Oral anti-diabetic pharmacological therapies for the ...

Cochrane Database of Systematic Reviews

Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes (Review) Brown J, Martis R, Hughes B, Rowan J, Crowther CA

Brown J, Martis R, Hughes B, Rowan J, Crowther CA. Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD011967. DOI: 10.1002/14651858.CD011967.pub2.

www.cochranelibrary.com

Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes (Review) Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 1 Hypertensive disorders of pregnancy. Analysis 1.2. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 2 Caesarean section. . . . . . . Analysis 1.3. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 3 Large-for-gestational age. . . . . Analysis 1.4. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 4 Use of additional pharmacotherapy. Analysis 1.5. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 5 Glycaemic control (end of treatment) (mg/dL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.6. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 6 Weight gain in pregnancy (Kg). . Analysis 1.7. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 7 Induction of labour. . . . . . Analysis 1.8. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 8 Perineal trauma. . . . . . . . Analysis 1.9. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 9 Stillbirth. . . . . . . . . . Analysis 1.10. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 10 Neonatal death. . . . . . . Analysis 1.11. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 11 Small-for-gestational age. . . . Analysis 1.12. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 12 Macrosomia. . . . . . . . Analysis 1.13. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 13 Birthweight (g). . . . . . . Analysis 1.14. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 14 Shoulder dystocia. . . . . . Analysis 1.15. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 15 Bone fracture. . . . . . . . Analysis 1.16. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 16 Nerve palsy. . . . . . . . Analysis 1.17. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 17 Gestational age at birth (weeks). Analysis 1.18. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 18 Neonatal hypoglycaemia. . . . Analysis 1.19. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 19 Hyperbilirubinaemia. . . . . Analysis 1.20. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 20 Admission to NICU. . . . . Analysis 2.1. Comparison 2 Metformin versus glibenclamide, Outcome 1 Hypertensive disorders of pregnancy. . . Analysis 2.2. Comparison 2 Metformin versus glibenclamide, Outcome 2 Caesarean section. . . . . . . . . . Analysis 2.3. Comparison 2 Metformin versus glibenclamide, Outcome 3 Perinatal mortality. . . . . . . . . Analysis 2.4. Comparison 2 Metformin versus glibenclamide, Outcome 4 Large-for-gestational age. . . . . . . Analysis 2.5. Comparison 2 Metformin versus glibenclamide, Outcome 5 Death or serious morbidity composite. . . Analysis 2.6. Comparison 2 Metformin versus glibenclamide, Outcome 6 Use of additional pharmacotherapy. . . . Analysis 2.7. Comparison 2 Metformin versus glibenclamide, Outcome 7 Maternal hypoglycaemia. . . . . . . Analysis 2.8. Comparison 2 Metformin versus glibenclamide, Outcome 8 Glycaemic control (mg/L; mmol/L). . . Analysis 2.9. Comparison 2 Metformin versus glibenclamide, Outcome 9 Weight gain in pregnancy (Kg). . . . . Analysis 2.10. Comparison 2 Metformin versus glibenclamide, Outcome 10 Induction of labour. . . . . . . . Analysis 2.11. Comparison 2 Metformin versus glibenclamide, Outcome 11 Perineal trauma. . . . . . . . . Analysis 2.12. Comparison 2 Metformin versus glibenclamide, Outcome 12 Stillbirth. . . . . . . . . . . . Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes (Review) Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

1 1 3 4 6 9 9 12 16 18 19 30 41 42 42 43 48 66 68 69 70 70 71 72 72 73 73 74 74 75 75 76 76 77 77 78 78 79 80 81 82 83 84 85 86 87 88 88 89 89 i

Analysis 2.13. Comparison 2 Metformin versus glibenclamide, Outcome 13 Macrosomia. . . . . . . . Analysis 2.14. Comparison 2 Metformin versus glibenclamide, Outcome 14 Birth trauma. . . . . . . Analysis 2.15. Comparison 2 Metformin versus glibenclamide, Outcome 15 Shoulder dystocia. . . . . . Analysis 2.16. Comparison 2 Metformin versus glibenclamide, Outcome 16 Gestational age at birth (weeks). Analysis 2.17. Comparison 2 Metformin versus glibenclamide, Outcome 17 Preterm birth. . . . . . . Analysis 2.18. Comparison 2 Metformin versus glibenclamide, Outcome 18 5-minute Apgar < 7. . . . . Analysis 2.19. Comparison 2 Metformin versus glibenclamide, Outcome 19 Birthweight (g). . . . . . . Analysis 2.20. Comparison 2 Metformin versus glibenclamide, Outcome 20 Ponderal index. . . . . . . Analysis 2.21. Comparison 2 Metformin versus glibenclamide, Outcome 21 Neonatal hypoglycaemia. . . Analysis 2.22. Comparison 2 Metformin versus glibenclamide, Outcome 22 Respiratory distress syndrome. . Analysis 2.23. Comparison 2 Metformin versus glibenclamide, Outcome 23 Hyperbilirubinaemia. . . . . Analysis 2.24. Comparison 2 Metformin versus glibenclamide, Outcome 24 Admission to NICU. . . . . Analysis 3.1. Comparison 3 Glibenclamide versus acarbose, Outcome 1 Caesarean section. . . . . . . Analysis 3.2. Comparison 3 Glibenclamide versus acarbose, Outcome 2 Perinatal mortality. . . . . . . Analysis 3.3. Comparison 3 Glibenclamide versus acarbose, Outcome 3 Large-for-gestational age. . . . . Analysis 3.4. Comparison 3 Glibenclamide versus acarbose, Outcome 4 Need for additional pharmacotherapy. Analysis 3.5. Comparison 3 Glibenclamide versus acarbose, Outcome 5 Maternal hypoglycaemia. . . . . Analysis 3.6. Comparison 3 Glibenclamide versus acarbose, Outcome 6 Weight gain in pregnancy (Kg). . . Analysis 3.7. Comparison 3 Glibenclamide versus acarbose, Outcome 7 Macrosomia. . . . . . . . . Analysis 3.8. Comparison 3 Glibenclamide versus acarbose, Outcome 8 Small-for-gestational age. . . . . Analysis 3.9. Comparison 3 Glibenclamide versus acarbose, Outcome 9 Birth trauma (not specified). . . . Analysis 3.10. Comparison 3 Glibenclamide versus acarbose, Outcome 10 Gestational age at birth (weeks). . Analysis 3.11. Comparison 3 Glibenclamide versus acarbose, Outcome 11 Preterm birth. . . . . . . . Analysis 3.12. Comparison 3 Glibenclamide versus acarbose, Outcome 12 Birthweight (Kg). . . . . . . Analysis 3.13. Comparison 3 Glibenclamide versus acarbose, Outcome 13 Neonatal hypoglycaemia. . . . Analysis 3.14. Comparison 3 Glibenclamide versus acarbose, Outcome 14 Respiratory distress syndrome. . ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

90 90 91 91 92 93 93 94 94 95 96 96 97 97 98 98 99 99 100 100 101 101 102 102 103 103 103 108 109 109 109 110 110

ii

[Intervention Review]

Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes Julie Brown1 , Ruth Martis1 , Brenda Hughes2 , Janet Rowan3 , Caroline A Crowther1,4 1 Liggins

Institute, The University of Auckland, Auckland, New Zealand. 2 Pharmacy, Auckland City Hospital, Auckland, New Zealand. Women’s Health, Auckland, New Zealand. 4 ARCH: Australian Research Centre for Health of Women and Babies, Robinson Research Institute, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Adelaide, Australia

3 National

Contact address: Julie Brown, Liggins Institute, The University of Auckland, Park Rd, Grafton, Auckland, 1142, New Zealand. [email protected]. Editorial group: Cochrane Pregnancy and Childbirth Group. Publication status and date: New, published in Issue 1, 2017. Review content assessed as up-to-date: 14 May 2016. Citation: Brown J, Martis R, Hughes B, Rowan J, Crowther CA. Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD011967. DOI: 10.1002/14651858.CD011967.pub2. Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Gestational diabetes mellitus (GDM) is a major public health issue with rates increasing globally. Gestational diabetes, glucose intolerance first recognised during pregnancy, usually resolves after birth and is associated with short- and long-term complications for the mother and her infant. Treatment options can include oral anti-diabetic pharmacological therapies. Objectives To evaluate the effects of oral anti-diabetic pharmacological therapies for treating women with GDM. Search methods We searched Cochrane Pregnancy and Childbirth’s Trials Register (14 May 2016), ClinicalTrials.gov, WHO ICTRP (14 May 2016) and reference lists of retrieved studies. Selection criteria We included published and unpublished randomised controlled trials assessing the effects of oral anti-diabetic pharmacological therapies for treating pregnant women with GDM. We included studies comparing oral anti-diabetic pharmacological therapies with 1) placebo/ standard care, 2) another oral anti-diabetic pharmacological therapy, 3) combined oral anti-diabetic pharmacological therapies. Trials using insulin as the comparator were excluded as they are the subject of a separate Cochrane systematic review. Women with pre-existing type 1 or type 2 diabetes were excluded. Data collection and analysis Two review authors independently assessed trials for inclusion and trial quality. Two review authors independently extracted data and data were checked for accuracy. Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes (Review) Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

1

Main results We included 11 studies (19 publications) (1487 women and their babies). Eight studies had data that could be included in meta-analyses. Studies were conducted in Brazil, India, Israel, UK, South Africa and USA. The studies varied in diagnostic criteria and treatment targets for glycaemic control for GDM. The overall risk of bias was ’unclear’ due to inadequate reporting of methodology. Using GRADE the quality of the evidence ranged from moderate to very low quality. Evidence was downgraded for risk of bias (reporting bias, lack of blinding), inconsistency, indirectness, imprecision and for oral anti-diabetic therapy versus placebo for generalisability. Oral anti-diabetic pharmacological therapies versus placebo/standard care There was no evidence of a difference between glibenclamide and placebo groups for hypertensive disorders of pregnancy (risk ratio (RR) 1.24, 95% confidence interval (CI) 0.81 to 1.90; one study, 375 women, very low-quality evidence), birth by caesarean section (RR 1.03, 95% CI 0.79 to 1.34; one study, 375 women, very low-quality evidence), perineal trauma (RR 0.98, 95% CI 0.06 to 15.62; one study, 375 women, very low-quality evidence) or induction of labour (RR 1.18, 95% CI 0.79 to 1.76; one study, 375 women; very low-quality evidence). No data were reported for development of type 2 diabetes or other pre-specified GRADE maternal outcomes (return to pre-pregnancy weight, postnatal depression). For the infant, there was no evidence of a difference in the risk of being born large-for-gestational age (LGA) between infants whose mothers had been treated with glibenclamide and those in the placebo group (RR 0.89, 95% CI 0.51 to 1.58; one study, 375, low-quality evidence). No data were reported for other infant primary or GRADE outcomes (perinatal mortality, death or serious morbidity composite, neurosensory disability in later childhood, neonatal hypoglycaemia, adiposity, diabetes). Metformin versus glibenclamide There was no evidence of a difference between metformin- and glibenclamide-treated groups for the risk of hypertensive disorders of pregnancy (RR 0.70, 95% CI 0.38 to 1.30; three studies, 508 women, moderate-quality evidence), birth by caesarean section (average RR 1.20, 95% CI 1.20; 95% CI 0.83 to 1.72, four studies, 554 women, I2 = 61%, Tau2 = 0.07 low-quality evidence), induction of labour (0.81, 95% CI 0.61 to 1.07; one study, 159 women; low-quality evidence) or perineal trauma (RR 1.67, 95% CI 0.22 to 12.52; two studies, 158 women; low-quality evidence). No data were reported for development of type 2 diabetes or other prespecified GRADE maternal outcomes (return to pre-pregnancy weight, postnatal depression). For the infant there was no evidence of a difference between the metformin- and glibenclamide-exposed groups for the risk of being born LGA (average RR 0.67, 95% CI 0.24 to 1.83; two studies, 246 infants, I2 = 54%, Tau2 = 0.30 low-quality evidence). Metformin was associated with a decrease in a death or serious morbidity composite (RR 0.54, 95% CI 0.31 to 0.94; one study, 159 infants, low-quality evidence). There was no clear difference between groups for neonatal hypoglycaemia (RR 0.86, 95% CI 0.42 to 1.77; four studies, 554 infants, low-quality evidence) or perinatal mortality (RR 0.92, 95% CI 0.06 to 14.55, two studies, 359 infants). No data were reported for neurosensory disability in later childhood or for adiposity or diabetes. Glibenclamide versus acarbose There was no evidence of a difference between glibenclamide and acarbose from one study (43 women) for any of their maternal or infant primary outcomes (caesarean section, RR 0.95, 95% CI 0.53 to 1.70; low-quality evidence; perinatal mortality - no events; low-quality evidence; LGA , RR 2.38, 95% CI 0.54 to 10.46; low-quality evidence). There was no evidence of a difference between glibenclamide and acarbose for neonatal hypoglycaemia (RR 6.33, 95% CI 0.87 to 46.32; low-quality evidence). There were no data reported for other pre-specified GRADE or primary maternal outcomes (hypertensive disorders of pregnancy, development of type 2 diabetes, perineal trauma, return to pre-pregnancy weight, postnatal depression, induction of labour) or neonatal outcomes (death or serious morbidity composite, adiposity or diabetes). Authors’ conclusions There were insufficient data comparing oral anti-diabetic pharmacological therapies with placebo/standard care (lifestyle advice) to inform clinical practice. There was insufficient high-quality evidence to be able to draw any meaningful conclusions as to the benefits of one oral anti-diabetic pharmacological therapy over another due to limited reporting of data for the primary and secondary outcomes in this review. Short- and long-term clinical outcomes for this review were inadequately reported or not reported. Current choice of oral anti-diabetic pharmacological therapy appears to be based on clinical preference, availability and national clinical practice guidelines. The benefits and potential harms of one oral anti-diabetic pharmacological therapy compared with another, or compared with placebo/ standard care remains unclear and requires further research. Future trials should attempt to report on the core outcomes suggested in this review, in particular long-term outcomes for the woman and the infant that have been poorly reported to date, women’s experiences and cost benefit. Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes (Review) Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

2

PLAIN LANGUAGE SUMMARY Oral medication for the treatment of women with gestational diabetes What is the issue? Globally the number of women being diagnosed with gestational diabetes mellitus (GDM) is increasing. GDM is an intolerance to glucose leading to high blood sugars, first recognised during pregnancy and usually resolving after birth. Standard care involves lifestyle advice on diet and exercise. Treatment for some women includes oral anti-diabetic medications, such as metformin and glibenclamide, which are an alternative to, or can be used alongside, insulin to control the blood sugar. This review aimed to investigate benefits of taking oral medication to treat GDM in pregnant women. Another Cochrane Review compares the effects of insulin with oral antidiabetic pharmacological therapies (Brown 2016). Why is this important? Women diagnosed with GDM are at a greater risk of experiencing complications such as high blood pressure during pregnancy and at birth. They have an increased risk of developing diabetes later in life. The babies of women who have been diagnosed with GDM can be larger than normal and this can cause injuries to the mother and the baby at birth. The birth is more likely to be induced or the baby born by caesarean section. These babies are at risk of developing diabetes as children or young adults. Finding the best medications to treat the women and prevent the complications that are linked to GDM is therefore important. What evidence did we find? We searched for studies on 14 May 2016. We included 11 randomised controlled trials involving 1487 mothers and their babies (but only eight trials contributed data to our analyses). The evidence was limited by the quality and number of studies and we advise caution when looking at the results. The criteria for diagnosis of GDM and treatment targets varied between studies, and each outcome is based on few studies with low numbers of women. Three studies compared oral medication with placebo/standard care but the following findings are from a single study (375 women). The quality of the evidence was very low or low. We found no differences between the oral medication and placebo group for the risk of high blood pressure, birth by caesarean section, induction of labour or perineal trauma. The number of babies born large-for-gestational age, with low blood sugars or dying at birth was not clearly different between the groups. Two studies (434 women) reported no difference in the need for insulin between the oral medication and placebo group. Six studies compared metformin with glibenclamide. The quality of the evidence was very low to moderate. We found no difference between metformin and glibenclamide for the risk of high blood pressure (three studies, 508 women, moderate-quality evidence), birth by caesarean section (four studies, 554 women, low-quality evidence), perineal trauma (two studies, 308 women, low-quality evidence) or induction of labour (one study, 159 women, low-quality evidence). We found no difference between metformin and glibenclamide for the baby having low blood sugars (four studies, 554 infants, low-quality evidence), being born large-for-gestational age (two studies, 246 infants) or dying at birth (all low- or very low-quality evidence). In one study, the babies of the mothers taking metformin were at reduced risk of having any serious outcome (low blood sugar, jaundice, being born large, breathing problems, injury at birth or death combined) (low-quality evidence). One small study (43 women) comparing glibenclamide with acarbose reported no differences in outcomes for mothers or their babies. None of the included studies provided any data on many of the outcomes pre-specified in this review, including long-term outcomes for the mother or for the baby as a child or an adult. What does this mean? There is not enough high-quality evidence available to guide us on if oral medication has better outcomes for women with gestational diabetes, and their babies, compared with a placebo or if one oral medication has better health outcomes than another oral medication. Because we are still unclear, further research is needed. Future studies should be encouraged to report on the outcomes suggested in this review and in particular the long-term outcomes for the woman and the infant that have been poorly reported to date.


3


S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Oral anti-diabetic pharm acological therapies versus placebo - m aternal outcom es Patient or population: wom en diagnosed with gestational diabetes; 24-30 weeks’ gestation; singleton pregnancy Setting: M edical Centre, USA. Intervention: oral anti-diabetic pharm acological therapy (glibenclam ide) Comparison: placebo Outcomes

Anticipated absolute effects∗ (95% CI)

Risk with placebo

Relative effect (95% CI)

of participants (studies)

Quality of the evidence Comments (GRADE)

Risk with oral anti- diabetic pharmacological therapies

Hypertensive disorders 167 per 1000 of pregnancy - (any type)

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

Developm ent of type see com m ent 2 diabetes - not m easured

see com m ent

not estim able

-

-

This was not a prespecif ied outcom e f or the included studies reporting on this com parison

Perineal traum a

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 f or anti-diabetic pharm acological therapy and 1/ 186 in the control (placebo) group

5 per 1000

4


Return to pre-preg- see com m ent nancy weight - not m easured

see com m ent

not estim able

-

-


Postnatal depression - see com m ent not m easured

see com m ent

not estim able

-

-


Induction of labour

222 per 1000 (149 to 331)

RR 1.18 (0.79 to 1.76)

375 (1 RCT)

⊕

Very low abc

188 per 1000

* The risk in the intervention group (and its 95% conf idence interval) is based on the assum ed risk in the com parison group and the relative effect of the intervention (and its 95% CI). CI: conf idence interval; RCT: random ised controlled trial; RR: risk ratio; OR: odds ratio GRADE Working Group grades of evidence High quality: We are very conf ident that the true ef f ect lies close to that of the estim ate of the ef f ect M oderate quality: We are m oderately conf ident in the ef f ect estim ate: The true ef f ect is likely to be close to the estim ate of the ef f ect, but there is a possibility that it is substantially dif f erent Low quality: Our conf idence in the ef f ect estim ate is lim ited: The true ef f ect m ay be substantially dif f erent f rom the estim ate of the ef f ect Very low quality: We have very little conf idence in the ef f ect estim ate: The true ef f ect is likely to be substantially dif f erent f rom the estim ate of ef f ect a Risk

of bias - we did not f ind a published protocol and there were m ore outcom es reported in the published paper than were listed in the trial registration docum ent - downgraded 1 level. b Generalisability - in this single study 93% of participants were Hispanic wom en. Results m ay not be generalisable to other populations - downgraded 1 level. c Im precision - evidence based on a single study - downgraded 1 level. d Im precision - wide conf idence intervals crossing the line of no ef f ect and low event rates suggestive of im precision downgraded 1 level.

5

BACKGROUND The original review by Alwan and colleagues, Treatments for gestational diabetes (Alwan 2009) has been split into three new review titles reflecting the complexity of treating women with gestational diabetes.

2006), maternal overweight (body mass index (BMI) equal to or greater than 25 kg/m²) or obesity (equal to or greater than 30 kg/ m²) (Kim 2010) and excessive weight gain during pregnancy, especially for those who are already overweight or obese (Hedderson 2010).

• Lifestyle interventions for the treatment of women with gestational diabetes mellitus (Brown 2015)

Pathophysiology of gestational diabetes

• 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) There will be similarities in the background, methods and outcomes between these three systematic reviews. Portions of the methods section of this review are based on a standard template used by Cochrane Pregnancy and Childbirth.

Description of the condition Gestational diabetes mellitus (GDM) often referred to as gestational diabetes can be defined as “glucose intolerance or hyperglycaemia (high blood glucose concentration) with onset or first recognition during pregnancy” (WHO 1999). GDM occurs when the body is unable to make enough insulin to meet the extra needs in pregnancy. The high blood sugars associated with GDM will return to normal after the birth of the baby. However, there are currently no universally accepted diagnostic criteria (ACOG 2013; Coustan 2010; HAPO 2008; Hoffman 1998; IADPSG 2010; Metzger 1998; NICE 2015). GDM may include previously undetected type 1 diabetes, type 2 diabetes or diabetes presenting only during pregnancy (HAPO 2008; IADPSG 2010; Metzger 1998; Nankervis 2014; WHO 2014). GDM is one of the most common pregnancy complications and the prevalence is rising worldwide with 1% to 36% of pregnancies being affected (Bottalico 2007; Cundy 2014; Duran 2014; Ferrara 2007; NICE 2015; Ragnarsdottir 2010; Tran 2013). The prevalence of GDM is likely to continue to increase along with the increasing prevalence of maternal obesity and associated type 2 diabetes (Bottalico 2007; Mulla 2010; Petry 2010). A variety of factors have been associated with an increased risk of developing GDM. Non-modifiable risk factors include advanced maternal age (Chamberlain 2013; Morisset 2010), high parity, non-white race or ethnicity (in particular South Asian, Middle Eastern), family history of diabetes, maternal high or low birthweight, polycystic ovarian syndrome (Cypryk 2008; Petry 2010; Solomon 1997), a history of having a previous macrosomic infant (birthweight 4000 g or more) and previous history of GDM (Petry 2010). Modifiable risk factors include physical inactivity (Chasan-Taber 2008), having a low-fibre and high-glycaemic load diet (Zhang

Normal pregnancy is associated with significant changes in maternal metabolism (Lain 2007). In early pregnancy, oestrogen and progesterone stimulate maternal beta-cell hyperplasia and insulin secretion, which promotes maternal nutrient storage (adipose and hepatic glycogen) to support later fetal growth. At this stage, insulin sensitivity is maintained or may even increase. However, as pregnancy progresses whole-body insulin sensitivity steadily decreases, such that by the third trimester it is reduced by almost half (Barbour 2007). Several factors contribute to this, including placental hormones (human placental lactogen and placental growth hormone), cytokines released from adipocytes (IL-6, TNF-alpha), increased free fatty acids and lower adiponectin concentrations (Clapp 2006; Devlieger 2008). This results in decreased post-prandial peripheral glucose disposal by up to 40% to 60% (Barbour 2007). Because glucose is transported to the fetus by facilitated diffusion, this state of physiological insulin resistance promotes fetal glucose uptake, a principal oxidative fuel and carbon source for the growing fetus. In normal pregnancy, maternal glycaemia is maintained by a significant increase in insulin secretion of up to 200% to 250% (Barbour 2007; Lain 2007; Suman Rao 2013). Regulation of fetal glucose metabolism requires (1) the maintenance of maternal glucose concentration through increasing maternal glucose production, and at the same time, developing maternal glucose intolerance and insulin resistance, (2) transfer of glucose to the fetus across the placenta and (3) production of fetal insulin and uptake of glucose into adipose tissue and skeletal muscle (Suman Rao 2013). Women with GDM have further reductions in insulin signalling, and glucose uptake is decreased beyond that of normal pregnancy (Barbour 2007). This results in glucose intolerance, though glycaemia in pregnancy represents a continuum. In GDM, the steeper maternal-fetal glucose gradient, especially post-prandial, leads to increased fetal glucose uptake which stimulates fetal insulin secretion. Insulin is a key fetal anabolic hormone and hyperinsulinaemia promotes fetal overgrowth leading to large-for-gestational age (LGA) infants, macrosomia, and possible organ damage (Catalano 2003; Ju 2008; Metzger 2008; Reece 2009). Women with GDM also have increased circulating inflammatory cytokines and lower adiponectin concentrations leading to increased lipolysis and fatty acid concentrations. Placental transfer of free fatty acids contributes to increased fetal adiposity, independent of glucose uptake (Knopp 1985). Thus, even women with well-controlled GDM still have increased risk of fetal macrosomia (Langer 2005).


