plot	1	159	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.61, 1.07]

11 Perineal trauma Show forest plot	2	308	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [0.22, 12.52]

12 Stillbirth Show forest plot	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.06, 14.55]

13 Macrosomia Show forest plot	2	308	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.23, 2.21]

14 Birth trauma Show forest plot	1	159	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

15 Shoulder dystocia Show forest plot	2	195	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.14, 6.89]

16 Gestational age at birth (weeks) Show forest plot	3	508	Mean Difference (IV, Fixed, 95% CI)	0.03 [‐0.22, 0.28]

17 Preterm birth Show forest plot	3	508	Risk Ratio (M‐H, Fixed, 95% CI)	1.59 [0.59, 4.29]

18 5‐minute Apgar < 7 Show forest plot	1	149	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

19 Birthweight (g) Show forest plot	2	349	Mean Difference (IV, Fixed, 95% CI)	‐209.13 [‐314.53, ‐103.73]

20 Ponderal index Show forest plot	1	200	Mean Difference (IV, Fixed, 95% CI)	‐0.09 [‐0.17, ‐0.01]

21 Neonatal hypoglycaemia Show forest plot	4	554	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.42, 1.77]

22 Respiratory distress syndrome Show forest plot	1	159	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.10, 2.69]

23 Hyperbilirubinaemia Show forest plot	2	205	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.37, 1.25]

24 Admission to NICU Show forest plot	2	349	Risk Ratio (M‐H, Fixed, 95% CI)	1.52 [0.65, 3.56]

Comparison 2. Metformin versus glibenclamide

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Comparison 3. Glibenclamide versus acarbose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Caesarean section Show forest plot	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.53, 1.70]

2 Perinatal mortality Show forest plot	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

3 Large‐for‐gestational age Show forest plot	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	2.38 [0.54, 10.46]

4 Need for additional pharmacotherapy Show forest plot	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.19, 1.27]

5 Maternal hypoglycaemia Show forest plot	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

6 Weight gain in pregnancy (Kg) Show forest plot	1	43	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐3.13, 1.93]

7 Macrosomia Show forest plot	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	7.20 [0.41, 125.97]

8 Small‐for‐gestational age Show forest plot	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

9 Birth trauma (not specified) Show forest plot	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

10 Gestational age at birth (weeks) Show forest plot	1	43	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.82, 0.62]

11 Preterm birth Show forest plot	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

12 Birthweight (Kg) Show forest plot	1	43	Mean Difference (IV, Fixed, 95% CI)	153.0 [‐123.52, 429.52]

13 Neonatal hypoglycaemia Show forest plot	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	6.33 [0.87, 46.32]

14 Respiratory distress syndrome Show forest plot	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 3. Glibenclamide versus acarbose

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