6

Screening and diagnosis of GDM Regardless of whether universal or selective (risk-factor), screening with a 50 g oral glucose challenge test is used, diagnosis of GDM is usually based on either a 75 g two-hour oral glucose tolerance test (OGTT) or a 100 g three-hour OGTT (ADA 2013; IADPSG 2010; Nankervis 2014; NICE 2015; WHO 1999). Recommendations regarding diagnostic criteria vary nationally and internationally (Table 1), and these diagnostic criteria have changed over time, sometimes due to changing understanding about the effects of hyperglycaemia on pregnancy and infant outcomes (Coustan 2010), but also because of a lack of evidence clearly demonstrating the clinical and cost-effectiveness of one criterion over another. The Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) study (HAPO 2008), a large, international observational study reported graded linear associations in the odds of several GDMassociated adverse outcomes and glucose levels at OGTT, with no clear threshold identified at which risk increased substantially. The International Association of the Diabetes and Pregnancy Study Groups (IADPSG) recommended diagnostic criteria using data from the HAPO study (IADPSG 2010). Applying the IADPSG criteria in most health environments will increase the number of women with GDM. A study conducted in Vietnam showed that depending on the criteria used, the diagnosis of GDM varied between 5.9% (American Diabetes Association - ADA), 20.4% (International Association of Diabetes in Pregnancy Study Groups IADPSG), 20.8% (Australasian Diabetes in Pregnancy Society ADIPS), and up to 24.3% (World Health Organization - WHO) (Tran 2013). A Bulgarian study also reported differences in prevalence based on the diagnostic criteria ranging from 10.8% (European Association for the Study of Diabetes - EASD), 13.5% (ADA), 16.2% (New Zealand Society for the Study of Diabetes - NZSSD), 17.1% (WHO), 21.2% (ADIPS), 31.6% (IADPSG) (Boyadzhieva 2012).

Clinical outcomes for women with gestational diabetes Adverse outcomes have been consistently reported at higher rates in women diagnosed with GDM and their infants compared to women without GDM (Crowther 2005; Landon 2009; Metzger 2008; Reece 2009). Women with GDM have an increased risk of developing preeclampsia, are more likely to have their labour induced (Anderberg 2010; Crowther 2005; Ju 2008; Landon 2009; Metzger 2008), and give birth by caesarean section (Landon 2009; Metzger 2008). The incidence of uterine rupture, shoulder dystocia and perineal lacerations are increased in women with GDM due to the increased likelihood of having a LGA or macrosomic baby (Jastrow 2010). Women who have experienced GDM are at a greater risk of metabolic dysfunction in later life (Shah 2008; Vohr 2008), with a crude cumulative incidence of type 2 diabetes of 10% to 20% within 10 years (Bellamy 2009; Kim 2002), but up to 50% when

adjusted for retention and length of follow-up (Kim 2002). Neonatal, infant and later outcomes related to gestational diabetes A significant adverse health outcome for babies born to mothers with GDM is being born LGA or macrosomic (Catalano 2003; Crowther 2005; Landon 2009; Metzger 2008; Reece 2009). Largefor-gestational age or macrosomic infants are at increased risk of birth injury, such as shoulder dystocia, perinatal asphyxia, bone fractures and nerve palsies (Esakoff 2009; Henriksen 2008; Langer 2005; Metzger 2008). Babies born to women with GDM, compared with babies born to women without GDM, have significantly greater skinfold measures and fat mass compared with infants of women with normal glucose tolerance (Catalano 2003). The offspring of women with GDM are heavier (adjusted for height) and have greater adiposity than the offspring of women with normal glycaemia during pregnancy (Pettitt 1985; Pettitt 1993), and are more likely to develop early overweight or obesity, type 2 diabetes (Hillier 2007; Pettitt 1993; Whincup 2008), or metabolic syndrome (a cluster of risk factors defined by the occurrence of three of the following: obesity, hypertension, hypertriglyceridaemia and low concentration of high-density lipoprotein (HDL) cholesterol) in childhood, adolescence or adulthood (Guerrero-Romero 2010; Harder 2009). The development of the metabolic syndrome during childhood is a risk factor for the development of adult type 2 diabetes at 25 to 30 years of age (Morrison 2008). These health problems repeat across generations (Dabelea 2005; Mulla 2010) and are important from a public health perspective, because with each generation the prevalence of diabetes increases. Other adverse outcomes which are increased for babies born to women with GDM include respiratory distress syndrome, hypoglycaemia (which if prolonged can cause brain injury), hyperbilirubinaemia, hypertrophic cardiomyopathy, hypocalcaemia, hypomagnesaemia, polycythaemia and admission to the neonatal nursery (Metzger 2008; Reece 2009).

Description of the intervention First-line treatment for women with GDM is usually a lifestyle intervention combining dietary and exercise components. Where glycaemic treatment targets are not attained by lifestyle interventions alone, or where initial glucose levels are considered to be very high, the option for treatment is to introduce a pharmacological intervention. Current options include subcutaneous insulin or oral anti-diabetic pharmacological therapies. There has been an increase in the use of oral anti-diabetic pharmacological therapies as an alternative to subcutaneous insulin (Ogunyemi 2011) for the treatment of women with GDM, due to lower costs, ease of administration and acceptability (Ryu 2014). The most commonly used therapies are glyburide (glibenclamide) and metformin, although there are other less frequently used anti-


7

diabetic pharmacological therapies such as acarbose (Kalra 2015). Despite their wide use, oral antidiabetic pharmacological therapies are not licensed for use during pregnancy in many countries (including Australia, New Zealand, UK, USA). First generation sulphonylureas First generation sulphonylureas, such as chlorpropamide and tolbutamide have been used to treat diabetes in pregnancy in the past. Both drugs cross the placenta and have been associated with prolonged neonatal hypoglycaemia (Christesen 1998; Kemball 1970). Second generation sulphonylureas Second generation sulphonylureas, such as glibenclamide (glyburide) or glipizide work by enhancing insulin secretion. In pregnancy, studies have focused on the use of glibenclamide as it was shown to have the least placental passage in vitro (Elliott 1991). However, with improved assays it is now estimated that cord plasma concentrations of glibenclamide can be 70% to 77% of maternal levels (Schwarz 2013). Glibenclamide is completely metabolised by the liver and the metabolites are excreted equally in bile and urine. Oral tablets are administered at a typical dose of 2.5 to 5 mg taken once a day. Dosage can be increased if glycaemic control is not achieved in increments of 2.5 mg daily at intervals of every seven days (Brayfield 2014). The maximum daily dose is usually 15 mg taken in divided doses. Glibenclamide is associated with weight gain during pregnancy and postpartum and maternal hypoglycaemia (Simmons 2015). Other commonly reported side effects include nausea, vomiting, sensations of fullness, abdominal pain, anorexia, heartburn and diarrhoea. Less common side effects include abnormal liver function, haematological reactions and dermatological reactions (www.medsafe.govt.nz). Glibenclamide is contraindicated in cases of renal and hepatic insufficiency (www.medsafe.govt.nz). Langer 2000 reported equivalence between glyburide and subcutaneous insulin for the primary outcome of glycaemic control and reported that glibenclamide was not detected in the cord blood of any of the babies whose mother had been treated with glibenclamide in their trial. Metformin Metformin is a biguanide that can be administered in immediate-release or sustained-release oral preparations. The drug is absorbed along the entire gastrointestinal mucosa, but absorption is incomplete. Typical doses and dose scheduling of metformin provide steady-state plasma concentrations within 24 to 48 hours of administration and are generally less than 1 microgram/mL. Metformin is excreted unchanged in the urine and is not metabolised by the liver. Tablets should be taken in divided doses with meals. The initial dose is typically 500 mg taken once or twice daily and may be increased over subsequent weeks, dependent on glycaemic control, up to a maximum of 1000 mg three times per day

(www.medsafe.govt.nz). In clinical trials using metformin during pregnancy the maximum dose is 2500 mg daily (Rowan 2008). Renal insufficiency is reported as a contra-indication to the prescription of metformin (www.fda.gov). Metformin is known to cross the placenta although there is no evidence to suggest that this leads to fetal abnormalities (Ekpebegh 2007; Gilbert 2006). Maternal lactic acidosis is a rare (0.03 cases per 1000 patient years) but is a serious metabolic condition that is associated with accumulation of metformin during treatment (www.medsafe.govt.nz). Metformin is commonly associated with gastrointestinal disturbances (diarrhoea, nausea, vomiting) (Simmons 2015). Mild erythema, reduced vitamin B12 absorption and a metallic taste are also reported as side effects of metformin (www.medsafe.govt.nz). As very little metformin is transferred to human breast milk it is thought to be safe during breastfeeding (Simmons 2015). A sentinel trial conducted by Rowan 2008 reported equivalence between metformin and subcutaneous insulin for maternal and infant outcomes.

Combined metformin and glibenclamide Metformin and glibenclamide are available in some regions in a combined formulation (Europe, USA).

Acarbose Acarbose is an alpha-glucosidase inhibitor that delays the digestion of carbohydrates, thus resulting in a reduced increase in postprandial blood glucose concentrations (www.accessdata.fda.gov/ scripts/cder/daf/). The typical initial dose is 75 to 150 mg taken in three divided doses. This can be further increased to a maximum of 600 mg per day (in divided doses) after four to eight weeks. Acarbose is metabolised within the gastrointestinal tract and the small amount that is excreted is via the urine (www.medsafe.govt.nz; www.accessdata.fda.gov/scripts/cder/daf/). Animal studies have not found an association between acarbose and fetal teratogenicity, but data are lacking in human studies (Kalra 2015). Acarbose is not associated with maternal hypoglycaemia but is frequently associated with gastrointestinal side effects (Simmons 2015). Acarbose is contraindicated in people with inflammatory bowel disease or similar conditions, malabsorption syndromes, severe hepatic or renal impairment (www.medsafe.govt.nz).

Oral insulin Oral insulin is currently under research development for the treatment of diabetes mellitus, which may include GDM (Fonte 2013; Iyer 2010). This systematic review will not include trials of oral insulin as they will be included in the review of Insulin for the treatment of women with gestational diabetes (Brown 2016).


8

How the intervention might work

OBJECTIVES

Glibenclamide

To evaluate the effects of oral anti-diabetic pharmacological therapies for treating women with GDM.

Glibenclamide stimulates increased insulin secretion by binding to pancreatic beta-cell receptors. There is reduced basal hepatic glucose production and enhancement of peripheral insulin action at post-receptor (probably intracellular) sites. The mechanism of action of glibenclamide requires functional beta-cells (Patanè 2000). Glibenclamide also inhibits glucagon-producing alpha cells in the pancreas and increases the release of somatostatin. There is a mild diuretic action which increases free water clearance (Radó 1974).

METHODS

Criteria for considering studies for this review

Metformin

Types of studies

Metformin actions are not completely understood but it inhibits glucogenesis in the liver, delays glucose absorption from the gastrointestinal tract and stimulates glucose uptake into the peripheral tissues. It has been suggested that as metformin increases insulin sensitivity, it does not stimulate insulin release, but does require the presence of insulin to potentiate its antihyperglycaemic effect. Both fasting and post-prandial blood glucose are lowered in individuals with diabetes. As metformin does not stimulate insulin secretion it is not associated with an increase in hypoglycaemia in diabetic or non-diabetic populations (www.medsafe.govt.nz). Metformin may protect β-cell function in the baby/child/adult and as a consequence reduce the cross generational effects of obesity and type 2 diabetes (Simmons 2015). During pregnancy the pharmacological action of metformin is altered slightly due to enhanced renal elimination, varying food absorption and gastrointestinal transit times (Simmons 2015).

We included published or unpublished randomised, quasi-randomised or cluster-randomised trials in full text or abstract format. We excluded cross-over trials. Conference abstracts were handled in the same way as full publications.

Acarbose Acarbose does not enhance insulin secretion. It reduces intestinal carbohydrate absorption by inhibiting the cleavage of disaccharides and oligosaccharides to monosaccharides in the small intestine resulting in reduced glucose absorption and lower post-prandial glucose concentrations (Kalra 2015).

Why it is important to do this review Although oral anti-diabetic pharmacological therapies are more acceptable to women with GDM (Rowan 2008), cost less and are easier to administer than subcutaneous insulin, the safety of these therapies is still unclear. The comparison of subcutaneous or oral insulin with oral anti-diabetic pharmacological therapies is the subject of a new Cochrane Review and will not therefore be covered in this review. The superiority of one anti-diabetic pharmacological therapy over another has not previously been addressed by a Cochrane systematic review.

Types of participants Participants were pregnant women diagnosed with gestational diabetes mellitus (GDM) (diagnosis as defined by the individual trial). Women with type 1 or type 2 diabetes diagnosed prior to pregnancy were excluded.

Types of interventions We included those anti-diabetic pharmacological therapies that were used during pregnancy including metformin, glibenclamide, acarbose, tolbutamide, chlorpropamide or any combination of these therapies. Only oral anti-diabetic pharmacological therapies were included in this review. We will include any new therapies prescribed for the treatment of women with GDM in updates of the review. • Oral anti-diabetic pharmacological therapy versus placebo or no pharmacological treatment. • A single oral anti-diabetic pharmacological therapy versus an alternative oral anti-diabetic pharmacological therapy (drug A versus drug B). • Any combination of oral anti-diabetic pharmacological therapies versus any combination of oral anti-diabetic pharmacological therapies (drug A followed by drug B versus drug B followed by drug A for example). • Oral anti-diabetic pharmacological therapy versus another intervention (excluding insulin) not specified above. We have not included the comparison of oral anti-diabetic pharmacological therapies versus insulin in this review as it will be covered in the review entitled Insulin for the treatment of women with gestational diabetes (Brown 2016).


9

Types of outcome measures

Primary outcomes

Maternal • Hypertensive disorders of pregnancy (including preeclampsia, pregnancy-induced hypertension, eclampsia as defined by trialists) • Caesarean section • Development of type 2 diabetes

Long-term outcomes for mother • Postnatal depression • Body mass index (BMI) • Postnatal weight retention or return to pre-pregnancy weight • Type 1 diabetes • Type 2 diabetes • Impaired glucose tolerance • Subsequent gestational diabetes • Cardiovascular health (as defined by trialists including blood pressure, hypertension, cardiovascular disease, metabolic syndrome) Fetal/neonatal outcomes

Neonatal • Perinatal (fetal and neonatal death) and later infant mortality • Large-for-gestational age (LGA) (as defined by trialists) • Death or serious morbidity composite (variously defined by trials, e.g. perinatal or infant death, shoulder dystocia, bone fracture or nerve palsy) • Neurosensory disability in later childhood (as defined by trialists)

Secondary outcomes

Maternal • Use of additional pharmacotherapy • Maternal hypoglycaemia (as defined by trialists) • Glycaemic control during/end of treatment (as defined by trialists) • Weight gain in pregnancy • Adherence to the intervention • Induction of labour • Placental abruption • Postpartum haemorrhage (as defined by trialists) • Postpartum infection • Perineal trauma/tearing • Breastfeeding at discharge, six weeks postpartum, six months or longer • Maternal mortality • Sense of well-being and quality of life • Behavioural changes associated with the intervention • Views of the intervention • Relevant biomarker changes associated with the intervention (including adiponectin, free fatty acids, triglycerides, high-density lipoproteins, low-density lipoproteins, insulin)

• Stillbirth • Neonatal death • Macrosomia (greater than 4000 g; or as defined by individual study) • Small-for-gestational age (as defined by trialists) • Birth trauma (shoulder dystocia, bone fracture, nerve palsy) • Gestational age at birth • Preterm birth (less than 37 weeks’ gestation; and less than 32 weeks’ gestation) • Five-minute Apgar less than seven • Birthweight and z score • Head circumference and z score • Length and z score • Ponderal index • Adiposity (including skinfold thickness measurements (mm), fat mass) • Neonatal hypoglycaemia (as defined by trialists) • Respiratory distress syndrome • Neonatal jaundice (hyperbilirubinaemia) (as defined by trialists) • Hypocalcaemia (as defined by trialists) • Polycythaemia (as defined by trialists) • Relevant biomarker changes associated with the intervention (including insulin, cord c-peptide) Later Infant/childhood outcomes • • • • • • • • • •

Weight and z scores Height and z scores Head circumference and z scores Adiposity (including BMI, skinfold thickness, fat mass) Educational attainment Blood pressure Type 1 diabetes Type 2 diabetes Impaired glucose tolerance Dyslipidaemia or metabolic syndrome


10

Child as an adult outcomes • Weight • Height • Adiposity (including BMI, skinfold thickness, fat mass) • Cardiovascular health (as defined by trialists including blood pressure, hypertension, cardiovascular disease, metabolic syndrome) • Employment, education and social status/achievement • Dyslipidaemia or metabolic syndrome • Type 1 diabetes • Type 2 diabetes • Impaired glucose tolerance Health service use • Number of antenatal visits or admissions • Number of hospital or health professional visits (including midwife, obstetrician, physician, dietician, diabetic nurse) • Admission to neonatal intensive care unit/nursery • Length of antenatal stay • Length of postnatal stay (maternal) • Length of postnatal stay (baby) • Cost of maternal care • Cost of offspring care • Costs associated with the intervention • Costs to families associated with the management provided • Cost of dietary monitoring (e.g. diet journals, dietician, nurse visits, etc) • Costs to families - change of diet, extra antenatal visits • Extra use of healthcare services (consultations, blood glucose monitoring, length and number of antenatal visits) • Women’s view of treatment advice • Duration of stay in neonatal intensive care unit or special care baby unit • Duration of maternal and neonatal hospital stay (antenatal, neonatal, postnatal)

and conference proceedings, and the list of journals reviewed via the current awareness service, please follow this link to the editorial information about the Cochrane Pregnancy and Childbirth in the Cochrane Library and select the ‘Specialized Register ’ section from the options on the left side of the screen. Briefly, Cochrane Pregnancy and Childbirth’s Trials Register is maintained by their Information Specialist and contains trials identified from: 1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL); 2. weekly searches of MEDLINE (Ovid); 3. weekly searches of Embase (Ovid); 4. monthly searches of CINAHL (EBSCO); 5. handsearches of 30 journals and the proceedings of major conferences; 6. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts. Search results are screened by two people and the full text of all relevant trial reports identified through the searching activities described above is reviewed. Based on the intervention described, each trial report is assigned a number that corresponds to a specific Pregnancy and Childbirth review topic (or topics), and is then added to the Register. The Information Specialist searches the Register for each review using this topic number rather than keywords. This results in a more specific search set that has been fully accounted for in the relevant review sections (Included studies; Excluded studies; Studies awaiting classification; Ongoing studies). In addition, we searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for unpublished, planned and ongoing trial reports (14 May 2016). The search terms we used are given in Appendix 1. Searching other resources We searched the reference lists of retrieved studies. We did not apply any language or date restrictions.

Search methods for identification of studies The following methods section of this review is based on a standard template used by Cochrane Pregnancy and Childbirth.

Data collection and analysis The following methods section of this review is based on a standard template used by Cochrane Pregnancy and Childbirth.

Electronic searches We searched Cochrane Pregnancy and Childbirth’s Trials Register by contacting their Information Specialist (16 May 2016). The Register is a database containing over 22,000 reports of controlled trials in the field of pregnancy and childbirth. For full search methods used to populate Pregnancy and Childbirth’s Trials Register including the detailed search strategies for CENTRAL, MEDLINE, Embase and CINAHL; the list of handsearched journals

Selection of studies Two review authors independently assessed for inclusion all the potential studies we identified as a result of the search strategy. We resolved any disagreements through discussion. A third person was not required. We created a study flow diagram to map out the number of records identified, included and excluded (Figure 1).


11

Figure 1. Study flow diagram


12

Data extraction and management We designed a form to extract data. For eligible studies, two review authors extracted the data using the agreed form. We resolved discrepancies through discussion. Consultation with a third person was not required. We entered data into Review Manager (RevMan) software (RevMan 2014) and checked for accuracy. When information regarding any of the above was unclear, we attempted to contact authors of the original reports to provide further details.

intervention a participant received. We considered that studies were at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes. We assessed the methods as: • low, high or unclear risk of bias for participants; • low, high or unclear risk of bias for personnel. (3.2) Blinding of outcome assessment (checking for possible detection bias)

Assessment of risk of bias in included studies Two review authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We resolved any disagreement by discussion. Consultation with a third person was not required. (1) Random sequence generation (checking for possible selection bias)

We described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups. We assessed the method as: • low risk of bias (any truly random process, e.g. random number table; computer random number generator); • high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number); • unclear risk of bias. (2) Allocation concealment (checking for possible selection bias)

We described for each included study the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We assessed the methods as: • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes); • high risk of bias (open random allocation; unsealed or nonopaque envelopes, alternation; date of birth); • unclear risk of bias. (3.1) Blinding of participants and personnel (checking for possible performance bias)

We described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which

We described for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes. We assessed methods used to blind outcome assessment as: • low, high or unclear risk of bias. (4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported and 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. No additional data that could be included in a meta-analysis were supplied by study authors. In future updates, where sufficient information is reported, or can be supplied by the study authors, we will re-include missing data in the analyses which we undertake. We assessed methods as: • low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups); • high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation); • unclear risk of bias. (5) Selective reporting (checking for reporting bias)

We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as: • low risk of bias (where it was clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review were reported);


13

• high risk of bias (where not all the study’s pre-specified outcomes were reported; one or more reported primary outcomes were not pre-specified; outcomes of interest were reported incompletely and so could not be used; study failed to include results of a key outcome that would have been expected to have been reported); • unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We described for each included study any important concerns we had about other possible sources of bias. We assessed whether each study was free of other problems that could put it at risk of bias: • low risk of other bias; • high risk of other bias; • unclear whether there is risk of other bias.

(7) Overall risk of bias

We made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions(Higgins 2011a). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it was likely to impact on the findings. We planned to explore the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis.

Assessment of the quality of the evidence using the GRADE approach

Neonatal outcomes

• LGA • Perinatal mortality • Death or serious morbidity composite (variously defined by studies, e.g. infant death, shoulder dystocia, bone fracture or nerve palsy) • Neonatal hypoglycaemia • Adiposity • Diabetes • Neurosensory disability in later childhood We used the GRADEpro Guideline Development Tool ( GRADEpro GDT) to import data from RevMan (RevMan 2014) in order to create ’Summary of findings’ tables. We produced a summary of the intervention effect and a measure of quality for each of the above outcomes using the GRADE approach. The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The evidence can be downgraded from ’high quality’ by one level for serious (or by two levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias. Measures of treatment effect

Dichotomous data

For dichotomous data, we presented results as summary risk ratio (RR) with 95% confidence intervals (CI).

Continuous data

We assessed the quality of the evidence using the GRADE approach as outlined in the GRADE Handbook in order to assess the quality of the body of evidence relating to the following outcomes. We selected up to a maximum of seven outcomes for the mother and seven for the infant covering both short- and longterm outcomes for the main comparisons.

For continuous data, we used the mean difference (MD) if outcomes were measured in the same way between trials. We used the standardised mean difference (SMD) to combine data from trials that measured the same outcome, but used different methods.

Maternal outcomes

Cluster-randomised trials

• Hypertensive disorders of pregnancy (including preeclampsia, pregnancy-induced hypertension, eclampsia) • Caesarean section • Development of type 2 diabetes • Perineal trauma • Return to pre-pregnancy weight • Postnatal depression • Induction of labour

We did not identify any cluster-randomised controlled trials in this version of the systematic review. In future updates, if cluster-randomised trials are identified, we will include cluster-randomised trials in the analyses along with individually-randomised trials. We will make adjustments using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Section 16.3.4 or 16.3.6) using an estimate of the intra-cluster correlation co-efficient (ICC) derived from the trial (if possible),

Unit of analysis issues


14

from a similar trial or from a study of a similar population (Higgins 2011b). If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. We will consider it reasonable to combine the results from both cluster-randomised trials and individually-randomised trials if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely. If cluster-randomised trials are included, we will seek statistical advice on appropriate analysis to enable inclusion of data in the meta-analyses.

Other unit of analysis issues

Multiple pregnancy There may be unit of analysis issues that arise when the women randomised have a multiple pregnancy. We did not include any studies including multiple pregnancies in this version of the systematic review. In future updates, if multiple pregnancies are identified, we will present maternal data as per woman randomised and neonatal data per infant.

Multiple-arm studies Where a trial has multiple intervention arms we planned to avoid ’double counting’ of participants by combining groups to create a single pair-wise comparison if possible. Where this was not possible, we planned to split the ’shared’ group into two or more groups with smaller sample size and include two or more (reasonably independent) comparisons. We did not identify any studies of multiple comparisons in this version of the systematic review.

Dealing with missing data For included studies, we noted levels of attrition. We planned to explore the impact of including studies with high levels of missing data (more than 20%) in the overall assessment of treatment effect by using sensitivity analysis. However, one of the included studies reported attrition greater than 20% (De Bacco 2015) and therefore we did not conduct sensitivity analyses based on attrition in this version of the review. In future updates we plan to explore attrition for sensitivity analysis if sufficient evidence is available. For all outcomes, we carried out analyses, as far as possible, on an intention-to-treat basis, that is, we attempted to include all participants randomised to each group in the analyses, and all participants were analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were known to be missing.

Assessment of heterogeneity We assessed statistical heterogeneity in each meta-analysis using the Tau², I² (Higgins 2003) and Chi² statistics. We regarded heterogeneity as substantial if an I² was greater than 40% and either a Tau² was greater than zero, or there was a low P value (less than 0.10) in the Chi² test for heterogeneity.

Assessment of reporting biases If there were 10 or more studies in the meta-analysis, we planned to investigate reporting biases (such as publication bias) using funnel plots. This was not possible in this version of the review. In future updates, where possible, we will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis We carried out statistical analysis using the Review Manager software (RevMan 2014). We used fixed-effect meta-analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: that is, where trials were examining the same intervention, and the trials’ populations and methods were judged sufficiently similar. If there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or if substantial statistical heterogeneity was detected, we used random-effects meta-analysis to produce an overall summary, if an average treatment effect across trials was considered clinically meaningful. The random-effects summary was treated as the average of the range of possible treatment effects and we tried to discuss the clinical implications of treatment effects differing between trials. If the average treatment effect was not clinically meaningful, we did not combine trials. If we used random-effects analyses, the results were presented as the average treatment effect with 95% CIs, and the estimates of Tau² and I².

Subgroup analysis and investigation of heterogeneity If we identified substantial heterogeneity, we investigated it using subgroup analyses. We considered whether an overall summary was meaningful, and if it was, used random-effects analysis to produce it.

Diagnostic tests used

• ADA 2013, IADPSG 2010, Nankervis 2014 versus ACOG 2013 versus NICE 2015 versus NICE 2008; WHO 1999; WHO 2014; Hoffman 1998 versus New Zealand Ministry of Health 2014 versus other not previously specified.


15

Timing of diagnosis of GDM

• Early (< 28 weeks’ gestation) versus late (≥ 28 weeks’ gestation) There was insufficient data for us to be able to explore subgroup analyses for this review. In future updates, if there is sufficient evidence, we plan to use the following outcomes in subgroup analysis. Maternal outcomes • Pre-eclampsia • Caesarean section • Development of type 2 diabetes

awaiting classification and one study (Moore 2016) is ongoing (see Characteristics of studies awaiting classification; Characteristics of ongoing studies).

Included studies Eleven studies (20 reports) were identified that met the inclusion criteria for this review (Bertini 2005; Casey 2015; Cortez 2006; De Bacco 2015; Fenn 2015; George 2015; Moore 2010; Myers 2014; Nachum 2015; Notelovitz 1971; Silva 2012). Three of these were published in conference abstract format only (Cortez 2006; De Bacco 2015; Nachum 2015).

Design

Neonatal outcomes • LGA • Perinatal death or later infant mortality • Death or serious morbidity composite (variously defined by trials, e.g. infant death, shoulder dystocia, bone fracture or nerve palsy) • Neurosensory disability in later childhood (as defined by trialists). We assessed subgroup differences by interaction tests available within RevMan (RevMan 2014). We reported the results of subgroup analyses quoting the Chi2 statistic and P value, and the interaction test I² value. Sensitivity analysis Where there was evidence of substantial heterogeneity, we explored this by using the quality of the included trials for the primary outcomes. We planned to compare trials that had low risk of bias for allocation concealment with those judged to be of unclear or high risk of bias. We planned to exclude conference abstracts from the meta-analysis. In future updates, where data are available we plan to investigate the effect of the randomisation unit (i.e. where included clusterrandomised trials along with individually-randomised trials).

All 11 studies were randomised parallel design.

Sample sizes

The 11 studies recruited a total of 1487 women and their babies. Sample size ranged from 40 women reported by Myers 2014 to 207 women reported by Notelovitz 1971.

Setting

Three studies were conducted in Brazil (Bertini 2005; De Bacco 2015; Silva 2012) and USA (Casey 2015; Cortez 2006; Moore 2010). Two studies were conducted in India (Fenn 2015; George 2015). One study each was conducted in South Africa (Notelovitz 1971), UK (Myers 2014) and Israel (Nachum 2015).

Participants

Maternal age was reported in six of the 11 studies (Table 2), maternal body mass index (BMI) (kg/m2 ) was reported in five of 11 studies (Table 3) and gestational age at study entry was reported in four of 11 studies (Table 4).

Interventions and comparisons

Four different comparisons were reported.

RESULTS Description of studies

Results of the search We identified 28 potential reports for inclusion in the review (Figure 1). Eleven studies (20 reports) were included and five studies were excluded. Two studies (Coiner 2015; Sheizaf 2006) are

Oral anti-diabetic pharmacological therapy versus placebo or usual care One study compared glibenclamide with placebo (Casey 2015); one study compared acarbose with placebo (Cortez 2006), one study compared metformin with standard care (Myers 2014) and one study compared tolbutamide and chlorpropamide with diet (Notelovitz 1971).


16

Metformin versus glibenclamide Five studies compared metformin with glibenclamide (De Bacco 2015; Fenn 2015; George 2015; Moore 2010; Silva 2012).

Glibenclamide versus acarbose One study compared glibenclamide with acarbose (Bertini 2005).

Glibenclamide with or without metformin versus metformin with or without glibenclamide One study compared glibenclamide plus metformin if glycaemic targets were not met, with metformin plus glibenclamide if glycaemic targets were not met (Nachum 2015).

Diagnostic criteria

Four different diagnostic criteria were used by the eight studies that reported this. • George 2015 and Casey 2015 used the National Diabetes Data Group (NDGG 1979) • Bertini 2005 and Silva 2012 used WHO (1999) criteria • Three studies (Fenn 2015; Moore 2010; Nachum 2015) used Carpenter and Coustan criteria • De Bacco 2015 used WHO criteria but the abstract did not state if this was 1999 or 2015 criteria • Cortez 2006, Myers 2014 and Notelovitz 1971 did not state which diagnostic criteria they used Refer to Table 1 and Table 5.

Treatment targets

Eight studies reported three different treatment targets for fasting blood glucose (Refer to Table 6): • less than 5.0 mmol/L (90 mg/dL) (Bertini 2005; Silva 2012); • less than 5.3 mmol/L (95 mg/dL) (Casey 2015; Cortez 2006; Fenn 2015; George 2015; Nachum 2015); • less than 5.8 mmol/L (105 mg/dL) (Moore 2010).

Four studies reported four different treatment targets for one-hour postprandial blood glucose: • less than 6.7 mmol/L (120 mg/dL) (Silva 2012); • less than 7.2 mmol/L (130 mg/dL) (George 2015) 90 minutes; • less than 7.5 mmol/L (135 mg/dL) (Cortez 2006); • less than 7.8 mmol/L (140 mg/dL) (Fenn 2015). Four studies reported two different treatment targets for two-hour postprandial blood glucose: • less than 5.5 mmol/L (100 mg/dL) (Bertini 2005); • less than 6.7 mmol/L (120 mg/dL) (Casey 2015; George 2015; Moore 2010). Notelovitz 1971 reported “good control” was obtained with a postprandial (timing not specified) blood glucose reading of less than 8.3 mmol/L (150 mg/dL). De Bacco 2015 and Myers 2014 did not provide details of glycaemic targets for treatment. The Notelovitz 1971 study included women with both GDM and pre-gestational diabetes. The proportions of women included with each type of diabetes were unclear and therefore the data have not been included in any meta-analyses. See Characteristics of included studies. Excluded studies We excluded five studies. One study comparing metformin and placebo was registered with the clinical studies registry ClinicalTrials.gov in 2010. Subsequent updates indicate that the study never started recruitment due to insufficient funding for enrolment of participants (Branch 2010). Hebert 2011, was a pharmacokinetic study and not an interventional study. We excluded Ainuddin 2013 as the comparison was ineligible for inclusion in this review, the trial compared metformin and insulin. We excluded two studies as the intervention was postpartum (Berens 2015; Smith 2015). See Characteristics of excluded studies.

Risk of bias in included studies Refer to Figure 2; Figure 3 and Characteristics of included studies for ’risk of bias’ summaries of the included studies.


17

Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies


18

Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study


19

Allocation We judged five of the 11 included studies to be of low risk of bias for random sequence generation as they all used computergenerated number tables (Casey 2015; Fenn 2015; George 2015; Moore 2010; Silva 2012). The remaining studies stated that they were randomised but did not provide sufficient details to make a judgement so we therefore considered them to be unclear risk of bias (Bertini 2005; Cortez 2006; De Bacco 2015; Myers 2014; Nachum 2015; Notelovitz 1971). We considered allocation concealment to be low risk of bias in five studies. Bertini 2005 reported using “brown envelopes containing outside the randomisation number and in the inside a sheet defining which therapy the patient was allocated to”; Casey 2015 reported that masking, allocation and assignment was done by the investigational drug pharmacy; George 2015 used “sequentially labelled opaque envelopes” that were maintained “in a central research office by research officers not involved in patient care”. Moore 2010 used “sequentially labelled, opaque, sealed envelopes” and Silva 2012 used sequential numbering in brown envelopes. Myers 2014 reported using “..prefilled sealed envelopes created by independent research midwives within the department”. The remaining studies provided no details as to the method of allocation concealment and we judged them to be of unclear risk of bias (Cortez 2006; De Bacco 2015; Fenn 2015; Nachum 2015; Notelovitz 1971). Blinding

Performance bias

Casey 2015 reported that the “subject”, “caregiver” and “investigator” were blinded and the study was placebo controlled (we obtained additional information from the study protocol). Sham dose adjustments were made in the placebo group. Fenn 2015 reported that the physician and the participant were blinded to treatment allocation and that medication was provided from the pharmacy in a sealed envelope. We judged these studies to be low risk of bias. Cortez 2006 reported that the study was double-blind but gave no details as to who was blinded. We judged the study to be of unclear risk of bias. Six studies reported that they were open label and therefore participants and staff were not blinded to the treatment allocation (Bertini 2005; De Bacco 2015; Moore 2010; Myers 2014; Nachum 2015; Silva 2012). George 2015 reported that the women in their study were not blinded to the treatment allocation. We considered these studies to be of high risk of bias. Notelovitz 1971 did not provide any details regarding blinding and we therefore judged it as being unclear risk of bias.

Detection bias

In the trial registration document, Casey 2015 reported that the “outcome assessor” was blinded. George 2015 reported that the neonatologists who cared for the infants after birth were blinded to treatment allocation. We judged these studies to be low risk of bias. Cortez 2006 reported that the study was double-blind but gave no details as to who was blinded. We judged the study to be of unclear risk of bias. Eight studies reported that they were open label or provided no details relating to blinding of outcome assessors, or both (Bertini 2005; De Bacco 2015; Fenn 2015; Moore 2010; Myers 2014; Nachum 2015; Notelovitz 1971; Silva 2012). We considered these studies to be of unclear risk of bias.

Incomplete outcome data There was no evidence of risk of attrition bias in six studies (Bertini 2005; Fenn 2015; George 2015; Moore 2010; Notelovitz 1971; Silva 2012). Casey 2015 reported a 5% (20/395) loss to followup but did not provide any reasons for the attrition. No details of attrition were provided by Cortez 2006, although the study stated that analysis was conducted by intention to treat. We judged this study to be of unclear risk of bias. In De Bacco 2015 8/36 (22%) women dropped out of the metformin arm and 24/45 (55%) dropped out of the glibenclamide arm. We judged this study to be high risk of bias. In the Myers 2014 pilot study, three women did not complete the trial and were not analysed, but it is unclear as to which group they were allocated - we assessed this study to be at an unclear risk of bias.

Selective reporting There was no evidence of risk of reporting bias in three studies (Bertini 2005; George 2015; Moore 2010). Casey 2015 reported additional maternal and neonatal outcomes to those listed a priori in the trial registration document. Three studies were only published in abstract form and or no full publication could be identified (Cortez 2006; De Bacco 2015; Myers 2014). One study failed to report on an outcome that had been prespecified (Silva 2012), two studies reported additional outcomes that were not pre-specified (Fenn 2015; Nachum 2015) and one study did not pre-specify any outcomes (Notelovitz 1971). We judged these studies to be of high risk of bias.

Other potential sources of bias


20

There was no evidence of other sources of bias in three studies (Bertini 2005; Moore 2010; Silva 2012). Fenn 2015 did not provide data for the population demographics and we were unable to judge the risk of bias, which we have allocated an unclear risk. In one study (George 2015) an interim analysis requested by the local data monitoring committee showed significant differences in outcomes and the study was stopped before the total sample size of 86 women per group was achieved. The intervention and control groups were balanced at baseline although the metformin group had higher fasting triglyceride levels. We judged the study to be of unclear risk of bias. Three studies were reported in abstract form only and there were no baseline demographic data (Cortez 2006; De Bacco 2015; Nachum 2015). The Myers 2014 study remains unpublished. We therefore judged these studies to be of high risk of bias. The Casey 2015 study appears to have been registered twice as NCT00942552 and as NCT00744965 with the same outcomes, interventions and sample size. The population was 93% Hispanic and therefore the results may not be generalisable to other ethnicities. We judged the study to be high risk of bias. We could not separate the data from the Notelovitz 1971 study for women with GDM and those with pregestational diabetes, and the study did not report the proportions of women for these categories. We did not, therefore, include the data in any metaanalyses.

One study reported on hypertensive disorders of pregnancy in a study that compared glibenclamide with a placebo (Casey 2015). Overall, for hypertensive disorders of pregnancy (any type) there was no difference between glibenclamide and placebo groups (risk ratio (RR) 1.24, 95% confidence interval (CI) 0.81 to 1.90; one study, n = 375 women; Analysis 1.1). Using GRADE the quality of the evidence was judged to be very low due to no published protocol being identified; more outcomes being reported than were listed in the trial registration documentation; evidence of indirectness, as 93% of population were Hispanic and evidence may not be generalisable; and publication bias, as the evidence was only based on a single study. The risk of developing a hypertensive disorder of pregnancy in the placebo group was 16.7%, if the woman had been treated with glibenclamide the risk would range from 13.5% to 31.7% (Summary of findings for the main comparison). For pregnancy-induced hypertension (persistent systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg) there was no difference between glibenclamide and placebo groups (RR 1.24, 95% CI 0.71 to 2.19; one study, n = 375 women; Analysis 1.1 ). For severe pregnancy-induced hypertension (proteinuria ≥ 2 g in 24 hours, or ≥ 2+ on dipstick, blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 110 mmHg, serum creatinine > 1.0 mg/dL, platelets < 100,000/mm3 , aspartate aminotransferase > 90 units/L, or symptoms such as persistent headache, scotomata or epigastric pain) there was no difference between glibenclamide and placebo groups (RR 1.23, 95% CI 0.59 to 2.56; one study, 375 women; Analysis 1.1).

Effects of interventions See: Summary of findings for the main comparison Oral anti-diabetic pharmacological therapies versus placebo maternal outcomes; Summary of findings 2 Oral anti-diabetic pharmacological therapies versus placebo - neonatal outcomes; Summary of findings 3 Metformin versus glibenclamide maternal outcomes; Summary of findings 4 Metformin versus glibenclamide - neonatal outcomes; Summary of findings 5 Glibenclamide versus acarbose - maternal outcomes; Summary of findings 6 Glibenclamide versus acarbose - neonatal outcomes

Oral anti-diabetic pharmacological therapy versus placebo or standard care (comparison 1) Three studies reported data for this comparison (Casey 2015; Cortez 2006; Myers 2014). Casey 2015 compared glibenclamide with placebo and Cortez 2006 compared acarbose with placebo. Myers 2014 compared metformin with standard care.

1.2 Caesarean section One study reported on caesarean section in a study that compared glibenclamide with a placebo (Casey 2015). There was no difference in the risk for birth by caesarean section between glibenclamide and placebo groups (RR 1.03, 95% CI 0.79 to 1.34; one study, n = 375 women; Analysis 1.2). Using GRADE the quality of the evidence was judged to be very low due to no published protocol being identified; more outcomes being reported than were listed in the trial registration documentation; evidence of indirectness, as 93% of population were Hispanic and evidence may not be generalisable; and publication bias, as the evidence was only based on a single study. The risk of birth by caesarean section in the placebo group was 36%. For women treated with glibenclamide the risk would range from 28.5% to 48.3% (Summary of findings for the main comparison).

Maternal primary outcomes

Development of type 2 diabetes

1.1 Hypertensive disorders of pregnancy

None of the included trials comparing oral anti-diabetic pharmacological therapies with placebo pre-specified development of type 2 diabetes as a study outcome.


21

Neonatal primary outcomes

95% CI -0.96 to 0.96; one study, n = 375 women; Analysis 1.6) (Casey 2015). Caution is required in interpreting these data from a single trial with evidence of imprecision.

1.3 LGA (90th percentile and above) There was no difference in the risk of being born LGA age between infants whose mothers had been treated with glibenclamide and those who had received placebo (RR 0.89, 95% CI 0.51 to 1.58; one study, 375 infants; Analysis 1.3) (Casey 2015). Using GRADE the quality of the evidence was judged to be low due to no published protocol being identified; more outcomes being reported than were listed in the trial registration documentation; evidence of indirectness, as 93% of population were Hispanic and evidence may not be generalisable; and publication bias as the evidence was only based on a single study. The risk of being born LGA if the mother had been treated with placebo was 11.8%, if the mother had been treated with glibenclamide the risk would have ranged from 6% to 18.7%.

1.7 Induction of labour There was no evidence of a difference between glibenclamide and placebo groups for the risk of induction of labour reported in one study (Casey 2015) (RR 1.18, 95% CI 0.79 to 1.76; one study, n = 375 women; Analysis 1.7). Using GRADE the quality of the evidence was judged to be very low due to no published protocol being identified; more outcomes being reported than were listed in the trial registration documentation; evidence of indirectness, as 93% of population were Hispanic and therefore the evidence may not be generalisable; and publication bias, as the evidence was only based on a single study. The risk for induction of labour in the placebo group was 18.8%, if the woman was treated with glibenclamide the risk would range from 14.9% to 33.1% (Summary of findings for the main comparison).

Other neonatal primary outcomes None of the included trials comparing oral anti-diabetic pharmacological therapies with placebo pre-specified perinatal death and later infant mortality, death or serious morbidity composite or neurosensory disability in later childhood as study outcomes.

Maternal secondary outcomes

1.4 Use of additional pharmacotherapy There was no evidence of a difference in the need for insulin between the anti-diabetic pharmacological therapy and placebo groups reported in two studies (Casey 2015; Cortez 2006) (RR 0.68, 95% CI 0.42 to 1.11; two studies, n = 434 women; Analysis 1.4). The Casey 2015 study used glibenclamide and the Cortez 2006 study used acarbose as the pharmacological intervention. Myers 2014 reported that 15/19 women in the standard care group were prescribed metformin and two women required insulin. It is not clear if any of the women in the metformin group required supplementary insulin.

1.8 Perineal trauma/tearing There was no evidence of a difference between glibenclamide and placebo groups for the risk of perineal trauma reported as thirdto fourth-degree tear reported in one study (Casey 2015) (RR 0.98, 95% CI 0.06 to 15.62; one study, n = 375 women; Analysis 1.8). Using GRADE the quality of the evidence was judged to be very low due to no published protocol being identified; more outcomes being reported than were listed in the trial registration documentation; evidence of indirectness, as 93% of population were Hispanic and evidence may not be generalisable; and wide CIs crossing the line of no effect and low event rates were suggestive of imprecision and publication bias, as the evidence was only based on a single study. If the risk of perineal trauma in the placebo group was 0.5%, then between 0% to 8% of the women treated with glibenclamide would be at risk of perineal trauma (Summary of findings for the main comparison). Other maternal secondary outcomes

Glibenclamide was associated with a reduction in fasting capillary glucose concentrations taken at the last three antenatal visits compared with placebo (mean difference (MD) -3.00 mg/dL, 95% CI -5.13 to -0.87; one study, n = 375 women; Analysis 1.5) (Casey 2015). Caution is required in interpreting these data from a single trial with evidence of imprecision.

No data were reported for any of the other pre-specified maternal secondary outcomes for this review (maternal hypoglycaemia, adherence to the intervention, placental abruption, postpartum haemorrhage, breastfeeding at discharge, six weeks postpartum, six months or longer, maternal mortality, sense of well-being and quality of life, behavioural changes associated with the intervention, views of the intervention, relevant biomarker changes associated with the intervention).

1.6 Weight gain in pregnancy

Long-term maternal outcomes

There was no evidence of a difference between glibenclamide and placebo groups for weight gain during pregnancy (MD 0.00 Kg,

No data were reported for long-term maternal outcomes (postnatal depression, BMI, postnatal weight retention or return to

1.5 Glycaemic control during/end of treatment


22

pre-pregnancy weight, type 1 diabetes, type 2 diabetes, impaired glucose tolerance, subsequent GDM, cardiovascular health (as defined by trialists including blood pressure, hypertension, cardiovascular disease, metabolic syndrome).

Neonatal secondary outcomes

1.9 Stillbirth One study reported on stillbirth (Casey 2015). There was no evidence of a difference in the risk of stillbirth between the glibenclamide and placebo groups (RR 0.49, 95% CI 0.05 to 5.38; one study, n = 375 infants; Analysis 1.9). Using GRADE the quality of the evidence was judged to be very low. This was due to no published protocol being identified; more outcomes being reported than were listed in the trial registration documentation; evidence of indirectness, as 93% of population were Hispanic and evidence may not be generalisable; and wide CIs crossing the line of no effect and low event rates were suggestive of imprecision and publication bias, as the evidence was only based on a single study. If the risk of stillbirth was 1.1% for the placebo group, between 0.1% to 5.8% of infants would have been stillborn if the woman was treated with glibenclamide. 1.10 Neonatal death There were no events of neonatal death reported in either the glibenclamide or the placebo group in one study including 375 infants (Casey 2015). 1.11 Small-for-gestational age There was no evidence of a difference in the risk of being born small-for-gestational age between the glibenclamide and placebo groups reported in one study (Casey 2015) (RR 1.11, 95% CI 0.58 to 2.10; one study, n = 375 infants; Analysis 1.11).

1.14 to 1.16 Birth trauma (shoulder dystocia, bone fracture, nerve palsy) Birth trauma was reported in one study (Casey 2015) comparing glibenclamide with placebo. There was no evidence of a difference in the risk for shoulder dystocia (RR 0.33, 95% CI 0.01 to 8.00; one study, n = 375 infants; Analysis 1.14); bone fracture (RR 0.74, 95% CI 0.17 to 3.25; one study, n = 375 infants; Analysis 1.15) or nerve palsy (RR 0.33, 95% CI 0.01 to 8.00; one study, n = 375; Analysis 1.15) between the glibenclamide and placebo groups. Caution is required when interpreting these data due to low event rates and wide CIs crossing the line of no effect suggesting imprecision.

1.17 Gestational age at birth There was no evidence of a difference between glibenclamide and placebo groups for the gestational age at birth (MD 0.00 weeks, 95% CI -0.32 to 0.32; one study, n = 375 infants; Analysis 1.17) (Casey 2015).

1.18 Neonatal hypoglycaemia There was no evidence of a difference in the risk for neonatal hypoglycaemia between the glibenclamide and the placebo groups (RR 1.97, 95% CI 0.36 to 10.62; one study, n = 375 infants; Analysis 1.18) (Casey 2015). Caution is required when interpreting these data due to low event rates and wide CIs crossing the line of no effect suggesting imprecision. Using GRADE the quality of the evidence was judged to be very low due to no published protocol being identified; more outcomes being reported than were listed in the trial registration documentation; evidence of indirectness, as 93% of population were Hispanic and evidence may not be generalisable; and wide CIs crossing the line of no effect and low event rates were suggestive of imprecision and publication bias, as the evidence was only based on a single study. If the risk of neonatal hypoglycaemia in the placebo group was 11%, between 4% to 11.4% of infants would experience hypoglycaemia if the woman was treated with glibenclamide.

1.12 Macrosomia There was no evidence of a difference in the risk of macrosomia (≥ 4 kg) between infants whose mothers had been treated with glibenclamide and those who had received placebo reported in one study (Casey 2015) (RR 0.71, 95% CI 0.36 to 1.41; one study, n = 375 infants; Analysis 1.12).

1.19 Neonatal jaundice (hyperbilirubinaemia) There was no evidence of a difference in the risk for neonatal jaundice between the glibenclamide and the placebo groups reported in one study (RR 1.97, 95% CI 0.50 to 7.75; one study, n = 375 infants; Analysis 1.19) (Casey 2015).

1.13 Birthweight There was no evidence of a difference in birthweight between infants whose mothers had been treated with glibenclamide and those who had received placebo reported in one study (Casey 2015) (MD -33.00 g, 95% CI -134.53 to 68.53; one study, n = 375 infants).

Other neonatal secondary outcomes No data were reported for any of the other neonatal secondary outcomes for this review (preterm birth (less than 37 weeks’ gestation; and less than 32 weeks’ gestation), five-minute Apgar less than seven, birthweight z score, head circumference and


23

z score, length and z score, ponderal index, adiposity, respiratory distress syndrome, hypocalcaemia, polycythaemia, relevant biomarker changes associated with the intervention).


2.1 Hypertensive disorders of pregnancy Later infant/childhood outcomes

No data were reported for childhood outcomes (weight and z scores, height and z scores, head circumference and z scores, adiposity, educational attainment, blood pressure, type 1 diabetes, type 2 diabetes, impaired glucose tolerance, dyslipidaemia or metabolic syndrome).

Child as an adult outcomes

No data were reported for child as an adult outcomes (weight, height, adiposity, cardiovascular health (as defined by trialists including blood pressure, hypertension, cardiovascular disease, metabolic syndrome), employment, education and social status/ achievement, dyslipidaemia or metabolic syndrome, type 1 diabetes, type 2 diabetes, impaired glucose tolerance).

Health service outcomes

1.20 Admission to NICU There was no evidence of a difference in the risk of admission to neonatal intensive care between the glibenclamide and the placebo groups reported in one study (Casey 2015) (RR 1.16, 95% CI 0.53 to 2.53; one study, n = 375 infants; Analysis 1.20).

Other health service outcomes No data were reported for the remaining health service outcomes (number of antenatal visits or admissions, number of hospital or health professional visits (including midwife, obstetrician, physician, dietician, diabetic nurse), length of antenatal stay, length of postnatal stay (maternal), length of postnatal stay (baby), cost of maternal care, cost of offspring care, costs associated with the intervention, costs to families associated with the management provided, cost of dietary monitoring (e.g. diet journals, dietician, nurse visits, etc), costs to families - change of diet, extra antenatal visits, extra use of healthcare services (consultations, blood glucose monitoring, length and number of antenatal visits), women’s view of treatment advice, duration of stay in neonatal intensive care unit or special care baby unit).

Metformin versus glibenclamide (comparison 2) Six studies compared metformin with glibenclamide (De Bacco 2015; Fenn 2015; George 2015; Moore 2010; Nachum 2015; Silva 2012).

Overall there was no evidence of a difference between metformin and glibenclamide-treated groups for the risk of hypertensive disorders of pregnancy (any definition) (RR 0.70, 95% CI 0.38 to 1.30; three studies, n = 508 women; Analysis 2.1). Using GRADE the quality of the evidence was judged to be moderate, due to the trials being open-label. If the risk of developing a hypertensive disorder of pregnancy was 8.8% in the glibenclamide group; for those treated with metformin the risk would range from 3.3% to 11.4%. One study reported data for pre-eclampsia (not defined) (Moore 2010). There was no evidence of a difference in the risk for preeclampsia (not defined) between women who had been treated with metformin and those who had been treated with glibenclamide (RR 0.66, 95% CI 0.11 to 3.82; one study, n = 149 women). Two studies reported on pregnancy-induced hypertension, George 2015 did not provide a definition and Silva 2012 reported on the presence of chronic arterial systemic hypertension (no further details). There was no difference in the risk for pregnancy-induced hypertension between women who had been treated with metformin and those who had been treated with glibenclamide (RR 0.71, 95% CI 0.37 to 1.37; two studies, n = 359 women (Analysis 2.1).

2.2 Caesarean section Four studies reported data for caesarean section (Fenn 2015; George 2015; Moore 2010; Silva 2012). There was no evidence of a difference in the risk for birth by caesarean section between women who had been treated with metformin and those who had been treated with glibenclamide (average RR 1.20, 95% CI 0.83 to 1.72; four studies, n = 554 women; I2 = 61%, Tau2 = 0.07) and the heterogeneity could not be explained through the diagnostic criteria used (Analysis 2.2). We excluded the study by Silva 2012 as this had unclear risk of bias for allocation concealment; heterogeneity increased to I2 = 69%, Tau2 = 0.11. The results of the Moore 2010 study, which included primarily Hispanic women with a mean BMI greater than 30 kg/m2 , appeared to differ from the other studies and, when removed from the meta-analysis, heterogeneity was reduced from I2 = 61% to I2 = 0% (RR 1.01, 95% CI 0.86 to 1.20; three studies, n = 405 women). The lack of difference between the metformin and glibenclamide groups for the chance of birth by caesarean section remained unaltered by the removal of Moore 2010. Using GRADE the overall quality of the evidence was low due to lack of blinding and substantial heterogeneity. If the risk of birth by caesarean section when the woman had been treated with glibenclamide was 39.2%, the risk if the woman had been treated with metformin would have ranged from 32.5% to 67.4%.


24

Development of type 2 diabetes

Neurosensory disability in later childhood

No data were reported for development of type 2 diabetes in any of the included studies for this comparison.

No data were reported for neurosensory disability in later childhood for this comparison.

Neonatal primary outcomes


2.3 Perinatal death

2.6 Use of additional pharmacotherapy

Two studies reported data for perinatal death, George 2015 reported no events in either the metformin or the glibenclamide groups; Silva 2012 reported one stillbirth in each group (RR 0.92, 95% CI 0.06 to 14.55; two studies, n = 359 infants) (Analysis 2.3). Using GRADE the quality of the evidence was considered to be very low due to lack of blinding, imprecision and low event rates. If the risk of perinatal death when the mother had been treated with glibenclamide was 6%, the risk if the mother had been treated with metformin would have ranged from 0% to 8.3%.

Five studies reported on the need for additional pharmacological therapy (Fenn 2015; George 2015; Moore 2010; Nachum 2015; Silva 2012). There was no evidence of a difference in the risk of requiring supplemental insulin between women who had been treated with metformin and those treated with glibenclamide (RR 0.66, 95% CI 0.28 to 1.57; five studies, n = 660 women; randomeffects model, I2 = 72%, Tau2 = 0.57; Analysis 2.6). The heterogeneity could not be explained through the diagnostic criteria used (data not shown). In sensitivity analysis we removed two studies which had unclear risk of bias for allocation concealment (Fenn 2015; Nachum 2015); heterogeneity was not affected by their removal (I2 = 77%, Tau2 = 0.50) (data not shown). The Moore 2010 study again appeared to have data that differed from the other studies included in the meta-analysis and exclusion of this study reduced heterogeneity to I2 = 8% but also suggested that the use of metformin was associated with a reduced requirement for additional pharmacotherapy (RR 0.56, 95% CI 0.33 to 0.95; four studies, n = 511 women). The authors of the Moore 2010 study suggested that their findings may differ from those of other studies as their study population comprised Hispanic women and they believe there may be an ethnically differential response to metformin in these women.

2.4 LGA There was no evidence of a difference in the risk of being born LGA when the mother was treated with metformin compared with glibenclamide reported in two studies (Fenn 2015; Silva 2012) (average RR 0.67, 95% CI 0.24 to 1.83; two studies, n = 246 infants; random-effects model, I2 = 54%, Tau2 = 0.30) (Analysis 2.4). Both studies defined LGA as being greater than 90th percentile in growth curves. The subgroup interaction test for diagnostic criteria used was not significant suggesting that there was no differential effect based on diagnostic criteria. Using GRADE the quality of the evidence was considered to be low due to imprecision and heterogeneity. If the risk of being born LGA if the mother had been treated with glibenclamide was 19%, the risk if the mother had been treated with metformin would have ranged from 4.6% to 35.4%.

2.5 Death or serious morbidity composite One study (George 2015) reported data for a composite of neonatal outcomes that included hypoglycaemia, hyperbilirubinaemia, macrosomia, respiratory illness, birth injury, stillbirth or neonatal death. Metformin was associated with a reduction in the risk of the composite outcome compared with glibenclamide (RR 0.54, 95% CI 0.31 to 0.94; one study, n = 159 infants; Analysis 2.5). The evidence should be interpreted with caution as it is based on a single small study. Using GRADE the quality of the evidence was judged to be low due to lack of blinding and publication bias. If the risk of mortality or serious neonatal mortality was 35% if the mother had been treated with glibenclamide, the risk if the mother had been treated with metformin would have ranged from 10.9% to 32.9%.

2.7 Maternal hypoglycaemia Three studies reported on maternal hypoglycaemia. Fenn 2015 and George 2015 did not provide any definitions of maternal hypoglycaemia and Moore 2010 used a cut off of 3.3 mmol/L (60 mg/dL). There was no difference in the risk of maternal hypoglycaemia between women who had been treated with metformin and those treated with glibenclamide (RR 0.89, 95% CI 0.36 to 2.19; three studies, n = 354 women; Analysis 2.7). The De Bacco 2015 study, currently published as a conference abstract, reported data for women who dropped out of the study with hypoglycaemia. Thirty-nine percent of women in the glibenclamide group (17/45) and 3% of women in the metformin group (1/36) “dropped out” of the study due to maternal hypoglycaemia. It is unclear whether they withdrew from the study due to treatment side effects or were lost to follow-up.

2.8 Glycaemic control during/at end of treatment


25

Three studies reported fasting and postprandial blood glucose concentrations (Moore 2010; Silva 2012; George 2015) and one study (Silva 2012) reported HbA1c concentration . Metformin was associated with an increase in fasting blood glucose concentration compared with glibenclamide (standardised mean difference (SMD) 0.19, 95% CI 0.02 to 0.37; three studies, n = 508 women; Analysis 2.8). There was no difference between metformin and glibenclamide for two-hour (after dinner, where reported) post-prandial blood glucose concentration (SMD 0.16, 95% CI -0.01 to 0.34; three studies, n = 508 women; Analysis 2.8). The data for Silva 2012 are for one-hour postprandial (mealtime not specified). One study (Silva 2012) found no evidence of a difference in HbA1c concentration in the third trimester of the pregnancy between treatment with metformin and treatment with glibenclamide (SMD -0.12 %, 95% CI -0.39 to 0.16; one study, n = 200 women). The De Bacco 2015 study, currently published as a conference abstract, reported data for women who “dropped out” of the study as they were unable to attain glycaemic control. Fourteen per cent of the women in the glibenclamide group (6/45) and 3% in the metformin group (1/36) dropped out because they were unable to maintain glycaemic control.

2.9 Weight gain in pregnancy Metformin was associated with a reduced weight during pregnancy compared with glibenclamide, reported by one study (Silva 2012) (MD -2.06 Kg, 95% CI -3.98 to -0.14; one study, n = 200 women; Analysis 2.9).

2.10 Induction of labour One study (George 2015) found no evidence of a difference in the risk for induction of labour between women who had been treated with metformin and those treated with glibenclamide (RR 0.81, 95% CI 0.61 to 1.07; one study; n = 159 women; Analysis 2.10). Using GRADE the quality of the evidence was judged to be low due to lack of blinding and publication bias. If the risk for induction of labour if treated with glibenclamide was 61.3%, the risk if treated with metformin would have ranged from 37.4% to 65.5%.

treated with metformin the risk would have ranged from 0.1% to 8%.

Other maternal secondary outcomes No data were reported for any of the remaining maternal secondary outcomes for this review (Adherence to the intervention, placental abruption, postpartum haemorrhage, postpartum infection, breastfeeding at discharge, six weeks postpartum, six months or longer, maternal mortality, sense of well-being and quality of life, behavioural changes associated with the intervention, views of the intervention, relevant biomarker changes associated with the intervention).

Long-term maternal outcomes

No data were reported for long-term maternal outcomes (postnatal depression, BMI, postnatal weight retention or return to prepregnancy weight, type 1 diabetes, type 2 diabetes, impaired glucose tolerance, subsequent GDM, cardiovascular health (as defined by trialists including blood pressure, hypertension, cardiovascular disease, metabolic syndrome).


2.12 Stillbirth One study (Silva 2012) found no evidence of a difference in the risk for fetal death for infants whose mothers had been treated with metformin or those treated with glibenclamide (RR 0.92, 95% CI 0.06 to 14.55; one study, n = 200 infants; Analysis 2.12).

2.13 Macrosomia Macrosomia was defined as birthweight of 3.7 kg or more by George 2015 and as 4.0 kg or more by Moore 2010. There was no evidence of a difference in the risk for macrosomia for infants whose mothers had been treated with metformin or those treated with glibenclamide (RR 0.72, 95% CI 0.23 to 2.21; two studies, n = 308 infants; Analysis 2.13).

2.11 Perineal trauma/tearing There was no evidence of a difference in the risk for third or fourth degree perineal tearing between women who had been treated with metformin and those treated with glibenclamide reported in two studies (George 2015; Moore 2010) (RR 1.67, 95% CI 0.22 to 12.52; two studies, n = 308 women; Analysis 2.11). Using GRADE the quality of the evidence was judged to be low due to lack of blinding, imprecision and low event rates. If the risk of perineal trauma for women treated with glibenclamide was 0.6%, for those

2.14 to 2.15 Birth trauma; shoulder dystocia One study reported no events of birth injury (no further details) in either the metformin- or the glibenclamide-treated groups ( George 2015). Two studies (Fenn 2015; Moore 2010) reported no evidence of a difference in the risk for shoulder dystocia for infants whose mothers had been treated with metformin or those treated with glibenclamide (RR 0.99, 95% CI 0.14 to 6.89; two studies, n = 195 infants) (Analysis 2.15).


26

2.16 Gestational age at birth

2.21 Neonatal hypoglycaemia

There was no evidence of a difference in gestational age at birth for infants whose mothers had been treated with metformin or those treated with glibenclamide reported in three studies (George 2015; Moore 2010; Silva 2012) (MD 0.03 weeks, 95% CI -0.22 to 0.28; three studies, n = 508 infants; Analysis 2.16). This is probably a reflection of local policies for timing of birth for women with GDM.

There was no evidence of a difference in the risk for neonatal hypoglycaemia (defined as less than 2.2 mmol/L; 40 mg/dL) in infants whose mothers had been treated with metformin or those treated with glibenclamide (RR 0.86, 95% CI 0.42 to 1.77; four studies, n = 554 infants; Analysis 2.21). Using GRADE the quality of the evidence was judged to be low due to lack of blinding and low event rates suggesting imprecision. If the risk of neonatal hypoglycaemia in the group treated with glibenclamide was 4.8%, for those treated with metformin the risk ranged from 1.9% to 8.3%.

2.17 Preterm birth (less than 37 weeks’ gestation); There was no evidence of a difference in the risk for preterm birth (less than 37 weeks’ gestation) for infants whose mothers had been treated with metformin or those treated with glibenclamide reported in three studies (George 2015; Moore 2010; Silva 2012) (RR 1.59, 95% CI 0.59 to 4.29; three studies, n = 508 infants; Analysis 2.17).

2.22 Respiratory distress syndrome There was no evidence of a difference in the risk for neonatal hypoglycaemia in infants whose mothers had been treated with metformin or those treated with glibenclamide reported by George 2015 (RR 0.51, 95% CI 0.10 to 2.69; one study, n = 159 infants; Analysis 2.22).

2.18 Five-minute Apgar less than seven There were no events of a five-minute Apgar score less than seven in either the metformin- or glibenclamide-treated groups in the single study reporting this outcome (Moore 2010). Silva 2012 reported no difference in Apgar scores less than seven with 5/104 events for the metformin group and 5/96 events for the glibenclamide group. However, they do not specify if this is at the one minute or five-minute assessment.

2.23 Neonatal jaundice (hyperbilirubinaemia) There was no evidence of a difference in the risk for hyperbilirubinaemia in infants whose mothers had been treated with metformin or those treated with glibenclamide reported by Fenn 2015 and George 2015 (RR 0.68, 95% CI 0.37 to 1.25; two studies, n = 205 infants; Analysis 2.23).

Relevant biomarkers associated with the intervention 2.19 Birthweight Three studies reported on birthweight. George 2015 reported data adjusted for gestational age, maternal height and gender (metformin 3064 g ± 202 versus glibenclamide 3037 g ± 204). We did not include data from this study in the meta-analysis because heterogeneity was I2 = 86% when we included the study and I2 = 0% when we removed it. We have contacted the study authors in an attempt to obtain the unadjusted data for birthweight. If these data are available we will add them to the meta-analysis in the next update of this review. For the remaining two studies (Moore 2010; Silva 2012), metformin was associated with a reduction in birthweight compared to glibenclamide (MD -209.13 g, 95% CI -314.53 to -103.73; two studies, I2 = 0% n = 249 infants; Analysis 2.19).

2.20 Ponderal index Metformin was associated with a reduced ponderal index compared with glibenclamide reported by Silva 2012 (MD -0.09 units, 95% CI -0.17 to -0.01; one study, n = 200 infants; Analysis 2.20).

Cord C-peptide greater than 1.7 micrograms per litre was reported in eight babies whose mothers had been treated with metformin and in five babies whose mothers had been treated with glibenclamide in one study (Fenn 2015).

Other outcomes not prespecified The De Bacco 2015 study, currently published as a conference abstract, reported data for women who dropped out of the study due to gastric intolerance. Two per cent of women (1/45) in the glibenclamide group and 17% in the metformin group (6/36) withdrew from the study due to gastric intolerance.

Other secondary neonatal outcomes No data were reported for the other neonatal secondary outcomes for this comparison (neonatal death, small-for-gestational age; bone fracture; nerve palsy; congenital malformation; head circumference and z scores; length and z scores; birthweight z scores, head circumference z scores, skinfold thickness measurements (mm); fat mass; hypocalcaemia; hypercalcaemia; polycythaemia).


27

Later infant/childhood outcomes



No data were reported for child as an adulthood outcomes (weight, height, adiposity, cardiovascular health (as defined by trialists including blood pressure, hypertension, cardiovascular disease, metabolic syndrome), employment, education and social status/ achievement, dyslipidaemia or metabolic syndrome, type 1 diabetes, type 2 diabetes, impaired glucose tolerance).


3.1 Caesarean section There was no evidence of a difference in the risk of caesarean section between women who had been treated with glibenclamide and those treated with acarbose (RR 0.95, 95% CI 0.53 to 1.70; one study, n = 43 women; low-quality evidence; Analysis 3.1). The evidence was downgraded for risk of bias (method of randomisation was unclear) and imprecision (single small study).

Other maternal primary outcomes No data were reported on hypertensive disorders of pregnancy or on the development of type 2 diabetes for this comparison.

Neonatal primary outcomes Health service outcomes

2.24 Admission to neonatal intensive care There was no evidence of a difference for admission to the neonatal intensive care unit between the metformin- and glibenclamidetreated groups reported by Moore 2010 and Silva 2012 (RR 1.52, 95% CI 0.65 to 3.56; two studies, n = 349 infants; Analysis 2.24).

Other health service outcomes No data were reported for other health service outcomes (number of antenatal visits or admissions, number of hospital or health professional visits (including midwife, obstetrician, physician, dietician, diabetic nurse), length of antenatal stay, length of postnatal stay (maternal), length of postnatal stay (baby), cost of maternal care, cost of offspring care, costs associated with the intervention, costs to families associated with the management provided, cost of dietary monitoring (e.g. diet journals, dietician, nurse visits, etc), costs to families - change of diet, extra antenatal visits, extra use of healthcare services (consultations, blood glucose monitoring, length and number of antenatal visits), women’s view of treatment advice, duration of stay in neonatal intensive care unit or special care baby unit).

3.2 Perinatal death and later infant mortality There were no cases of perinatal death for either glibenclamideor acarbose-treated women reported by Bertini 2005. Absolute effects could not be reported due to no events being reported for the outcome. The quality of the evidence was low due to selective reporting and evidence being based on a single study.

3.3 LGA Bertini 2005 found no evidence of a difference in the risk for being born LGA (greater than 90th percentile) between infants whose mothers had been treated with glibenclamide and those treated with acarbose (RR 2.38, 95% CI 0.54 to 10.46; one study, n = 43 women; Analysis 3.3). if the risk for being LGA was 10.5% in those infants whose mothers were treated with acarbose, between 5.7% to 100% of those whose mothers had been treated with glibenclamide would be born LGA. The quality of the evidence was judged to be low due to selective reporting and evidence being based on a single study.

Other neonatal primary outcomes No data were reported for death, serious morbidity composite or neurosensory disability in later childhood for this comparison.


3.4 Use of additional pharmacotherapy Acarbose versus other oral anti-diabetic agent (comparison 3) We identified a single small study (n = 43) that compared glibenclamide with acarbose (Bertini 2005).

Bertini 2005 reported no difference in the need for additional insulin between women who had been treated with glibenclamide and those treated with acarbose (RR 0.49, 95% CI 0.19 to 1.27; one study, n = 43 women; Analysis 3.4).


28

3.5 Maternal hypoglycaemia

3.9 Birth trauma

There were no events of maternal hypoglycaemia (requiring hospitalisation) for either glibenclamide- or acarbose-treated women reported by Bertini 2005.

There were no events of birth trauma (not specified) for either glibenclamide- or acarbose-treated women reported by Bertini 2005.

3.6 Weight gain in pregnancy

3.10 Gestational age at birth

There was no evidence of a difference in weight gain in pregnancy between women who had been treated with glibenclamide and those treated with acarbose reported by Bertini 2005 (MD -0.60 Kg, 95% CI -3.13 to 1.93; one study, n = 43 women; Analysis 3.6).

There was no evidence of a difference in gestational age at birth between infants whose mothers had been treated with glibenclamide and those treated with acarbose (MD -0.10 weeks, 95% CI -0.82 to 0.62; one study, n = 43 women; Analysis 3.10).

3.11 Preterm birth Other maternal secondary outcomes No data were reported for the other maternal secondary outcomes of this review (glycaemic control during/end of treatment, adherence to the intervention, induction of labour, placental abruption, postpartum haemorrhage, postpartum infection, perineal trauma/tearing, breastfeeding at discharge, six weeks postpartum, six months or longer, maternal mortality, sense of well-being and quality of life, behavioural changes associated with the intervention, views of the intervention, relevant biomarker changes associated with the intervention).

There were no events of preterm birth for either glibenclamideor acarbose-treated women reported by Bertini 2005.

3.12 Birthweight There was no evidence of a difference in birthweight between infants whose mothers had been treated with glibenclamide and those treated with acarbose (MD 153.00 g, 95% CI -123.52 to 429.52; one study, n = 43 women; Analysis 3.12 ).

3.13 Neonatal hypoglycaemia Long-term maternal outcomes

No data were reported for long-term maternal outcomes (postnatal depression, BMI, postnatal weight retention or return to prepregnancy weight, type 1 diabetes, type 2 diabetes, impaired glucose tolerance, subsequent GDM, cardiovascular health (as defined by trialists including blood pressure, hypertension, cardiovascular disease, metabolic syndrome).

There was no evidence of a difference in the risk of neonatal hypoglycaemia (2.2 mmol/L; less than 40 mg/dL) for infants whose mothers had been treated with glibenclamide and those treated with acarbose (RR 6.33, 95% CI 0.87 to 46.32; one study, n = 43 women; low-quality evidence; Analysis 3.13). If neonatal hypoglycaemia occurred in 5.3% of infants whose mothers had been treated with acarbose, the risk for those whose mothers had been treated with glibenclamide would range from 4.6% to 100%. The quality of the evidence was judged to be very low due to selective reporting, evidence being based on a single study and imprecision.


3.14 Respiratory distress syndrome 3.7 Macrosomia There was no evidence of a difference in the risk of macrosomia (greater than 4 kg) for infants whose mothers had been treated with glibenclamide and those treated with acarbose (RR 7.20, 95% CI 0.41 to 125.97; one study, n = 43 women; Analysis 3.7).

3.8 Small-for-gestational age There were no events of being born small-for-gestational age (not defined) for either glibenclamide or acarbose treated women reported by Bertini 2005.

There were no events of respiratory distress syndrome for either glibenclamide or acarbose treated women reported by Bertini 2005.

Other neonatal secondary outcomes No other neonatal secondary outcomes were reported for this comparison (stillbirth, neonatal death, five-minute Apgar less than seven, birthweight z score, head circumference and z score, length and z score, ponderal index, adiposity, neonatal jaundice (hyperbilirubinaemia), hypocalcaemia, polycythaemia, relevant biomarker changes associated with the intervention).


29

Later infant/childhood outcomes



No data were reported for child as an adult outcomes (weight, height, adiposity, cardiovascular health (as defined by trialists including blood pressure, hypertension, cardiovascular disease, metabolic syndrome), employment, education and social status/ achievement, dyslipidaemia or metabolic syndrome, type 1 diabetes, type 2 diabetes, impaired glucose tolerance).

Health service outcomes

Admission to neonatal intensive care

One infant in the glibenclamide group was admitted to neonatal intensive care. The difference was not significant when compared with acarbose (RR 2.49, 95% CI 0.10 to 64.62; one study, n = 43).

Other health service outcomes No data were reported for other health service outcomes (number of antenatal visits or admissions, number of hospital or health professional visits (including midwife, obstetrician, physician, dietician, diabetic nurse), admission to neonatal intensive care unit/ nursery, length of antenatal stay, length of postnatal stay (maternal), length of postnatal stay (baby), cost of maternal care, cost of offspring care, costs associated with the intervention, costs to families associated with the management provided, cost of dietary monitoring (e.g. diet journals, dietician, nurse visits), costs to families - change of diet, extra antenatal visits, extra use of healthcare services (consultations, blood glucose monitoring, length and number of antenatal visits), women’s view of treatment advice, duration of stay in neonatal intensive care unit or special care baby unit).


30


A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

Oral anti-diabetic pharm acological therapies versus placebo - neonatal outcom es Patient or population: inf ants of wom en diagnosed with gestational diabetes Setting: M edical Centre, USA Intervention: oral anti-diabetic pharm acological therapies (glibenclam ide) Comparison: placebo Outcomes





Risk with placebo

Risk with oral anti- diabetic pharmacological therapies

Large-f or-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 m ortality

see com m ent

see com m ent

not estim able

-

-

None of the included studies pre-specif ied this outcom e

Death or serious m or- see com m ent bidity com posite - not reported

see com m ent

not estim able

-

-


Neonatal hypoglycaem ia

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 f or oral antidiabetic pharm acological therapy and 2/ 186 f or placebo group

see com m ent

not estim able

-

-


11 per 1000

Adiposity see com m ent (neonate, child, adult) not m easured 31


Diabetes (child, adult) - see com m ent not m easured

see com m ent

not estim able

-

-


Neurosensory disability see com m ent in later childhood - not m easured

see com m ent

not estim able

-

-



of bias - we did not f ind a published protocol and there were m ore outcom es reported in the published paper than were listed in the trial registration docum ent - downgraded 1 level. b This single trial com prised 93% Hispanic wom en. The results m ay not be generalisable - downgraded 1 level. c Im precision - evidence was based on a single trial only - downgraded 1 level. d Im precison - wide conf idence intervals crossing the line of no ef f ect and low event rates - downgraded 1 level.

32


M etf orm in versus glibenclam ide - m aternal outcom es Patient or population: wom en diagnosed with gestational diabetes Setting: trials conducted in Brazil, India and the USA Intervention: m etf orm in Comparison: glibenclam ide Outcomes


Risk with clamide




gliben- Risk with metformin

Hypertensive disorders 88 per 1000 of pregnancy

62 per 1000 (33 to 114)

RR 0.70 (0.38 to 1.30)

508 (3 RCTs)

⊕⊕⊕ M oderate 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

Developm ent of type see com m ent 2 diabetes - not m easured

see com m ent

not estim able

-

-

None of the included studies f or this com parison had pre-specif ied developm ent of type 2 diabetes as an outcom e

Perineal traum a

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 f or m etf orm in and 1/ 154 f or glibenclam ide

see com m ent

not estim able

-

-

None of the included studies f or this com parison had return to prepregnancy weight as a pre-specif ied outcom e

6 per 1000

Return to pre-preg- see com m ent nancy weight - not m easured

33


Postnatal depression - see com m ent not m easured

see com m ent

not estim able

-

-

Induction of labour

496 per 1000 (374 to 655)

RR 0.81 (0.61 to 1.07)

159 (1 RCT)

⊕⊕

Low ae

613 per 1000

None of the included studies f or this com parison had postnatal depression as a pre-specif ied outcom e


of bias - all studies were open label - downgraded 1 level. of bias - 3 of the 4 studies were open label and 3 of 4 studies were unclear f or blinding of outcom e assessors. 2 studies reported additional outcom es that were not pre-specif ied - downgraded 1 level. c Inconsistency - heterogeneity was high, I 2 = 61% downgraded 1 level. d Im precision - wide conf idence intervals along with low event rates suggest im precision - downgraded 1 level. e Im precision - evidence was based on a single trial - downgraded 1 level. b Risk

34


M etf orm in versus glibenclam ide - neonatal outcom es Patient or population: Inf ants of wom en diagnosed with gestational diabetes Setting: trials conducted in Brazil, India and the USA Intervention: m etf orm in Comparison: glibenclam ide Outcomes





Risk with clamide

gliben- Risk with metformin


193 per 1000

129 per 1000 (46 to 354)

RR 0.67 (0.24 to 1.83)

246 (2 RCTs)

⊕⊕

Low ab


6 per 1000

5 per 1000 (0 to 83)

RR 0.92 (0.06 to 14.55)

359 (2 RCTs)

⊕

Very low c

Death or serious m or- 350 per 1000 bidity com posite

189 per 1000 (109 to 329)

RR 0.54 (0.31 to 0.94)

159 (1 RCT)

⊕⊕

Low d


41 per 1000 (20 to 84)

RR 0.86 (0.42 to 1.77)

554 (4 RCTs)

⊕⊕

Low ae

see com m ent

not estim able

-

-

48 per 1000

Adiposity - not m ea- see com m ent sured

Note that event rates were very low. 1 study had no event of perinatal death in either the m etf orm in nor the glibenclam ide group. The second study had 1 death in each group

None of trials f or ison had adiposity com e

the included this com parpre-specif ied as a trial out-

35


Diabetes - not m ea- see com m ent sured

see com m ent

not estim able

-

-

None of the included trials f or this com parison had pre-specif ied diabetes as a trial outcom e

Neurosensory disability see com m ent in later childhood - not m easured

see com m ent

not estim able

-

-

None of the included trials f or this com parison had pre-specif ied neurosensory disability as a trial outcom e

* The risk in the intervention group (and its 95% conf idence interval) is based on the assum ed risk in the com parison group and the relative effect of the intervention (and its 95% CI). CI: conf idence interval; RCT: random ised controlled trial; RR: risk ratio; OR: odds ratio GRADE Working Group grades of evidence High quality: We are very conf ident that the true ef f ect lies close to that of the estim ate of the ef f ect M oderate quality: We are m oderately conf ident in the ef f ect estim ate: The true ef f ect is likely to be close to the estim ate of the ef f ect, but there is a possibility that it is substantially dif f erent Low quality: Our conf idence in the ef f ect estim ate is lim ited: The true ef f ect m ay be substantially dif f erent f rom the estim ate of the ef f ect Very low quality: We have very little conf idence in the ef f ect estim ate: The true ef f ect is likely to be substantially dif f erent f rom the estim ate of ef f ect a

Risk of bias - allocation concealm ent was unclear in 1 study. 1 study was open label - downgraded 1 level. - heterogeneity was I 2 = 54%, which could not be explained by the diagnostic criteria used - downgraded 1 level. c Risk of bias - includes open label study/ studies with no evidence of blinding of participants or researchers - downgraded 1 level. d Im precision - evidence based on a single sm all study - downgraded 1 level. e Im precision - event rates low (< 30) - downgraded 1 level.

b Inconsistency

36


Glibenclam ide versus acarbose - m aternal outcom es Patient or population: wom en diagnosed with gestational diabetes; 11 to 33 weeks’ gestation; singleton pregnancy Setting: M aternity hospital, Brazil Intervention: Glibenclam ide Comparison: Acarbose Outcomes


Risk with acarbose




Risk with other oral anti- diabetic agent

Hypertensive disorders see com m ent of pregnancy - not reported

see com m ent

not estim able

-

-

No data were reported f or this outcom e

Caesarean section

526 per 1000

500 per 1000 (279 to 895)

RR 0.95 (0.53 to 1.70)

43 (1 RCT)

⊕⊕

Low ab

Developm ent of type 2 see com m ent diabetes - not reported

see com m ent

not estim able

-

-


Perineal traum a - not re- see com m ent ported

see com m ent

not estim able

-

-


Return to pre-preg- see com m ent nancy weight - not reported

see com m ent

not estim able

-

-


Postnatal depression - see com m ent not reported

see com m ent

not estim able

-

-


Induction of labour - not see com m ent reported

see com m ent

not estim able

-

-


37


* The risk in the intervention group (and its 95% conf idence interval) is based on the assum ed risk in the com parison group and the relative effect of the intervention (and its 95% CI). CI: conf idence interval; RCT: random ised controlled trial; RR: risk ratio; OR: odds ratio GRADE Working Group grades of evidence High quality: We are very conf ident that the true ef f ect lies close to that of the estim ate of the ef f ect M oderate quality: We are m oderately conf ident in the ef f ect estim ate: The true ef f ect is likely to be close to the estim ate of the ef f ect, but there is a possibility that it is substantially dif f erent Low quality: Our conf idence in the ef f ect estim ate is lim ited: The true ef f ect m ay be substantially dif f erent f rom the estim ate of the ef f ect Very low quality: We have very little conf idence in the ef f ect estim ate: The true ef f ect is likely to be substantially dif f erent f rom the estim ate of ef f ect a M ethod

of random isation was unclear and the study was open-label - downgraded -1 level. based on a single sm all study - downgraded -1 level.

b Evidence

38


Glibenclam ide versus acarbose - neonatal outcom es Patient or population: wom en with gestational diabetes Setting: m aternity hospital, Brazil Intervention: glibenclam ide Comparison: acarbose Outcomes





Risk with acarbose

Risk with clamide


105 per 1000

251 per 1000 (57 to 1000)

RR 2.38 (0.54 to 10.46)

43 (1 RCT)

⊕⊕

Low ab


see com m ent

see com m ent

not estim able

43 (1 RCT)

⊕⊕

Low ab

No events were reported in either group

Death or serious m or- see com m ent bidity com posite - not reported

see com m ent

not estim able

-

-



333/ 1000 (46 to 1000)

RR 6.33 (0.87 to 46.32) 43 (1 RCT)

⊕⊕

Low ab

Low event rates and sam ple size (8/ 24 in glibenclam ide group and 1/ 19 in acarbose group)

Adiposity - not reported see com m ent

see com m ent

not estim able

-

-


Diabetes - not reported see com m ent

see com m ent

not estim able

-

-


53/ 1000

gliben-

39


Neurosensory disability see com m ent in later childhood - not reported

see com m ent

not estim able

-

-


* The risk in the intervention group (and its 95% conf idence interval) is based on the assum ed risk in the com parison group and the relative effect of the intervention (and its 95% CI). CI: conf idence interval; RCT: random ised controlled trial; RR: risk ratio; OR: odds ratio GRADE Working Group grades of evidence High quality: We are very conf ident that the true ef f ect lies close to that of the estim ate of the ef f ect M oderate quality: We are m oderately conf ident in the ef f ect estim ate: The true ef f ect is likely to be close to the estim ate of the ef f ect, but there is a possibility that it is substantially dif f erent Low quality: Our conf idence in the ef f ect estim ate is lim ited: The true ef f ect m ay be substantially dif f erent f rom the estim ate of the ef f ect Very low quality: We have very little conf idence in the ef f ect estim ate: The true ef f ect is likely to be substantially dif f erent f rom the estim ate of ef f ect a

Risk of bias - evidence of selective reporting - downgraded 1 level. - evidence based on a single sm all study with wide conf idence intervals - downgraded 1 level.

b Im precision

40

DISCUSSION

Summary of main results There was no evidence of a difference between women treated with oral anti-diabetic pharmacological therapies compared with placebo for hypertensive disorders of pregnancy, induction of labour, perineal trauma or risk of birth by caesarean section (Summary of findings for the main comparison). Oral anti-diabetic pharmacological therapy did appear to lower fasting capillary blood glucose concentrations compared with placebo in one study of 375 Hispanic women (Casey 2015). No data were reported for development of type 2 diabetes or return to pre-pregnancy weight or postnatal depression. There was no evidence of a difference in the risk for being born LGA between infants whose mothers received glibenclamide or placebo (Summary of findings 2). There was no evidence of a difference in the risk of macrosomia or in birthweight between infants whose mothers had been treated with glibenclamide and those treated with placebo. No data were reported for perinatal mortality, death or serious morbidity composite, neonatal hypoglycaemia, diabetes or adiposity. Evidence was limited to two studies both of which used a different oral antidiabetic pharmacological therapy. Outcomes of interest for this review were poorly reported. We found few differences between groups for the comparison of metformin versus glibenclamide. Metformin was associated with an increase in fasting blood glucose levels compared with glibenclamide, but no difference in postprandial glucose levels (Summary of findings 3). There was no evidence of a difference between groups for hypertensive disorders of pregnancy, birth by caesarean section, perineal trauma or induction of labour. No data were reported for postnatal depression or development of type 2 diabetes. Metformin was associated with a reduced risk of death or serious morbidity composite (hypoglycaemia, hyperbilirubinaemia, macrosomia, respiratory illness, birth injury, stillbirth or neonatal death) compared with glibenclamide. There was no evidence of a difference between groups for being born LGA, perinatal mortality or neonatal hypoglycaemia. No data were reported for adiposity of diabetes (Summary of findings 4). The evidence for each outcome was based on a limited number of studies with low sample size. The limited evidence for glibenclamide versus acarbose did not identify any differences between groups for the limited maternal and infant outcomes that were reported. There was no evidence of a difference between groups for birth by caesarean section. No data were reported for hypertensive disorders of pregnancy, induction of labour, development of type 2 diabetes, perineal trauma, return to pre-pregnancy weight or postnatal depression (Summary of findings 5). There were no events reported in either group for perinatal mortality. There was no evidence of a difference between groups for being born LGA or neonatal hypoglycaemia. No data were reported for death or serious morbidity composite, adiposity or diabetes (Summary of findings 6).

Overall completeness and applicability of evidence All of the studies reported on women with GDM, although the proportion of women with GDM in the Notelovitz 1971 study could not be clearly ascertained and therefore we could not include the data in a meta-analysis. The number of studies identified was limited for some of the comparisons. In one study we questioned the generalisability of the data due to the demographics of the women recruited being 93% Hispanic (Casey 2015). Oral anti-diabetic agent versus placebo or usual care was reported as a comparison by three studies(Cortez 2006; Myers 2014; Notelovitz 1971); metformin versus glibenclamide was reported by four studies (Fenn 2015; George 2015; Moore 2010; Silva 2012); one study compared glibenclamide with acarbose (Bertini 2005) and one study compared glibenclamide with the addition of metformin if glycaemic targets were not met against metformin with the addition of glibenclamide if glycaemic targets were not met (Nachum 2015). No data were reported on long-term maternal or neonatal/child outcomes and no data were reported on direct or indirect costs of the interventions. Health service outcomes were very poorly reported. Clinicians and women may also be interested in the comparison of oral anti-diabetic pharmacological therapies compared with insulin and we refer the reader to another Cochrane Review that includes this comparison (Brown 2016). None of the studies reported long-term GRADE outcomes for development of type 2 diabetes and postnatal depression for the mother, and none reported adiposity and diabetes for the infants.

Quality of the evidence Eleven included studies (1487 women and their babies) were identified. Two studies are awaiting classification. Overall we judged the evidence to be of unclear risk of bias due to lack of methodological details provided in the individual studies. Two studies reported data for the comparison of oral anti-diabetic pharmacological therapies versus placebo, the main methodological limitations were a lack of adequate reporting to make a judgement regarding risk of bias, lack of generalisability and evidence being based on a single study for many of the reported outcomes. The overall quality of the evidence was judged to be very low using GRADE methodology (Summary of findings for the main comparison; Summary of findings 2. Six studies reported data for the comparison of metformin and glibenclamide, the most commonly used oral anti-diabetic pharmacological therapies. The evidence was generally of moderate to low quality and was downgraded due to lack of blinding, imprecision and evidence being based on a single trial (Summary of findings 3; Summary of findings 4). One study reported on the comparison of glibenclamide versus


41

acarbose, the evidence was considered to be of low quality in the one outcome of interest for this review that was reported and used for assessment of quality using GRADE. The evidence was downgraded for unclear randomisation and only being based on a single study (Summary of findings 5; Summary of findings 6).

Implications for practice

Potential biases in the review process

Implications for research

We conducted a comprehensive search of the literature including both full papers and conference abstracts with no language restrictions. Two researchers independently undertook identification of studies for inclusion in this review, data extraction and data entry. The main limitation of this systematic review is the lack of studies overall and a lack of studies for each comparison. We could not include any data in meta-analyses for chlorpropamide or tolbutamide. These drugs are known to cross the placenta and, due to concerns about risks of congenital abnormalities, are not recommended during pregnancy in high- and middle-income countries. We could not estimate the extent of their use in low-income countries. There was a lack of data reported for the outcomes of interest for this review. Long-term outcomes were not reported.

Oral anti-diabetic pharmacological therapies are becoming more widely used for treating women with gestational diabetes mellitus (GDM). Uncertainty remains due to the limited evidence to support the use of one oral anti-diabetic pharmacological therapy over another.

Due to lack of data reported for the outcomes of interest in this review, the evidence is uncertain as to whether one oral anti-diabetic pharmacological therapy is safer or more effective than another. The choice in use of oral anti-diabetic pharmacological therapy is likely dependent on factors such as preference of the woman, availability and national clinical practice guidelines.

Future research trials should be encouraged to report on the core outcomes suggested in this review and in particular the long-term outcomes for the woman and the infant that have been poorly reported to date.

ACKNOWLEDGEMENTS

Agreements and disagreements with other studies or reviews A systematic review by Balsells 2015 included a head-to-head comparison of metformin with glibenclamide and included two studies (Moore 2010; Silva 2012), both of which are included in this review. Our results concur with the majority of their findings although Balsells 2015 reported that metformin was associated with a reduction in the risk of being born LGA or macrosomic whereas our analyses suggest no difference between metformin and glibenclamide for these outcomes. Another systematic review (Amin 2015) compared glibenclamide with metformin in three included studies (George 2015; Moore 2010; Silva 2012). Their data and that of our review are in agreement, with the exception of LGA and macrosomia, which the Amin 2015 systematic review combined in a composite outcome that reflected an increased risk in infants whose mothers had been treated with glibenclamide (RR 1.94, 95%CI 1.03 to 3.66; three studies, 508 infants) and for which our systematic review reports data separately, finding no evidence of a difference either for macrosomia (RR 0.72, 95%CI 0.23 to 2.21; two studies, 308 infants) or LGA (RR 0.67, 95%CI 0.24 to 1.83; two studies, 246 infants).

AUTHORS’ CONCLUSIONS

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


42

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.

REFERENCES

References to studies included in this review Bertini 2005 {published data only} ∗ Bertini AM, Silva JC, Taborda W, Becker F, Bebber FRL, Viesi JMZ, et al. Perinatal outcomes and the use of oral hypoglycaemic agents. Journal of Perinatal Medicine 2005; 33:519–23. [4803279] Silva JC, Taborda W, Becker F, Aquim G, Viese J, Bertini AM. Preliminary results of the use of oral hypoglycemic drugs on gestational diabetes mellitus [Resultados preliminares do uso de anti–hiperglicemiantes orais no diabete melito gestacional]. Revista Brasileira de Ginecologia y Obstetricia 2005;27(8):461–6. [4803280] Casey 2015 {published data only} Abbassi-Ghanavati M, Caey B, Shivvers S, Tudela C, McIntire D, Leveno K. Randomized trial of glyburide plus diet compared with placebo plus diet in women with gestational diabetes. American Journal of Obstetrics and Gynecology 2014;210:S179. [4803282] ∗ Casey B, Duryea EL, Abbassi-Ghanavati M, Tudela CM, Shivvers SA, McIntire DD, et al. Glyburide in women with mild gestational diabetes: a randomized controlled trial. Obstetrics & Gynecology 2015;126(2):303–9. [4803283] Cortez 2006 {published data only} Cortez J, Tarsa M, Agent S, Chmait R, Moore T. Randomized controlled trial of acarbose vs. placebo in the treatment of gestational diabetes. American Journal of Obstetrics and Gynecology 2006;195(6 Suppl 1):S149. [4803285] De Bacco 2015 {published data only} ∗ De Bacco G, Genro V, Salazer C, Opperman M. High rate of hypoglycemia in diabetic pregnant women on use of glyburide. Diabetology & Metabolic Syndrome 2015;7(Suppl 1):A85. [4803287] Oppermann MLR. Oral antidiabetic agents in pregnancy [Oral antidiabetic agents on gestational diabetes: Modulating effect on fetal growth – a clinical randomized trial]. clinicaltrials.gov/show/NCT02091336 Date first received: 25 February 2014. [4803288] Fenn 2015 {published data only} Fenn MG, Isac M, George M, Korula S. Comparison of metformin with glyburide in gestational diabetes: a double blind randomised clinical trial. Journal of Evolution of Medical and Dental Sciences 2015;4(28):4803–8. [4803290] George 2015 {published data only} CTRI/2014/02/004418. Metformin vs glyburide in gestational diabetes - a randomised controlled trial.

ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=8029 Date first received: 18 February 2014. [4803292] ∗ George A, Mathews JE, Sam D, Beck M, Benjamin, SJ, Abraham A, et al. Comparison of neonatal outcomes in women with gestational diabetes with moderate hyperglycaemia on metformin or glibenclamide - a randomised controlled trial. Australian and New Zealand Journal of Obstetrics and Gynaecology 2015;55:47–52. [4803293] Moore 2010 {published data only} Moore L, Clokey D, Curet L. A randomized controlled trial of metformin and glyburide in gestational diabetes. American Journal of Obstetrics and Gynecology 2008;199(6 Suppl 1):S34. [4803295] Moore L, Clokey D, Robinson A. A randomized trial of metformin compared to glyburide in the treatment of gestational diabetes. American Journal of Obstetrics and Gynecology 2005;193(6 Suppl):S92. [4803296] ∗ Moore LE, Clokey D, Rappaport VJ, Curet LB. Metformin compared with glyburide in gestational diabetes: a randomized controlled trial. Obstetrics & Gynecology 2010; 115(1):55–9. [4803297] Myers 2014 {published data only} ∗ EUCTR: 2013-004065-13. Metformin treatment vs a diabetes model of antenatal care in women with mild fasting hyperglycaemia diagnosed in pregnancy: a pilot study. clinicaltrialsregister.eu/ctr-search/trial/2013-00406513/GB Date first received: 23 October 2013. [4803299] ISRCTN86503951. Management of mild gestational diabetes mellitus (GDM). isrctn.com/ISRCTN86503951 Date first received: 8 January 2014. [4803300] Nachum 2015 {published and unpublished data} Nachum Z, Zafran N, Salim R, Hissin N, Hasanein J, Letova YGZ, et al. A comparison between two oral hypoglycemics: glyburide and metformin and their combination for the treatment of gestational diabetes mellitus - a prospective randomized controlled trial. American Journal of Obstetrics and Gynecology 2015;212(1 Suppl 1):S23. [4803302] Notelovitz 1971 {published data only} Notelovitz M. Sulphonylurea therapy in the treatment of the pregnant diabetic. South African Medical Journal 1971; 45:226–9. [4803304] Silva 2012 {published data only} Bertini AM. Up to date treatment of gestational diabetes mellitus. Journal of Perinatal Medicine 2009;37(Suppl 1):3. [4803306] ∗ Silva JC, Fachin DRRN, Coral ML, Bertini AM. Perinatal impact of the use of metformin and glyburide for the


43

treatment of gestational diabetes mellitus. Journal of Perinatal Medicine 2012;40(3):225–8. [4803307] Silva JC, Pacheco C, Bizato J, de Souza BV, Ribeiro TE, Bertini AM. Metformin compared with glyburide for the management of gestational diabetes. International Journal of Gynecology & Obstetrics 2010;111(1):37–40. [4803308]

References to studies excluded from this review Ainuddin 2013 {published data only} NCT01855763. Metformin in gestational diabetes and type 2 diabetes in pregnancy in a developing country. clinicaltrials.gov/show/NCT01855763 Date first received: 9 May 2013. [4803310] Berens 2015 {published data only} Berens P, Viteri O, Hutchinson M, Blackwell S, Smith J, Ramin S, et al. The effects of metformin on breastfeeding in women with gestational diabetes compared to placebo. American Journal of Obstetrics and Gynecology 2015;212(1 Suppl 1):S340. [4803312] Branch 2010 {unpublished data only} NCT01171456. Early intervention for gestational diabetes. clinicaltrials.gov/show/NCT01171456 Date first received: 13 July 2010. [4803314] Hebert 2011 {published data only} NCT01329016. Glyburide and metformin for gestational diabetes mellitus. clinicaltrials.gov/show/NCT01329016 Date first received: 22 March 2011. [4803316] Smith 2015 {published data only} Smith J, Sallman MA, Berens P, Viteri O, Hutchinson M, Ramin S, et al. Metformin improved lipid profiles in women with gestational diabetes in the first six weeks postpartum. American Journal of Obstetrics and Gynecology 2015;212(1 Suppl 1):S324. [4803318]

References to studies awaiting assessment Coiner 2015 {published data only} Coiner J, Rowe M, DeVente JT. The treatment of diabetes in pregnancy; metformin vs glyburide and insulin biomedical evidence of fetopathy. American Journal of Obstetrics and Gynecology 2014;210(1 Suppl 1):S148. [4803320] Sheizaf 2006 {published data only} NCT00414245. Metformin for the treatment of diabetes in pregnancy. clinicaltrials.gov/ct2/show/record/ NCT00414245 Date first received: 20 December 2006. [4803322]

References to ongoing studies Moore 2016 {unpublished data only} NCT02726490. Glyburide vs Glucovance in the treatment of GDM (GGIG). clinicaltrials.gov/show/NCT02726490 Date first received: 29 March 2016. [4803324]

Additional references

ACOG 2013 American College of Obstetricians and Gynecologists. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. Obstetrics & Gynecology 2013;122(2 Pt 1):406–16. ADA 2013 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2013;36(Suppl 1): 567–74. Amin 2015 Amin M, Suksomboon N, Poolsup N, Malik O. Comparison of glyburide with metformin in treating gestational diabetes mellitus: a systematic review and metaanalysis. Clinical Drug Investigation 2015;35(6):343–51. Anderberg 2010 Anderberg E, Kallen K, Berntorp K. The impact of gestational diabetes mellitus on pregnancy outcome comparing different cut-off criteria for abnormal glucose tolerance. Acta Obstetricia et Gynecologica Scandinavica 2010;89(12):1532–7. Balsells 2015 Balsells M, Garcia-Patterson A, Solà I, Roqué M, Gich I, Corcoy R. Glibenclamide, metformin and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ 2015;350:h102. Barbour 2007 Barbour LA, McCurdy CE, Hernandez TL, Kirwan JP, Catalano PM, Friedman JE. Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes. Diabetes Care 2007;30(Suppl 2):S111–S119. Bellamy 2009 Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet 2009;373(9677):1173–9. Bottalico 2007 Bottalico JN. Recurrent gestational diabetes: risk factors, diagnosis, management, and implications. Seminars in Perinatology 2007;31(3):176–84. Boyadzhieva 2012 Boyadzhieva MV, Atanasova I, Zacharieva S, Tankova T, Dimitrova V. Comparative analysis of current diagnostic criteria for gestational diabetes mellitus. Obstetric Medicine 2012;5:71–7. Brayfield 2014 Brayfeld A (editor). Martindale: The Complete Drug Reference. London: Pharmaceutical Press, 2014. Brown 2015 Brown J, Alwan NA, West J, Brown S, McKinlay CJD, Farrar D, et al. Lifestyle interventions for the treatment of women with gestational diabetes. Cochrane Database of Systematic Reviews 2015, Issue 11. [DOI: 10.1002/ 14651858.CD011970] Brown 2016 Brown J, Grzeskowiak L, Williamson K, Downie MR, Crowther CA. Insulin for the treatment of women with


44

gestational diabetes. Cochrane Database of Systematic Reviews 2016, Issue 1. [DOI: 10.1002/14651858.CD012037] Canadian Diabetes Association 2013 Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Canadian Journal of Diabetes 2013;37 (Suppl 1):S1–S212. Catalano 2003 Catalano PMA, Huston-Presley TL, Amini SB. Increased fetal adiposity: a very sensitive marker of abnormal in utero development. American Journal of Obstetrics & Gynecology 2003;189(6):1698–704. Chamberlain 2013 Chamberlain C, McNamara B, Williams E, Yore D, Oldenburg B, Oats J, et al. Diabetes in pregnancy among indigenous women in Australia, Canada, New Zealand and the United States. Diabetes/Metabolism Research Reviews 2013;29(4):241–56. Chasan-Taber 2008 Chasan-Taber L, Schmidt MD, Pekow P, Sternfeld B, Manson JE, Solomon CG, et al. Physical activity and gestational diabetes mellitus among Hispanic women. Journal of Women’s Health 2008;17(6):999–1008. Christesen 1998 Christesen H, Melender A. Prolonged elimination of tolbutamide in a premature newborn with hyperinsulinaemic hypoglycaemia. European Journal of Endocrinology 1998; 138(6):698–701. Clapp 2006 Clapp JF. Effects of diet and exercise on insulin resistance during pregnancy. Metabolic Syndrome and Related Disorders 2006;4(2):84–90. Coustan 2010 Coustan DR, Lowe LP, Metzger BE, Dyer AR, International Association of Diabetes and Pregnancy Study Groups. The hyperglycemia and adverse pregnancy outcome (HAPO) study: paving the way for new diagnostic criteria for gestational diabetes mellitus. American Journal of Obstetrics and Gynecology 2010;202(6):654.e1–654.e6. Crowther 2005 Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS, et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. New England Journal of Medicine 2005;352(24):2477–86. Cundy 2014 Cundy T, Ackermann E, Ryan EA. Gestational diabetes: new criteria may triple the prevalence but effect on outcomes is unclear. BMJ 2014;348:g1567. Cypryk 2008 Cypryk K, Szymczak W, Czupryniak L, Sobczak M, Lewinski A. Gestational diabetes mellitus - an analysis of risk factors. Endokrynologia Polska (Warszawa) 2008;59(5): 393–7.

Dabelea 2005 Dabelea D, Snell-Bergeon JK, Hartsfield CL, Bischoff KJ, Hamman RF, McDuffie RS, et al. Increasing prevalence of gestational diabetes mellitus (GDM) over time and by birth cohort: Kaiser Permanente of Colorado GDM Screening Program. Diabetes Care 2005;28(3):579–84. Devlieger 2008 Devlieger R, Casteels K, Van Assche FA. Reduced adaptation of the pancreatic B cells during pregnancy is the major causal factor for gestational diabetes: current knowledge and metabolic effects on the offspring. Acta Obstetricia et Gynecologica Scandinavica 2008;87(12):1266–70. Duran 2014 Duran A, Saenz S, Torrejon M, Bordiu E, del Valle L, Galindo M, et al. Introduction of IADPSG criteria for the screening and diagnosis of gestational diabetes mellitus results in improved pregnancy outcomes at a lower cost in a large cohort of pregnant women: the St. Carlos gestational diabetes study. Diabetes Care 2014;37:2442–50. Ekpebegh 2007 Ekpebegh CO, Coetzee EJ, Van der Merwe L, Levett NS. A 10-year retrospective analysis of pregnancy outcome in pregestational Type 2 diabetes: comparison of insulin and oral glucose-lowering agents. Diabetic Medicine 2007;24 (3):253–8. Elliott 1991 Elliott BD, Langer O, Schenker S, Johnson RF. Insignificant transfer of glyburide occurs across the human placenta. American Journal of Obstetrics and Gynecology 1991;165(4 Pt 1):807–12. Esakoff 2009 Esakoff TF, Cheng YW, Sparks TN, Caughey AB. The association between birthweight 4000g or greater and perinatal outcomes in patients with and without gestational diabetes mellitus. American Journal of Obstetrics and Gynecology 2009;200(6):672.e1–672.e4. Ferrara 2007 Ferrara A. Increasing prevalence of gestational diabetes mellitus: a public health perspective. Diabetes Care 2007; 30(Suppl 2):S141–S146. Fonte 2013 Fonte P, Araujo F, Reis S, Sarmento B. Oral insulin delivery: how far are we?. Journal of Diabetes Science and Technology 2013;7(2):520–31. Gilbert 2006 Gilbert C, Valois M, Koren G. Pregnancy outcome after first-trimester exposure to metformin: a meta-analysis. Fertility and Sterility 2006;86(3):658–63. Guerrero-Romero 2010 Guerrero-Romero F, Aradillas-García C, Simental-Mendia LE, Monreal-Escalante E, de la Cruz Mendoza E, RodríguezMoran M. Birth weight, family history of diabetes, and metabolic syndrome in children and adolescents. Journal of Pediatrics 2010;156(5):719–23.


45

HAPO 2008 The HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. New England Journal of Medicine 2008;358:1991–2002. Harder 2009 Harder T, Roepke K, Diller N, Stechling Y, Dudenhausen JW, Plagemann A. Birth weight, early weight gain, and subsequent risk of type 1 diabetes: systematic review and meta-analysis. American Journal of Epidemiology 2009;169 (12):1428–36. Hedderson 2010 Hedderson MM, Gunderson EP, Ferrara A. Gestational weight gain and risk of gestational diabetes mellitus. Obstetrics & Gynecology 2010;115(3):597–604. Henriksen 2008 Henriksen T. The macrosomic fetus: a challenge in current obstetrics. Acta Obstetricia et Gynecologica Scandinavica 2008;87(2):134–45. Higgins 2003 Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327: 557–60. Higgins 2011a Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org. Higgins 2011b Higgins JPT, Deeks JJ, Altman DG (editors). Chapter 16: Special topics in statistics. In: Higgins JPT, Green S (editors), Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org. Hillier 2007 Hillier TA, Pedula KL, Schmidt MM, Mullen JA, Charles MA, Pettitt DJ. Childhood obesity and metabolic imprinting: the ongoing effects of maternal hyperglycemia. Diabetes Care 2007;30(9):2287–92. Hoffman 1998 Hoffman L, Nolan C, Wilson JD, Oats JJ, Simmons D. The Australasian Diabetes in Pregnancy Society. Gestational diabetes mellitus-management guidelines. Medical Journal of Australia 1998;169(2):93–7. IADPSG 2010 International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PA, Damm P, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33(3): 676–82.

Iyer 2010 Iyer H, Khedkar A, Verma M. Oral insulin - a review of current status. Obesity and Metabolism 2010;12(3):179–85. Jastrow 2010 Jastrow N, Roberge S, Gauthier RJ, Laroche L, Duperron L, Brassard N, et al. Effect of birth weight on adverse obstetric outcomes in vaginal birth after cesarean delivery. Obstetrics & Gynecology 2010;115(2 Pt 1):338–43. Ju 2008 Ju H, Rumbold AR, Willson KJ, Crowther CA. Effect of birth weight on adverse obstetric outcomes in vaginal birth after caesarean delivery. BMC Pregnancy and Childbirth 2008;8:31. Kalra 2015 Kalra B, Gupta Y, Singla R, Klara S. Use of oral anti-diabetic agents in pregnancy: a pragmatic approach. North American Journal of Medicine & Science 2015;7(1):6–12. Kemball 1970 Kemball ML, McIver C, Milner RDG, Nourse CH, Schiff D, Tiernan JR. Neonatal hypoglycaemia in infants of diabetic mothers given sulphonyureas drugs in pregnancy. Archives of Disease in Childhood 1970;45(243):696–701. Kim 2002 Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 2002;25:1862–8. Kim 2010 Kim SY, England L, Wilson HG, Bish C, Satten GA, Dietz P. Percentage of gestational diabetes attributable to overweight and obesity. American Journal of Public Health 2010;100(6):1047–52. Knopp 1985 Knopp RH, Bergelin RO, Wahl PW, Walden CE. Relationships of infant birth size to maternal lipoproteins, apoproteins, fuels, hormones, clinical chemistries, and body weight at 36 weeks gestation. Diabetes 1985;34(Suppl 2): 71–7. Lain 2007 Lain KY, Catalano PM. Metabolic changes in pregnancy. Clinical Obstetrics and Gynecology 2007;50(4):938–48. Landon 2009 Landon MB, Spong CY, Thom E, Carpenter MW, Ramin SM, Casey B, et al. A multicenter, randomized trial of treatment for mild gestational diabetes. New England Journal of Medicine 2009;361(14):1339–48. Langer 2000 Langer O, Conway D, Berkus M, Xenakis E-J, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. New England Journal of Medicine 2000;343(16):1134–8. Langer 2005 Langer O, Yogev Y, Most O, Xenakis EM. Gestational diabetes: the consequences of not treating. American Journal of Obstetrics and Gynecology 2005;192(4):989–97.


46

Metzger 1998 Metzger BE, Coustan DR. Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 1998;21 (Suppl 2):B161–7. Metzger 2008 Metzger B for The HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. New England Journal of Medicine 2008;358:1991–2002. Ministry of Health 2014 Ministry of Health. Screening, Diagnosis and Management of Gestational Diabetes in New Zealand: A Clinical Practice Guideline. Wellington: Ministry of Health, 2014. Morisset 2010 Morisset AS, St-Yves A, Veillette J, Weisnagel SJ, Tchernof A, Robitaille J. Prevention of gestational diabetes mellitus: a review of studies on weight management. Diabetes/ Metabolism Research and Reviews 2010;26(1):17–25. Morrison 2008 Morrison JA, Friedman LA, Wang P, Glueck CJ. Metabolic syndrome in childhood predicts adult metabolic syndrome and type 2 diabetes mellitus 25 to 30 years later. Journal of Pediatrics 2008;152(2):201–6. Mulla 2010 Mulla WR, Henry TQ, Homko CJ. Gestational diabetes screening after HAPO: has anything changed?. Current Diabetes Reports 2010;10(3):224–8. Nankervis 2014 Nankervis A, McIntyre HD, Moses R, Ross GP, Callaway L, Porter C, et al. ADIPS consensus guidelines for the testing and diagnosis of hyperglycaemia in pregnancy in Australia and New Zealand. adips.org/downloads/ 2014ADIPSGDMGuidelinesV18.11.2014˙000.pdf (accessed 2014). NICE 2008 National Institute for Health and Clinical Excellence (NICE). Diabetes in Pregnancy: Management of Diabetes and its Complications from Pre-conception to the Postnatal Period. NICE clinical guideline 63. London: NICE, 2008. NICE 2015 National Institute for Health and Clinical Excellence (NICE). Diabetes in Pregnancy: Management of Diabetes and its Complications from Pre-conception to the Postnatal Period. NICE clinical guideline NG3. London: NICE, 2015. Ogunyemi 2011 Ogunyemi DA, Fong A, Rad S, Kjos SL. Attitudes and practices of healthcare providers regarding gestational diabetes: results of a survey conducted at the 2010 meeting of the International Association of Diabetes in Study group (IADPSG). Diabetes Medicine 2011;28(8):976–86. Patanè 2000 Patane G, Piro S, Anello M, Rabuazzo, Vigneri R, Purrello F. Exposure to glibenclamide increases rat beta cells sensitivity to glucose. British Journal of Pharmacology 2000;129: 887–92.

Petry 2010 Petry CJ. Gestational diabetes: risk factors and recent advances in its genetics and treatment. British Journal of Nutrition 2010;104(6):775–87. Pettitt 1985 Pettitt DJ, Bennett PH, Knowler WC, Baird HR, Aleck KA. Gestational diabetes mellitus and impaired glucose tolerance during pregnancy. Long-term effects on obesity and glucose tolerance in the offspring. Diabetes 1985;34 (Suppl 2):119–22. Pettitt 1993 Pettitt DJ, Nelson RG, Saad MF, Bennett PH, Knowler WC. Diabetes and obesity in the offspring of Pima Indian women with diabetes during pregnancy. Diabetes Care 1993;16(1):310–4. Radó 1974 Radó JP, Borbély L, Szende L, Fischer J, Takó J. Investigation of the diuretic effect of glibenclamide in healthy subjects and in patients with pituitary and nephrogenic diabetes insipidus. Hormone and Metabolic Research 1974;6(4): 289–92. Ragnarsdottir 2010 Ragnarsdottir LH, Conroy S. Development of macrosomia resulting from gestational diabetes mellitus: physiology and social determinants of health. Advances in Neonatal Care 2010;10(1):7–12. Reece 2009 Reece EA, Leguizamon G, Wiznitzer A. Gestational diabetes: the need for a common ground. Lancet 2009;373 (9677):1789–97. RevMan 2014 [Computer program] The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014. Rowan 2008 Rowan JA, Hague WM, Gao W, Battin MR, Moore MP, for the MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. New England Journal of Medicine 2008;358(19):2003–15. Ryu 2014 Ryu RJ, Hays KE, Hebert MF. Gestational diabetes mellitus management with oral hypoglycemic agents. Seminars in Perinatology 2014;38(8):508–15. Schwarz 2013 Schwarz R, Rosenn B, Aleksa K, Koren G. Transplacental transfer of glyburide; is it clinically significant?. American Journal of Obstetrics and Gynecology 2013;208(Suppl 1):S25. Shah 2008 Shah BR, Retnakaran R, Booth GL. Increased risk of cardiovascular disease in young women following gestational diabetes mellitus. Diabetes Care 2008;31(8):1668–9.


47

Simmons 2015 Simmons D. Safety considerations with pharmacological treatment of gestational diabetes mellitus. Drug Safety 2015; 38(1):65–78. [DOI: 10.1007/s40264-014-0253-9] Solomon 1997 Solomon CG, Willett WC, Carey VJ, Rich-Edwards J, Hunter DJ, Colditz GA, et al. A prospective study of pregravid determinants of gestational diabetes mellitus. JAMA 1997;278(13):1078–83. Suman Rao 2013 Suman Rao PN, Shashidhar A, Ashok C. In utero fuel homeostasis: lessons for a clinician. Indian Journal of Endocrinology and Metabolism 2013;17(1):60–8. Tran 2013 Tran TS, Hirst JE, Do MA, Morris JM, Jeffrey HE. Early prediction of gestational diabetes mellitus in Vietnam: clinical impact of currently recommended diagnostic criteria. Diabetes Care 2013;36(3):618–24. Vohr 2008 Vohr BR, Boney CM. Gestational diabetes: the forerunner for the development of maternal and childhood obesity and metabolic syndrome?. Journal of Maternal-Fetal Medicine 2008;21(3):149–57.

Whincup 2008 Whincup PH, Kaye SJ, Owen CG, Huxley R, Cook DG, Anazawa S, et al. Birth weight and risk of type 2 diabetes: a systematic review. JAMA 2008;300(24):2886–97. WHO 1999 World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Report of a WHO Consultation. Part 1. Geneva, Switzerland: WHO, 1999. WHO 2014 World Health Organization. WHO Diagnostic Criteria and Classification of Hyperglycaemia First Detected in Pregnancy. Report WHO/NMH/MND/13.2. Geneva, Switzerland: WHO, 2014. Zhang 2006 Zhang C, Liu S, Solomon CG, Hu FB. Dietary fiber intake, dietary glycemic load, and the risk for gestational diabetes mellitus. Diabetes Care 2006;29(10):2223–30.

References to other published versions of this review Alwan 2009 Alwan N, Tuffnell DJ, West J. Treatments for gestational diabetes. Cochrane Database of Systematic Reviews 2009, Issue 3. [DOI: 10.1002/14651858.CD003395.pub2] ∗ Indicates the major publication for the study


48

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Bertini 2005 Methods

Randomised, parallel, open-label study

Participants

70 women Inclusion criteria: women diagnosed with GDM whose glycaemic targets were not adequately controlled by diet and exercise alone. GDM diagnosed using WHO criteria 75 g OGTT fasting ≥ 6.1 mmol/L (110 mg/dL); 2-h value ≥ 7.8 mmol/L (140 mg/ dL). Gestational age 11-33 weeks, singleton pregnancy Exclusion criteria: presence of a pathology requiring faster glucose control (e.g. antenatal corticosteroids), other pathologies affecting therapy or perinatal results (no details) Setting: maternity hospital Joinville SC, Brazil Timing: October 2003-July 2004

Interventions

Glyburide (n = 24) - initial dose 5 mg in the morning, increasing every 7 d until glycaemic control achieved up to a maximum of 20 mg Acarbose (n = 19) - initial dose 50 mg before main meals with 50 mg increments every 7 d until glycaemic control achieved to a maximum of 300 mg Insulin (n = 27) - not applicable for this systematic review Where maximum dose was met without adequate glycaemic control insulin therapy was commenced

Outcomes

No primary outcomes were listed for the mother. Secondary outcomes included fasting and postprandial glucose levels, gestational age at birth, severe hypoglycaemia requiring hospitalisation, BMI, gestational weight gain, type of delivery, other occurrences For the infant, primary outcomes: fetal weight, fetal hypoglycaemia; secondary outcomes: birthweight, macrosomia, LGA, capillary blood glucose, neonatal hypoglycaemia, bilirubin level, calcium level, duration of hospitalisation, admission to NICU, death, discharge status

Notes

Sample size calculation - no details ITT analysis - no Funding - no details

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk bias)

State that randomised but no details

Allocation concealment (selection bias)

“Randomization was done by using brown envelopes containing outside the randomization number and in the inside a sheet defining which therapy the patient was allocated to”

Low risk


49

Bertini 2005

(Continued)

Blinding of participants and personnel High risk (performance bias) All outcomes

Open label study. “SInce this study compares 3 therapies with different administration procedures, this was not a blind study”

Blinding of outcome assessment (detection Unclear risk bias) All outcomes

Open label study. No details as to whether outcome assessors were blinded

Incomplete outcome data (attrition bias) All outcomes

Low risk

71 women in total were randomised and 1 was later excluded due to severe asthma that required corticotherapy. This woman was excluded from further analysis

Selective reporting (reporting bias)

Low risk

No evidence of selective reporting although an original protocol was not viewed

Other bias

Low risk

No differences in baseline

Casey 2015 Methods

Randomised, parallel study

Participants

395 women Inclusion criteria: at least 2 abnormal values on a 3-h 100 g OGTT using NDDG criteria and fasting values > 5.8 mmol/L (105 mg/dL); 24-30 weeks’ gestation; singleton pregnancy Exclusion criteria: established pre-gestational diabetes; abnormal gestational diabetes screening (≥ 140 mg/dL) prior to 24 weeks’ gestation, multiple pregnancy; known major fetal anomaly or fetal demise; any renal disease with serum creatinine > 1.0 mg/dL; known liver disease such as hepatitis; maternal or fetal conditions likely to require imminent or very preterm delivery such as pre-eclampsia, preterm premature rupture of membranes, preterm labour, and IUGR; known hypersensitivity or allergic reaction to glyburide Setting: medical centre, Dallas, Texas, USA Timing: September 2008-October 2012

Interventions

All women underwent monitored diet with weekly diary logs and 4 times daily glucose monitoring. Treatment targets were fasting < 5.3 mmol/L (95 mg/dL) and < 6.7 mmol/ L (120 mg/dL) for 2-h post-prandial glucose readings Glibenclamide (n = 189) starting dose 2.5 mg and titrated up to a maximum of 20 mg/ d based on weekly maternal capillary glucose readings Placebo (n = 186) identical capsule to glibenclamide

Outcomes

Primary - birthweight decrease of 200 g Secondary outcomes - mean capillary blood glucose, need for insulin, chorioamnionitis, pregnancy-induced hypertension, need for operative birth, shoulder dystocia, perineal trauma, maternal weight gain, birthweight, SGA, LGA, admission to neonatal intensive care, fracture clavicle, Erbs palsy, hyperbilirubinaemia, active treatment of hypoglycaemia, cord blood pH 3.7 kg), hypoglycaemia (≤ 2.2 mmol/L), need for phototherapy, RDS, stillbirth, neonatal death, birth trauma Secondary outcomes: birthweight, maternal glycaemic control, hypertension, preterm birth < 34 weeks, induction of labour, mode of birth, complications of birth

Notes

Power calculation: yes based on composite outcome ITT analysis: yes Funding: none specified Conflicts of interest: not detailed in manuscript

Risk of bias Bias



Random sequence generation (selection Low risk bias)

“computer generated random list”


“sequentially labelled opaque envelopes” “arranged...in a central research office by research officers not involved in patient care”

Low risk


Women were not blinded

Blinding of outcome assessment (detection Low risk bias) All outcomes

Research officers collecting data were masked to allocation. After birth all babies were monitored by neonatologists who were masked to study participation


Low risk

In the glibenclamide group 6 women did not receive the allocated intervention (obstetrician withdrew 1 woman, 4 women withdrew, 1 woman gave birth elsewhere) In the metformin group 4 women did not receive the allocated intervention (1 withdrew from study and 3 gave birth elsewhere)


Low risk

The outcome of preterm birth < 34 weeks’ gestation was not listed as an outcome in the Trial Registration on the Clinical Trials Registry India (CTRI/2014/02/004418 - registered retrospectively) but was listed and reported in the published manuscript


56

George 2015

Other bias

(Continued)

Unclear risk

An interim analysis requested by the local data monitoring committee showed significant differences in outcomes and the study was stopped before the total sample size of 86 women per group was achieved Groups were balanced at baseline although the metformin group had higher fasting triglyceride levels

Moore 2010 Methods


Participants

149 women diagnosed with GDM following a 1-h 50 g OGCT (≥ 7.2 mmol/L; 130 mg/dL) followed by a 3-h 100 g OGTT using Carpenter and Coustan criteria with 2 or more abnormal results. All women initially treated with diet and exercise counselling. Treatment targets were fasting 5.8 mmol/L (105 mg/dL); or 2-h postprandial blood glucose level 6.7 mmol/L (120 mg/dL). Mean age of women in the glyburide group was 29.6 ± 7.8 years and in the metformin group was 31 ± 7.1 years. Mean BMI in glyburide group was 32.7 ± 7.0 kg/m2 and in the metformin group was 32.8 ± 5.8 kg/m2 . Both groups comprised 88% Hispanic women Inclusion criteria: between 11 and 33 weeks’ gestation Exclusion criteria: history of significant renal or hepatic disease, chronic hypertension requiring medication, or substance misuse Setting: University of New Mexico, Albuquerque, USA Timing: July 2003-May 2008.

Interventions

Metformin (n = 75) initial dose of 500 mg per day taken in divided doses and increased as required to a maximum of 2000 g/d Glibenclamide (n = 74) initial dose of 2.5 mg twice daily increased as required to a maximum of 20 mg daily

Outcomes

Primary outcome: glycaemic control Secondary outcomes: medication failure rate, macrosomia (> 4000 g), admission to NICU, 5-minute Apgar less than 7, birth trauma, pre-eclampsia, maternal and neonatal hypoglycaemia, route of delivery

Notes

Elective delivery was planned at 38 weeks by induction of labour or repeat caesarean section as required ITT - all randomised women were included in the analysis Power calculation - yes, based on a difference in glycaemic control between groups Funding - no details Conflicts of interest - authors state in the manuscript that there were no financial or other conflicts

Risk of bias Bias




57

Moore 2010

(Continued)


“computer generated random list”


“Sequentially labelled, opaque, sealed envelopes”

Low risk


Study participants and care providers were not blinded to the treatment allocation


No details provided


Low risk

All women randomised were analysed. In the glyburide group 3 women never took the drug and 3 relocated before birth. In the metformin group, 5 women had only 2 prenatal visits, 2 relocated and 1 could not tolerate the gastrointestinal side effects and only took 2 doses of metformin


Low risk

All outcomes prespecified in the methods were reported in the results section

Other bias

Low risk

There were no group differences at baseline

Myers 2014 Methods

Parallel, randomised controlled trial (pilot study)

Participants

40 women (target for study was 60) Inclusion criteria: women with mild GDM (fasting blood glucose 5.1-5.4 mmol/L, 2h < 8.5 mmol/L) Exclusion criteria: multiple pregnancy, previous stillbirth, previous shoulder dystocia requiring obstetric manoeuvres, < 16 years old, unable to consent, known allergy or contra-indication to study medication, liver abnormalities, renal dysfunction, acute or chronic disease which might cause tissue hypoxia, lactation Setting: Manchester, UK Timing: unclear

Interventions

Metformin up to 2000 mg/daily with initial dose of 500 mg/day from 26-28 weeks’ gestation to birth +/- insulin if treatment targets not met (no home monitoring) (n = 18) Standard care with dietary advice +/- metformin or insulin if treatment targets not met. Self-monitoring of blood glucose pre-meal and 1-h postprandial (n = 19)

Outcomes

Anxiety, blood glucose, serum insulin, HOMA-IR, acceptability, need for insulin (taken from trial registration document)


58

Myers 2014

(Continued)

Notes

EudraCT number: 2013-004065-13/ ISRCTN86503951

Risk of bias Bias




No details provided


Trial registration document states “..prefilled sealed envelopes created by independent research midwives within the department”

Low risk


“open label”


No details


Unclear risk

3 women did not complete the trial and were not analysed, unclear as to which group they were allocated


High risk

No prespecified outcomes were provided in the conference abstract. Data were reported on n = 40 when according to the trial registration documentation the sample size was n = 60

Other bias

High risk

No reported differences at baseline although differences were reported between participants and non-participants. Evidence in conference abstract format only at present

Nachum 2015 Methods

Randomised, parallel controlled study

Participants

106 women Inclusion criteria: women diagnosed with GDM using Carpenter and Coustan criteria, 14-33 weeks’ gestation, aged 18-45 years, 1 week of dietary treatment, sonographic dating of the pregnancy earlier than 24 weeks Exclusion criteria: suspected IUGR earlier than 24 weeks’ gestation, major fetal malformation, pregestational diabetes mellitus


59

Nachum 2015

(Continued) Setting: Israel Timing: 2012-2014

Interventions

Glibenclamide (n = 55) maximum dose 20 mg per day Metformin (n = 51) maximum dose 2550 mg per day If treatment targets not met then the other drug was added. If both failed then insulin was added Self-monitoring of blood sugar 7 times/d

Outcomes

Primary outcome - glycaemic control

Notes

Sample size calculation - yes based on glycaemic control ITT analysis - not clear in conference abstract Funding - no details in conference abstract Conflicts of interest - no details of whether there was a conflict was stated in the conference abstract

Risk of bias Bias




States randomised but no details


No details

Unclear risk


Open label, participants were not blinded


No details


High risk

Unclear as the data were only reported in a conference abstract


High risk

Unclear as outcomes appear to be reported that were not listed in methods section or in the study registration document

Other bias

High risk

Data were presented as a conference abstract only


60

Notelovitz 1971 Methods

Randomised parallel trial

Participants

207 women from South Africa Inclusion criteria: women who had been screened using a 2-h 100 g OGTT with blood glucose values ≥ 7.8 mmol/L (140 mg/dL), remaining duration of pregnancy allowing for 6 weeks of intervention. Included women with known diabetes, glycosuria, family and obstetric histories suggestive of diabetes Exclusion criteria: established diabetics already on a specific treatment were not randomised Setting: Durban, South Africa Timing: not stated

Interventions

Chlorpropramide (n = 58) maximum dose 250 mg/day Tolbutamide (n = 46) maximum dose 1.5 g/day Insulin (n = 47) Dietary restriction alone (n = 56) Those participants who failed to respond to a treatment were usually then given insulin

Outcomes

None prespecified

Notes

Power calculation - not stated ITT analysis - yes Funding - financial support received from Pfizer laboratories Conflicts of interest - not reported

Risk of bias Bias




“random sample basis”, no other details


Unclear risk

No details

Blinding of participants and personnel Unclear risk (performance bias) All outcomes

No details


No details


Low risk

All women randomised appear to have data


High risk

There were no pre-specified outcomes for the mother or the infant


61

Notelovitz 1971

Other bias

(Continued)

High risk

Paper states that there were no differences between interventions at baseline. The data for GDM and other diabetes could not be separated. The proportion of women with GDM could not be determined and the data have therefore not been included in any meta-analysis

Silva 2012 Methods


Participants

200 women. Mean age in metformin group 32.6 ± 5.6 years and for glyburide group 31.3 ± 5.4 years Women with GDM requiring additional pharmacotherapy. Diagnosis was by WHO criteria Inclusion criteria: > 18 years of age, gestational age 11-33 weeks, single gestation, fetal abdominal circumference > 10% and < 75%, absence of other pathologies that might interfere with perinatal results or hypoglycaemic therapy. Capilliary glucose testing fasting 5.0 mmol/L (90 mg/dL), 1-h postprandial after breakfast lunch and supper < 6. 7 mmol/L (120 mg/dL); 2 abnormal values required Exclusion criteria: intolerance to drugs, unwillingness to participate, fetal risk (abdominal circumference < 10% or > 97%), lack of follow-up or fetal malformation diagnosed at birth Setting: hospital medical centre, Santa Catarina, Brazil Timing: July 2008-September 2010

Interventions

Glyburide (n = 96) starting dose 2.5 mg before breakfast and dinner and increased by 2.5 to 5 mg/week until glycaemic control achieved or to a maximum of 20 mg/d Metformin (n = 104) starting dose 500 mg at breakfast and dinner and increased by 500-1000 mg weekly until glycaemic control achieved or a maximum of 2500 mg/d Insulin was started at 0.7 IU/kg/day regular insulin preprandial and NHP insulin at bedtime when glycaemic targets were not met

Outcomes

Primary outcomes - maternal glucose control, weight, neonatal glucose levels Maternal - weight gain during pregnancy, need for change in therapy, HbA1c, ketonuria, gestational age at birth, severe hypoglycaemia requiring hospitalisation, mode of birth, complications with hypertensive disorders Neonatal - birthweight, LGA, macrosomia, fetal hypoglycaemia, CGT after birth, duration of hospitalisation, death, hospital discharge conditions

Notes

Sample size calculations: no details Funding: no details ITT analysis: where possible

Risk of bias Bias




62

Silva 2012

(Continued)


“randomized”, “computer generated randomization”


Sequential numbering in brown envelopes with the name of the group glyburide or metformin

Low risk


“Open clinical study”


No details


Low risk

2 women were excluded due to intrauterine death, 1 from each group


High risk

Maternal and infant outcomes reported. However macrosomia was prespecified but not reported

Other bias

Low risk

No differences in baseline

BMI: body mass index GDM: gestational diabetes mellitus ITT: intention to treat IUGR: intrauterine growth restriction LGA: large-for-gestational age NICU: neonatal intensive care unit OGTT: oral glucose tolerance test RDS: respiratory distress syndrome SGA: small-for-gestational age

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Ainuddin 2013

Wrong comparator; metformin versus insulin

Berens 2015

Postpartum intervention

Branch 2010

This study comparing metformin and placebo was registered with ClinicalTrials.gov in 2010. Subsequent updates indicate that the study never started to recruit due to insufficient funding for enrolment of participants

Hebert 2011

This is a pharmacokinetic study and not an intervention study


63

(Continued)

Smith 2015

Postpartum intervention

Characteristics of studies awaiting assessment [ordered by study ID] Coiner 2015 Methods

Unclear if this is a randomised trial

Participants

32 women who had undergone amniocentesis for fetal lung maturity

Interventions

Control - non diabetic Metformin only Glibenclamide only Metformin and insulin

Outcomes

Amniotic levels of insulin, glucose and adiponectin

Notes

We are attempting to identify and contact the authors of this study as it is not clear if the women were randomised to treatment or not prior to the amniocentesis. This appears to be unlikely given that there is a control group of women without diabetes. It is also unclear if these are women with GDM or pregestational diabetes

Sheizaf 2006 Methods

Parallel, randomised controlled trial

Participants

200 pregnant women Inclusion: women diagnosed with GDM or type 2 diabetes, singleton pregnancy Exclusion: diabetic nephropathy or proliferative retinopathy, unable to swallow tablets Setting: Israel

Interventions

Metformin (no other details) Comparison (not specified)

Outcomes

None prespecified

Notes

This study was first registered in 2006 (NCT00414245) but does not appear to have started recruitment. We contacted investigators in December 2015 to ascertain study status and to find out what the comparison was in the study

GDM: gestational diabetes mellitus


64

Characteristics of ongoing studies [ordered by study ID] Moore 2016 Trial name or title

Glibenclamide (glyburide) versus Glucovance in the treatment of GDM (GGIG)

Methods

Parallel randomised controlled trial

Participants

Inclusion criteria: GDM, > 12 weeks’ gestation, able to consent Exclusion criteria: unable to consent, pre-existing diabetes, glucose-6-phosphate dehydrogenase deficiency, serum creatinine > 1, liver disease, allergy to sulfa, allergy to glyburide, allergy to metformin, fetal anomaly

Interventions

Glibenclamide 2.5 mg at bedtime increased to a maximum of 20 mg if needed, versus Glucovance (combination of glibenclamide and metformin) (2.5/500) once daily at bedtime increased if required to 20/2000

Outcomes

Glycaemic control, maternal hypoglycaemia, birthweight, Apgar scores, admission to NICU, neonatal hypoglycaemia

Starting date

June 2016

Contact information

Lisa Moore: [email protected]

Notes

GDM: gestational diabetes mellitus NICU: neonatal intensive care unit


65

DATA AND ANALYSES

Comparison 1. Oral anti-diabetic agents versus placebo

Outcome or subgroup title

No. of studies

1 Hypertensive disorders of pregnancy 1.1 Hypertensive disorders of pregnancy (any type) 1.2 Pregnancy-induced hypertension 1.3 Pre-eclampsia 2 Caesarean section 3 Large-for-gestational age 4 Use of additional pharmacotherapy 4.1 Placebo 5 Glycaemic control (end of treatment) (mg/dL) 6 Weight gain in pregnancy (Kg) 7 Induction of labour 8 Perineal trauma 9 Stillbirth 10 Neonatal death 11 Small-for-gestational age 12 Macrosomia 13 Birthweight (g)

1

14 Shoulder dystocia 15 Bone fracture 16 Nerve palsy 17 Gestational age at birth (weeks) 18 Neonatal hypoglycaemia 19 Hyperbilirubinaemia 20 Admission to NICU

No. of participants

Statistical method

Effect size

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

1

375


1.24 [0.81, 1.90]

1

375


1.24 [0.71, 2.19]

1 1 1 2

375 375 375 434

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

1.23 [0.59, 2.56] 1.03 [0.79, 1.34] 0.89 [0.51, 1.58] 0.68 [0.42, 1.11]

2 1

434 375

Risk Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)

0.68 [0.42, 1.11] -3.0 [-5.13, -0.87]

1 1 1 1 1 1 1 1

375 375 375 375 375 375 375 375

Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)

1 1 1 1 1 1 1

375 375 375 375 375 375 375

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.0 [-0.96, 0.96] 1.18 [0.79, 1.76] 0.98 [0.06, 15.62] 0.49 [0.05, 5.38] 0.0 [0.0, 0.0] 1.11 [0.58, 2.10] 0.71 [0.36, 1.41] -33.0 [-134.53, 68. 53] 0.33 [0.01, 8.00] 0.74 [0.17, 3.25] 0.33 [0.01, 8.00] 0.0 [-0.32, 0.32] 1.97 [0.36, 10.62] 1.97 [0.50, 7.75] 1.16 [0.53, 2.53]

Comparison 2. Metformin versus glibenclamide

Outcome or subgroup title 1 Hypertensive disorders of pregnancy 1.1 Pre-eclampsia

No. of studies

No. of participants

3

508


0.70 [0.38, 1.30]

1

149


0.66 [0.11, 3.82]

Statistical method


Effect size

66

1.2 Pregnancy-induced hypertension 2 Caesarean section 2.1 Carpenter and Coustan criteria 2.2 National Diabetes Data Group criteria 2.3 World Health Organization (1999) 3 Perinatal mortality 4 Large-for-gestational age 4.1 Carpenter and Coustan criteria 4.2 World Health Organization (1999) 5 Death or serious morbidity composite 6 Use of additional pharmacotherapy 7 Maternal hypoglycaemia 8 Glycaemic control (mg/L; mmol/L) 8.1 Fasting blood glucose 8.2 Postprandial blood glucose 8.3 HbA1c 9 Weight gain in pregnancy (Kg) 10 Induction of labour 11 Perineal trauma 12 Stillbirth 13 Macrosomia 14 Birth trauma 15 Shoulder dystocia 16 Gestational age at birth (weeks) 17 Preterm birth 18 5-minute Apgar < 7 19 Birthweight (g)

2

359


0.71 [0.37, 1.37]

4 2

554 195

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

1.20 [0.83, 1.72] 2.36 [0.53, 10.52]

1

159

Risk Ratio (M-H, Random, 95% CI)

1.12 [0.75, 1.68]

1

200


0.95 [0.78, 1.15]

2 2 1

359 246 46

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

0.92 [0.06, 14.55] 0.67 [0.24, 1.83] 1.25 [0.38, 4.07]

1

200


0.44 [0.21, 0.92]

1

159


0.54 [0.31, 0.94]

5

660


0.66 [0.28, 1.57]

3 3

354

Risk Ratio (M-H, Fixed, 95% CI) Std. Mean Difference (IV, Fixed, 95% CI)

0.89 [0.36, 2.19] Subtotals only

3 3 1 1 1 2 1 2 1 2 3 3 1 2

508 508 200 200 159 308 200 308 159 195 508 508 149 349

Std. Mean Difference (IV, Fixed, 95% CI) Std. Mean Difference (IV, Fixed, 95% CI) Std. Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)

20 Ponderal index 21 Neonatal hypoglycaemia 22 Respiratory distress syndrome 23 Hyperbilirubinaemia 24 Admission to NICU

1 4 1 2 2

200 554 159 205 349

Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.19 [0.02, 0.37] 0.16 [-0.01, 0.34] -0.12 [-0.39, 0.16] -2.06 [-3.98, -0.14] 0.81 [0.61, 1.07] 1.67 [0.22, 12.52] 0.92 [0.06, 14.55] 0.72 [0.23, 2.21] 0.0 [0.0, 0.0] 0.99 [0.14, 6.89] 0.03 [-0.22, 0.28] 1.59 [0.59, 4.29] 0.0 [0.0, 0.0] -209.13 [-314.53, 103.73] -0.09 [-0.17, -0.01] 0.86 [0.42, 1.77] 0.51 [0.10, 2.69] 0.68 [0.37, 1.25] 1.52 [0.65, 3.56]


67

Comparison 3. Glibenclamide versus acarbose

No. of studies

No. of participants

1 Caesarean section 2 Perinatal mortality 3 Large-for-gestational age 4 Need for additional pharmacotherapy 5 Maternal hypoglycaemia 6 Weight gain in pregnancy (Kg) 7 Macrosomia 8 Small-for-gestational age 9 Birth trauma (not specified) 10 Gestational age at birth (weeks) 11 Preterm birth 12 Birthweight (Kg)

1 1 1 1

43 43 43 43

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.95 [0.53, 1.70] 0.0 [0.0, 0.0] 2.38 [0.54, 10.46] 0.49 [0.19, 1.27]

1 1 1 1 1 1 1 1

43 43 43 43 43 43 43 43

Risk Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)

13 Neonatal hypoglycaemia 14 Respiratory distress syndrome

1 1

43 43

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0] -0.60 [-3.13, 1.93] 7.20 [0.41, 125.97] 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] -0.10 [-0.82, 0.62] 0.0 [0.0, 0.0] 153.0 [-123.52, 429. 52] 6.33 [0.87, 46.32] 0.0 [0.0, 0.0]

Outcome or subgroup title

Statistical method

Effect size

Analysis 1.1. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 1 Hypertensive disorders of pregnancy. Review:

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

Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 1 Hypertensive disorders of pregnancy

Study or subgroup

Anti-diabetic agent

Control

n/N

n/N

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Hypertensive disorders of pregnancy (any type) Casey

2015

Subtotal (95% CI)

39/189

31/186

100.0 %

1.24 [ 0.81, 1.90 ]

189

186

100.0 %

1.24 [ 0.81, 1.90 ]

24/189

19/186

100.0 %

1.24 [ 0.71, 2.19 ]

189

186

100.0 %

1.24 [ 0.71, 2.19 ]

Total events: 39 (Anti-diabetic agent), 31 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.98 (P = 0.33) 2 Pregnancy-induced hypertension Casey

2015

Subtotal (95% CI)

Total events: 24 (Anti-diabetic agent), 19 (Control)

0.01

0.1

Antidiabetic agent

1

10

100

Control

(Continued . . . ) Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes (Review) Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

68

(. . . Study or subgroup

Risk Ratio

Weight

Continued) Risk Ratio

Anti-diabetic agent

Control

n/N

n/N

15/189

12/186

100.0 %

1.23 [ 0.59, 2.56 ]

189

186

100.0 %

1.23 [ 0.59, 2.56 ]

M-H,Fixed,95% CI

M-H,Fixed,95% CI

Heterogeneity: not applicable Test for overall effect: Z = 0.75 (P = 0.45) 3 Pre-eclampsia Casey

2015

Subtotal (95% CI)

Total events: 15 (Anti-diabetic agent), 12 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.55 (P = 0.58) Test for subgroup differences: Chi2 = 0.00, df = 2 (P = 1.00), I2 =0.0%

0.01

0.1

1

Antidiabetic agent

10

100

Control

Analysis 1.2. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 2 Caesarean section. Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 2 Caesarean section

Study or subgroup

Casey

Anti-diabetic agent

Control

n/N

n/N

70/189

67/186

100.0 %

1.03 [ 0.79, 1.34 ]

189

186

100.0 %

1.03 [ 0.79, 1.34 ]

2015

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI


Total events: 70 (Anti-diabetic agent), 67 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.20 (P = 0.84) Test for subgroup differences: Not applicable

0.01

0.1

Anti-diabetic agent

1

10

100

Control


69

Analysis 1.3. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 3 Large-for-gestational age. Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 3 Large-for-gestational age

Study or subgroup

Casey

Anti-diabetic agent

Placebo

n/N

n/N

20/189

22/186

100.0 %

0.89 [ 0.51, 1.58 ]

189

186

100.0 %

0.89 [ 0.51, 1.58 ]

2015

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI


Total events: 20 (Anti-diabetic agent), 22 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.38 (P = 0.70) Test for subgroup differences: Not applicable

0.01

0.1

1

Anti-diabetic agent

10

100

Placebo

Analysis 1.4. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 4 Use of additional pharmacotherapy. Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 4 Use of additional pharmacotherapy

Study or subgroup

Anti-diabetic agent

Control

n/N

n/N

Risk Ratio

Weight

2015

4/189

4/186

17.0 %

0.98 [ 0.25, 3.88 ]

Cortez 2006

12/29

20/30

83.0 %

0.62 [ 0.38, 1.03 ]

Total (95% CI)

218

216

100.0 %

0.68 [ 0.42, 1.11 ]

M-H,Fixed,95% CI


1 Placebo Casey

Total events: 16 (Anti-diabetic agent), 24 (Control) Heterogeneity: Chi2 = 0.41, df = 1 (P = 0.52); I2 =0.0% Test for overall effect: Z = 1.54 (P = 0.12) Test for subgroup differences: Not applicable

0.01

0.1

Oral anti-diabetic

1

10

100

Control


70

Analysis 1.5. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 5 Glycaemic control (end of treatment) (mg/dL). Review:


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

Study or subgroup

Casey

Anti-diabetic agent

2015

Total (95% CI)

Mean Difference

Control

N

Mean(SD)

N

Mean(SD)

189

84 (10)

186

87 (11)

189

Weight

IV,Fixed,95% CI

Mean Difference IV,Fixed,95% CI

100.0 %

-3.00 [ -5.13, -0.87 ]

100.0 % -3.00 [ -5.13, -0.87 ]

186

Heterogeneity: not applicable Test for overall effect: Z = 2.76 (P = 0.0057) Test for subgroup differences: Not applicable

-20

-10

Anti-diabetic agent

0

10

20

Favours control


71

Analysis 1.6. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 6 Weight gain in pregnancy (Kg). Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 6 Weight gain in pregnancy (Kg)

Study or subgroup

Casey

Experimental

2015

Total (95% CI)

Mean Difference

Control

N

Mean(SD)

N

Mean(SD)

189

7.3 (4.5)

186

7.3 (5)

189

Weight

IV,Fixed,95% CI


186

100.0 %

0.0 [ -0.96, 0.96 ]

100.0 %

0.0 [ -0.96, 0.96 ]


-20

-10

Anti-diabetic agent

0

10

20

Control

Analysis 1.7. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 7 Induction of labour. Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 7 Induction of labour

Study or subgroup

Casey

Anti-diabetic agent

Control

n/N

n/N

42/189

35/186

100.0 %

1.18 [ 0.79, 1.76 ]

189

186

100.0 %

1.18 [ 0.79, 1.76 ]

2015

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.01

0.1

Anti-diabetic agent

1

10

100

Control


72

Analysis 1.8. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 8 Perineal trauma. Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 8 Perineal trauma

Study or subgroup

Casey

Anti-diabetic agent

Control

n/N

n/N

1/189

1/186

100.0 %

0.98 [ 0.06, 15.62 ]

189

186

100.0 %

0.98 [ 0.06, 15.62 ]

2015

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.001 0.01 0.1

1

Anti-diabetic agent

10 100 1000 Control

Analysis 1.9. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 9 Stillbirth. Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 9 Stillbirth

Study or subgroup

Casey

Anti-diabetic agent

Control

n/N

n/N

1/189

2/186

100.0 %

0.49 [ 0.05, 5.38 ]

189

186

100.0 %

0.49 [ 0.05, 5.38 ]

2015

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.001 0.01 0.1 Anti-diabetic agent

1

10 100 1000 Control


73

Analysis 1.10. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 10 Neonatal death. Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 10 Neonatal death

Study or subgroup

Casey

Anti-diabetic agent

Control

n/N

n/N

0/189

0/186

Not estimable

189

186

Not estimable

2015

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI


Total events: 0 (Anti-diabetic agent), 0 (Control) Heterogeneity: not applicable Test for overall effect: not applicable Test for subgroup differences: Not applicable

0.01

0.1

1

Anti-diabetic agent

10

100

Control

Analysis 1.11. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 11 Small-for-gestational age. Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 11 Small-for-gestational age

Study or subgroup

Casey

Anti-diabetic agent

Control

n/N

n/N

18/189

16/186

100.0 %

1.11 [ 0.58, 2.10 ]

189

186

100.0 %

1.11 [ 0.58, 2.10 ]

2015

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.002

0.1

Anti-diabetic agent

1

10

500

Control


74

Analysis 1.12. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 12 Macrosomia. Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 12 Macrosomia

Study or subgroup

Casey

Anti-diabetic agent

Placebo

n/N

n/N

13/189

18/186

100.0 %

0.71 [ 0.36, 1.41 ]

189

186

100.0 %

0.71 [ 0.36, 1.41 ]

2015

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI


Total events: 13 (Anti-diabetic agent), 18 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.98 (P = 0.33) Test for subgroup differences: Not applicable

0.01

0.1

1

10

Anti-diabetic agent

100

Placebo

Analysis 1.13. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 13 Birthweight (g). Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 13 Birthweight (g)

Study or subgroup

Casey

Anti-diabetic agent

2015

Total (95% CI)

Mean Difference

Control

N

Mean(SD)

N

Mean(SD)

189

3322 (481)

186

3355 (521)

189

Weight

IV,Fixed,95% CI


100.0 %

-33.00 [ -134.53, 68.53 ]

100.0 % -33.00 [ -134.53, 68.53 ]

186


-500

-250

Anti-diabetic agent

0

250

500

Control


75

Analysis 1.14. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 14 Shoulder dystocia. Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 14 Shoulder dystocia

Study or subgroup

Casey

Anti-diabetic agent

Control

n/N

n/N

0/189

1/186

100.0 %

0.33 [ 0.01, 8.00 ]

189

186

100.0 %

0.33 [ 0.01, 8.00 ]

2015

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.001 0.01 0.1

1

Anti-diabetic agent

10 100 1000 Control

Analysis 1.15. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 15 Bone fracture. Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 15 Bone fracture

Study or subgroup

Casey

Anti-diabetic agent

Control

n/N

n/N

3/189

4/186

100.0 %

0.74 [ 0.17, 3.25 ]

189

186

100.0 %

0.74 [ 0.17, 3.25 ]

2015

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.002

0.1

Anti-diabetic agent

1

10

500

Control


76

Analysis 1.16. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 16 Nerve palsy. Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 16 Nerve palsy

Study or subgroup

Casey

Anti-diabetic agent

Control

n/N

n/N

0/189

1/186

100.0 %

0.33 [ 0.01, 8.00 ]

189

186

100.0 %

0.33 [ 0.01, 8.00 ]

2015

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.001 0.01 0.1

1

Anti-diabetic agent

10 100 1000 Control

Analysis 1.17. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 17 Gestational age at birth (weeks). Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 17 Gestational age at birth (weeks)

Study or subgroup

Casey

Anti-diabetic agent

2015

Total (95% CI)

Mean Difference

Control

N

Mean(SD)

N

Mean(SD)

189

39 (2)

186

39 (1)

189

Weight

IV,Fixed,95% CI


186

100.0 %

0.0 [ -0.32, 0.32 ]

100.0 %

0.0 [ -0.32, 0.32 ]


-4

-2

Anti-diabetic agent

0

2

4

Control


77

Analysis 1.18. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 18 Neonatal hypoglycaemia. Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 18 Neonatal hypoglycaemia

Study or subgroup

Casey

Anti-diabetic agent

Control

n/N

n/N

4/189

2/186

100.0 %

1.97 [ 0.36, 10.62 ]

189

186

100.0 %

1.97 [ 0.36, 10.62 ]

2015

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.001 0.01 0.1

1

Anti-diabetic agent

10 100 1000 Control

Analysis 1.19. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 19 Hyperbilirubinaemia. Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 19 Hyperbilirubinaemia

Study or subgroup

Casey

Anti-diabetic agent

Control

n/N

n/N

6/189

3/186

100.0 %

1.97 [ 0.50, 7.75 ]

189

186

100.0 %

1.97 [ 0.50, 7.75 ]

2015

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.001 0.01 0.1 Anti-diabetic agent

1

10 100 1000 Control


78

Analysis 1.20. Comparison 1 Oral anti-diabetic agents versus placebo, Outcome 20 Admission to NICU. Review:


Comparison: 1 Oral anti-diabetic agents versus placebo Outcome: 20 Admission to NICU

Study or subgroup

Casey

Anti-diabetic agent

Control

n/N

n/N

13/189

11/186

100.0 %

1.16 [ 0.53, 2.53 ]

189

186

100.0 %

1.16 [ 0.53, 2.53 ]

2015

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.01

0.1

Anti-diabetic agent

1

10

100

Control


79

Analysis 2.1. Comparison 2 Metformin versus glibenclamide, Outcome 1 Hypertensive disorders of pregnancy. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 1 Hypertensive disorders of pregnancy

Study or subgroup

Metformin

Glibenclamide

n/N

n/N

Risk Ratio

Weight

2/75

3/74

13.5 %

0.66 [ 0.11, 3.82 ]

75

74

13.5 %

0.66 [ 0.11, 3.82 ]

7/79

9/80

40.0 %

0.79 [ 0.31, 2.01 ]

7/104

10/96

46.5 %

0.65 [ 0.26, 1.63 ]

183

176

86.5 %

0.71 [ 0.37, 1.37 ]

250

100.0 %

0.70 [ 0.38, 1.30 ]

M-H,Fixed,95% CI


1 Pre-eclampsia Moore 2010

Subtotal (95% CI)

Total events: 2 (Metformin), 3 (Glibenclamide) Heterogeneity: not applicable Test for overall effect: Z = 0.47 (P = 0.64) 2 Pregnancy-induced hypertension George 2015 Silva 2012

Subtotal (95% CI)

Total events: 14 (Metformin), 19 (Glibenclamide) Heterogeneity: Chi2 = 0.09, df = 1 (P = 0.77); I2 =0.0% Test for overall effect: Z = 1.01 (P = 0.31)

Total (95% CI)

258

Total events: 16 (Metformin), 22 (Glibenclamide) Heterogeneity: Chi2 = 0.09, df = 2 (P = 0.95); I2 =0.0% Test for overall effect: Z = 1.11 (P = 0.26) Test for subgroup differences: Chi2 = 0.01, df = 1 (P = 0.93), I2 =0.0%

0.01

0.1

Favours metformin

1

10

100

Favours glibenclamide


80

Analysis 2.2. Comparison 2 Metformin versus glibenclamide, Outcome 2 Caesarean section. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 2 Caesarean section

Study or subgroup

Metformin

Glibenclamide

Risk Ratio MH,Random,95% CI

Weight


n/N

n/N

Fenn 2015

15/23

11/23

23.9 %

1.36 [ 0.81, 2.30 ]

Moore 2010

11/75

2/74

5.4 %

5.43 [ 1.25, 23.65 ]

98

97

29.3 %

2.36 [ 0.53, 10.52 ]

1 Carpenter and Coustan criteria

Subtotal (95% CI)

Total events: 26 (Metformin), 13 (Glibenclamide) Heterogeneity: Tau2 = 0.89; Chi2 = 3.82, df = 1 (P = 0.05); I2 =74% Test for overall effect: Z = 1.13 (P = 0.26) 2 National Diabetes Data Group criteria George 2015

Subtotal (95% CI)

31/79

28/80

29.6 %

1.12 [ 0.75, 1.68 ]

79

80

29.6 %

1.12 [ 0.75, 1.68 ]

68/104

66/96

41.1 %

0.95 [ 0.78, 1.15 ]

104

96

41.1 %

0.95 [ 0.78, 1.15 ]

273

100.0 %

1.20 [ 0.83, 1.72 ]

Total events: 31 (Metformin), 28 (Glibenclamide) Heterogeneity: not applicable Test for overall effect: Z = 0.55 (P = 0.58) 3 World Health Organization (1999) Silva 2012

Subtotal (95% CI)

Total events: 68 (Metformin), 66 (Glibenclamide) Heterogeneity: not applicable Test for overall effect: Z = 0.51 (P = 0.61)

Total (95% CI)

281

Total events: 125 (Metformin), 107 (Glibenclamide) Heterogeneity: Tau2 = 0.07; Chi2 = 7.65, df = 3 (P = 0.05); I2 =61% Test for overall effect: Z = 0.96 (P = 0.34) Test for subgroup differences: Chi2 = 1.83, df = 2 (P = 0.40), I2 =0.0%

0.05

0.2

Favours metformin

1

5

20



81

Analysis 2.3. Comparison 2 Metformin versus glibenclamide, Outcome 3 Perinatal mortality. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 3 Perinatal mortality

Study or subgroup

George 2015 Silva 2012

Total (95% CI)

Metformin

Glibenclamide

n/N

n/N

Risk Ratio

Weight

0/79

0/80

1/104

1/96

100.0 %

0.92 [ 0.06, 14.55 ]

183

176

100.0 %

0.92 [ 0.06, 14.55 ]

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI Not estimable

Total events: 1 (Metformin), 1 (Glibenclamide) Heterogeneity: not applicable Test for overall effect: Z = 0.06 (P = 0.95) Test for subgroup differences: Not applicable

0.01

0.1

Favours metformin

1

10

100



82

Analysis 2.4. Comparison 2 Metformin versus glibenclamide, Outcome 4 Large-for-gestational age. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 4 Large-for-gestational age

Study or subgroup

Metformin

Glibenclamide


Weight


n/N

n/N

5/23

4/23

40.1 %

1.25 [ 0.38, 4.07 ]

23

23

40.1 %

1.25 [ 0.38, 4.07 ]

9/104

19/96

59.9 %

0.44 [ 0.21, 0.92 ]

104

96

59.9 %

0.44 [ 0.21, 0.92 ]

119

100.0 %

0.67 [ 0.24, 1.83 ]

1 Carpenter and Coustan criteria Fenn 2015

Subtotal (95% CI)

Total events: 5 (Metformin), 4 (Glibenclamide) Heterogeneity: not applicable Test for overall effect: Z = 0.37 (P = 0.71) 2 World Health Organization (1999) Silva 2012

Subtotal (95% CI)

Total events: 9 (Metformin), 19 (Glibenclamide) Heterogeneity: not applicable Test for overall effect: Z = 2.18 (P = 0.029)

Total (95% CI)

127

Total events: 14 (Metformin), 23 (Glibenclamide) Heterogeneity: Tau2 = 0.30; Chi2 = 2.18, df = 1 (P = 0.14); I2 =54% Test for overall effect: Z = 0.79 (P = 0.43) Test for subgroup differences: Chi2 = 2.18, df = 1 (P = 0.14), I2 =54%

0.01

0.1

Favours metformin

1

10

100



83

Analysis 2.5. Comparison 2 Metformin versus glibenclamide, Outcome 5 Death or serious morbidity composite. Review:


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

Study or subgroup

George 2015

Total (95% CI)

Metformin

Glibenclamide

n/N

n/N

Risk Ratio

Weight

15/79

28/80

100.0 %

0.54 [ 0.31, 0.94 ]

79

80

100.0 %

0.54 [ 0.31, 0.94 ]

M-H,Fixed,95% CI


Total events: 15 (Metformin), 28 (Glibenclamide) Heterogeneity: not applicable Test for overall effect: Z = 2.20 (P = 0.028) Test for subgroup differences: Not applicable

0.01

0.1

Favours metformin

1

10

100



84

Analysis 2.6. Comparison 2 Metformin versus glibenclamide, Outcome 6 Use of additional pharmacotherapy. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 6 Use of additional pharmacotherapy

Study or subgroup

Metformin

Glibenclamide


Weight


n/N

n/N

Fenn 2015

2/23

6/23

16.8 %

0.33 [ 0.07, 1.48 ]

George 2015

0/79

2/80

6.6 %

0.20 [ 0.01, 4.15 ]

Moore 2010

26/75

12/74

29.1 %

2.14 [ 1.17, 3.91 ]

2/51

9/55

16.9 %

0.24 [ 0.05, 1.06 ]

22/104

28/96

30.7 %

0.73 [ 0.45, 1.18 ]

332

328

100.0 %

0.66 [ 0.28, 1.57 ]

Nachum 2015 Silva 2012

Total (95% CI)

Total events: 52 (Metformin), 57 (Glibenclamide) Heterogeneity: Tau2 = 0.57; Chi2 = 14.38, df = 4 (P = 0.01); I2 =72% Test for overall effect: Z = 0.93 (P = 0.35) Test for subgroup differences: Not applicable

0.01

0.1

Favours metformin

1

10

100

Favours glyburide


85

Analysis 2.7. Comparison 2 Metformin versus glibenclamide, Outcome 7 Maternal hypoglycaemia. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 7 Maternal hypoglycaemia

Study or subgroup

Metformin

Glibenclamide

n/N

n/N

Fenn 2015

3/23

6/23

66.7 %

0.50 [ 0.14, 1.76 ]

George 2015

3/79

2/80

22.1 %

1.52 [ 0.26, 8.85 ]

Moore 2010

2/75

1/74

11.2 %

1.97 [ 0.18, 21.30 ]

177

177

100.0 %

0.89 [ 0.36, 2.19 ]

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI


Total events: 8 (Metformin), 9 (Glibenclamide) Heterogeneity: Chi2 = 1.59, df = 2 (P = 0.45); I2 =0.0% Test for overall effect: Z = 0.25 (P = 0.80) Test for subgroup differences: Not applicable

0.002

0.1

Favours metformin

1

10

500



86

Analysis 2.8. Comparison 2 Metformin versus glibenclamide, Outcome 8 Glycaemic control (mg/L; mmol/L). Review:


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

Study or subgroup

Metformin

Std. Mean Difference

Glyburide

Weight

IV,Fixed,95% CI

Std. Mean Difference

N

Mean(SD)

N

Mean(SD)

IV,Fixed,95% CI

George 2015

79

4.9 (0.6)

80

4.8 (0.8)

31.4 %

0.14 [ -0.17, 0.45 ]

Moore 2010

75

94.3 (15)

74

90.9 (13)

29.3 %

0.24 [ -0.08, 0.56 ]

104

90.52 (11.78)

96

88.2 (11.7)

39.3 %

0.20 [ -0.08, 0.47 ]

100.0 %

0.19 [ 0.02, 0.37 ]

1 Fasting blood glucose

Silva 2012

Subtotal (95% CI)

258

250

Heterogeneity: Chi2 = 0.19, df = 2 (P = 0.91); I2 =0.0% Test for overall effect: Z = 2.16 (P = 0.031) 2 Postprandial blood glucose George 2015 (1)

79

7 (0.3)

80

6.7 (1.3)

31.1 %

0.32 [ 0.00, 0.63 ]

Moore 2010 (2)

75

123 (17)

74

119 (19)

29.3 %

0.22 [ -0.10, 0.54 ]

104

126.5 (21)

96

126.4 (17)

39.6 %

0.01 [ -0.27, 0.28 ]

100.0 %

0.16 [ -0.01, 0.34 ]

100.0 %

-0.12 [ -0.39, 0.16 ]

100.0 %

-0.12 [ -0.39, 0.16 ]

Silva 2012

Subtotal (95% CI)

258

250

Heterogeneity: Chi2 = 2.28, df = 2 (P = 0.32); I2 =12% Test for overall effect: Z = 1.85 (P = 0.064) 3 HbA1c Silva 2012

Subtotal (95% CI)

104

104

5.5 (0.8)

96

5.6 (0.9)

96

Heterogeneity: not applicable Test for overall effect: Z = 0.83 (P = 0.41) Test for subgroup differences: Chi2 = 3.69, df = 2 (P = 0.16), I2 =46%

-0.5

-0.25

Favours metformin

0

0.25

0.5

Favours glyburide

(1) 2 hour postprandial (dinner) (2) 2 hour postprandial dinner (Moore 2010)


87

Analysis 2.9. Comparison 2 Metformin versus glibenclamide, Outcome 9 Weight gain in pregnancy (Kg). Review:


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

Study or subgroup

Metformin

Silva 2012

Total (95% CI)

Mean Difference

Glibenclamide

N

Mean(SD)

N

Mean(SD)

104

7.78 (7.42)

96

9.84 (6.42)

104

Weight

IV,Fixed,95% CI


96

100.0 %

-2.06 [ -3.98, -0.14 ]

100.0 %

-2.06 [ -3.98, -0.14 ]


-4

-2

0

Favours metformin

2

4


Analysis 2.10. Comparison 2 Metformin versus glibenclamide, Outcome 10 Induction of labour. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 10 Induction of labour

Study or subgroup

George 2015

Total (95% CI)

Metformin

Glyburide

n/N

n/N

Risk Ratio

Weight

39/79

49/80

100.0 %

0.81 [ 0.61, 1.07 ]

79

80

100.0 %

0.81 [ 0.61, 1.07 ]

M-H,Fixed,95% CI


Total events: 39 (Metformin), 49 (Glyburide) Heterogeneity: not applicable Test for overall effect: Z = 1.49 (P = 0.14) Test for subgroup differences: Not applicable

0.05

0.2

Favours metformin

1

5

20

Favours glyburide


88

Analysis 2.11. Comparison 2 Metformin versus glibenclamide, Outcome 11 Perineal trauma. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 11 Perineal trauma

Study or subgroup

Metformin

Glyburide

n/N

n/N

George 2015

1/79

1/80

66.4 %

1.01 [ 0.06, 15.91 ]

Moore 2010

1/75

0/74

33.6 %

2.96 [ 0.12, 71.52 ]

154

154

100.0 %

1.67 [ 0.22, 12.52 ]

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI


Total events: 2 (Metformin), 1 (Glyburide) Heterogeneity: Chi2 = 0.25, df = 1 (P = 0.62); I2 =0.0% Test for overall effect: Z = 0.50 (P = 0.62) Test for subgroup differences: Not applicable

0.01

0.1

1

Favours metformin

10

100

Favours glyburide

Analysis 2.12. Comparison 2 Metformin versus glibenclamide, Outcome 12 Stillbirth. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 12 Stillbirth

Study or subgroup

Silva 2012

Total (95% CI)

Metformin

Glyburide

n/N

n/N

Risk Ratio

Weight

1/104

1/96

100.0 %

0.92 [ 0.06, 14.55 ]

104

96

100.0 %

0.92 [ 0.06, 14.55 ]

M-H,Fixed,95% CI



0.01

0.1

Favours metformin

1

10

100

Favours glyburide


89

Analysis 2.13. Comparison 2 Metformin versus glibenclamide, Outcome 13 Macrosomia. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 13 Macrosomia

Study or subgroup

Metformin

Glyburide

n/N

n/N

George 2015 (1)

4/79

3/80

42.5 %

1.35 [ 0.31, 5.84 ]

Moore 2010 (2)

1/75

4/74

57.5 %

0.25 [ 0.03, 2.16 ]

154

154

100.0 %

0.72 [ 0.23, 2.21 ]

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI


Total events: 5 (Metformin), 7 (Glyburide) Heterogeneity: Chi2 = 1.65, df = 1 (P = 0.20); I2 =39% Test for overall effect: Z = 0.58 (P = 0.56) Test for subgroup differences: Not applicable

0.002

0.1

1

Favours metformin

10

500

Favours glyburide

(1) Defined as 3.7 kg or greater (2) Defined as 4 kg or greater

Analysis 2.14. Comparison 2 Metformin versus glibenclamide, Outcome 14 Birth trauma. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 14 Birth trauma

Study or subgroup

Metformin

Glyburide

n/N

n/N

Risk Ratio

Weight

George 2015

0/79

0/80

Not estimable

Total (95% CI)

79

80

Not estimable

M-H,Fixed,95% CI


Total events: 0 (Metformin), 0 (Glyburide) Heterogeneity: not applicable Test for overall effect: not applicable Test for subgroup differences: Not applicable

0.01

0.1

Favours metformin

1

10

100

Favours glyburide


90

Analysis 2.15. Comparison 2 Metformin versus glibenclamide, Outcome 15 Shoulder dystocia. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 15 Shoulder dystocia

Study or subgroup

Metformin

Glyburide

n/N

n/N

Fenn 2015

1/23

0/23

24.9 %

3.00 [ 0.13, 70.02 ]

Moore 2010

0/75

1/74

75.1 %

0.33 [ 0.01, 7.95 ]

98

97

100.0 %

0.99 [ 0.14, 6.89 ]

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.002

0.1

1

Favours metformin

10

500

Favours glyburide

Analysis 2.16. Comparison 2 Metformin versus glibenclamide, Outcome 16 Gestational age at birth (weeks). Review:


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

Study or subgroup

Metformin

Mean Difference

Glyburide

Weight

Mean Difference

N

Mean(SD)

N

Mean(SD)

George 2015

79

38.1 (1.6)

80

37.8 (1.6)

25.9 %

0.30 [ -0.20, 0.80 ]

Moore 2010

75

38 (2)

74

38 (1)

24.9 %

0.0 [ -0.51, 0.51 ]

104

38.3 (1.4)

96

38.4 (1.2)

49.2 %

-0.10 [ -0.46, 0.26 ]

100.0 %

0.03 [ -0.22, 0.28 ]

Silva 2012

Total (95% CI)

258

IV,Fixed,95% CI

IV,Fixed,95% CI

250

Heterogeneity: Chi2 = 1.64, df = 2 (P = 0.44); I2 =0.0% Test for overall effect: Z = 0.22 (P = 0.83) Test for subgroup differences: Not applicable

-1

-0.5

Favours metformin

0

0.5

1

Favours glyburide


91

Analysis 2.17. Comparison 2 Metformin versus glibenclamide, Outcome 17 Preterm birth. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 17 Preterm birth

Study or subgroup

Metformin

Glyburide

n/N

n/N

George 2015

3/79

1/80

16.1 %

3.04 [ 0.32, 28.59 ]

Moore 2010

2/75

1/74

16.3 %

1.97 [ 0.18, 21.30 ]

5/104

4/96

67.5 %

1.15 [ 0.32, 4.17 ]

258

250

100.0 %

1.59 [ 0.59, 4.29 ]

Silva 2012

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.01

0.1

Favours metformin

1

10

100

Favours glyburide


92

Analysis 2.18. Comparison 2 Metformin versus glibenclamide, Outcome 18 5-minute Apgar < 7. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 18 5-minute Apgar < 7

Study or subgroup

Metformin

Glyburide

n/N

n/N

0/75

0/74

Not estimable

75

74

Not estimable

Moore 2010

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI


Total events: 0 (Metformin), 0 (Glyburide) Heterogeneity: not applicable Test for overall effect: not applicable Test for subgroup differences: Not applicable

0.01

0.1

1

Favours metformin

10

100

Favours glyburide

Analysis 2.19. Comparison 2 Metformin versus glibenclamide, Outcome 19 Birthweight (g). Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 19 Birthweight (g)

Study or subgroup

Moore 2010 Silva 2012

Total (95% CI)

Metformin

Mean Difference

Glyburide

Weight

Mean Difference

N

Mean(SD)

N

Mean(SD)

75

3103 (600)

74

3330 (334)

45.8 %

-227.00 [ -382.66, -71.34 ]

104

3194 (521)

96

3388 (512)

54.2 %

-194.00 [ -337.23, -50.77 ]

179

IV,Fixed,95% CI

IV,Fixed,95% CI

100.0 % -209.13 [ -314.53, -103.73 ]

170

Heterogeneity: Chi2 = 0.09, df = 1 (P = 0.76); I2 =0.0% Test for overall effect: Z = 3.89 (P = 0.00010) Test for subgroup differences: Not applicable

-200

-100

Favours metformin

0

100

200

Favours glyburide


93

Analysis 2.20. Comparison 2 Metformin versus glibenclamide, Outcome 20 Ponderal index. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 20 Ponderal index

Study or subgroup

Metformin

Silva 2012

Total (95% CI)

Mean Difference

Glyburide

N

Mean(SD)

N

Mean(SD)

104

2.87 (0.31)

96

2.96 (0.29)

104

Weight

IV,Fixed,95% CI


96

100.0 %

-0.09 [ -0.17, -0.01 ]

100.0 %

-0.09 [ -0.17, -0.01 ]


-0.2

-0.1

0

Favours metformin

0.1

0.2

Favours glyburide

Analysis 2.21. Comparison 2 Metformin versus glibenclamide, Outcome 21 Neonatal hypoglycaemia. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 21 Neonatal hypoglycaemia

Study or subgroup

Metformin

Glibenclamide

n/N

n/N

Fenn 2015

0/23

0/23

Not estimable

George 2015 (1)

0/79

0/80

Not estimable

Moore 2010

1/75

0/74

3.6 %

2.96 [ 0.12, 71.52 ]

11/104

13/96

96.4 %

0.78 [ 0.37, 1.66 ]

281

273

100.0 %

0.86 [ 0.42, 1.77 ]

Silva 2012

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI


Total events: 12 (Metformin), 13 (Glibenclamide) Heterogeneity: Chi2 = 0.64, df = 1 (P = 0.42); I2 =0.0% Test for overall effect: Z = 0.41 (P = 0.68) Test for subgroup differences: Not applicable

0.001 0.01 0.1 Favours metformin

1

10 100 1000 Favours glibenclamide


94

(1) Defined as less than or equal to 2.2 mmol/L

Analysis 2.22. Comparison 2 Metformin versus glibenclamide, Outcome 22 Respiratory distress syndrome. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 22 Respiratory distress syndrome

Study or subgroup

Metformin

Glyburide

n/N

n/N

Risk Ratio

Weight

George 2015

2/79

4/80

100.0 %

0.51 [ 0.10, 2.69 ]

Total (95% CI)

79

80

100.0 %

0.51 [ 0.10, 2.69 ]

M-H,Fixed,95% CI



0.01

0.1

Favours metformin

1

10

100

Favours glyburide


95

Analysis 2.23. Comparison 2 Metformin versus glibenclamide, Outcome 23 Hyperbilirubinaemia. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 23 Hyperbilirubinaemia

Study or subgroup

Metformin

Glyburide

n/N

n/N

0/23

3/23

16.4 %

0.14 [ 0.01, 2.62 ]

George 2015 (1)

14/79

18/80

83.6 %

0.79 [ 0.42, 1.47 ]

Total (95% CI)

102

103

100.0 %

0.68 [ 0.37, 1.25 ]

Fenn 2015

Risk Ratio

Weight

M-H,Fixed,95% CI



0.1 0.2

0.5

1

Favours metformin

2

5

10

Favours glyburide

(1) Requiring phototherapy only

Analysis 2.24. Comparison 2 Metformin versus glibenclamide, Outcome 24 Admission to NICU. Review:


Comparison: 2 Metformin versus glibenclamide Outcome: 24 Admission to NICU

Study or subgroup

Moore 2010 Silva 2012

Total (95% CI)

Metformin

Glyburide

n/N

n/N

Risk Ratio

Weight

4/75

1/74

12.1 %

3.95 [ 0.45, 34.48 ]

9/104

7/96

87.9 %

1.19 [ 0.46, 3.06 ]

179

170

100.0 %

1.52 [ 0.65, 3.56 ]

M-H,Fixed,95% CI



0.01

0.1

Favours metformin

1

10

100

Favours glyburide


96

Analysis 3.1. Comparison 3 Glibenclamide versus acarbose, Outcome 1 Caesarean section. Review:


Comparison: 3 Glibenclamide versus acarbose Outcome: 1 Caesarean section

Study or subgroup

other anti-diabetic agent

Acarbose

n/N

n/N

12/24

10/19

100.0 %

0.95 [ 0.53, 1.70 ]

24

19

100.0 %

0.95 [ 0.53, 1.70 ]

Bertini 2005

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI


Total events: 12 (other anti-diabetic agent), 10 (Acarbose) Heterogeneity: not applicable Test for overall effect: Z = 0.17 (P = 0.86) Test for subgroup differences: Not applicable

0.01

0.1

1

Other anti-diabetic agent

10

100

Acarbose

Analysis 3.2. Comparison 3 Glibenclamide versus acarbose, Outcome 2 Perinatal mortality. Review:


Comparison: 3 Glibenclamide versus acarbose Outcome: 2 Perinatal mortality

Study or subgroup

Glyburide

Acarbose

n/N

n/N

0/24

0/19

Not estimable

24

19

Not estimable

Bertini 2005

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI


Total events: 0 (Glyburide), 0 (Acarbose) Heterogeneity: not applicable Test for overall effect: not applicable Test for subgroup differences: Not applicable

0.01

0.1

Favours glyburide

1

10

100

Favours acarbose


97

Analysis 3.3. Comparison 3 Glibenclamide versus acarbose, Outcome 3 Large-for-gestational age. Review:


Comparison: 3 Glibenclamide versus acarbose Outcome: 3 Large-for-gestational age

Study or subgroup

Bertini 2005

Total (95% CI)

Glyburide

Acarbose

n/N

n/N

Risk Ratio

Weight

6/24

2/19

100.0 %

2.38 [ 0.54, 10.46 ]

24

19

100.0 %

2.38 [ 0.54, 10.46 ]

M-H,Fixed,95% CI


Total events: 6 (Glyburide), 2 (Acarbose) Heterogeneity: not applicable Test for overall effect: Z = 1.14 (P = 0.25) Test for subgroup differences: Not applicable

0.01

0.1

1

Favours glyburide

10

100

Favours acarbose

Analysis 3.4. Comparison 3 Glibenclamide versus acarbose, Outcome 4 Need for additional pharmacotherapy. Review:


Comparison: 3 Glibenclamide versus acarbose Outcome: 4 Need for additional pharmacotherapy

Study or subgroup

Bertini 2005

Total (95% CI)

Glyburide

Acarbose

n/N

n/N

Risk Ratio

Weight

5/24

8/19

100.0 %

0.49 [ 0.19, 1.27 ]

24

19

100.0 %

0.49 [ 0.19, 1.27 ]

M-H,Fixed,95% CI



0.01

0.1

Favours glyburide

1

10

100

Favours acarbose


98

Analysis 3.5. Comparison 3 Glibenclamide versus acarbose, Outcome 5 Maternal hypoglycaemia. Review:


Comparison: 3 Glibenclamide versus acarbose Outcome: 5 Maternal hypoglycaemia

Study or subgroup

Glyburide

Acarbose

n/N

n/N

0/24

0/19

Not estimable

24

19

Not estimable

Bertini 2005

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.01

0.1

1

10

Favours glyburide

100

Favours acarbose

Analysis 3.6. Comparison 3 Glibenclamide versus acarbose, Outcome 6 Weight gain in pregnancy (Kg). Review:


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

Study or subgroup

Glyburide

Bertini 2005

Total (95% CI)

Mean Difference

Acarbose

N

Mean(SD)

N

Mean(SD)

24

10 (5.2)

19

10.6 (3.2)

24

Weight

IV,Fixed,95% CI


19

100.0 %

-0.60 [ -3.13, 1.93 ]

100.0 %

-0.60 [ -3.13, 1.93 ]


-10

-5

Favours glyburide

0

5

10

Favours acarbose


99

Analysis 3.7. Comparison 3 Glibenclamide versus acarbose, Outcome 7 Macrosomia. Review:


Comparison: 3 Glibenclamide versus acarbose Outcome: 7 Macrosomia

Study or subgroup

Glyburide

Acarbose

n/N

n/N

4/24

0/19

100.0 %

7.20 [ 0.41, 125.97 ]

24

19

100.0 %

7.20 [ 0.41, 125.97 ]

Bertini 2005

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.01

0.1

1

Favours glyburide

10

100

Favours acarbose

Analysis 3.8. Comparison 3 Glibenclamide versus acarbose, Outcome 8 Small-for-gestational age. Review:


Comparison: 3 Glibenclamide versus acarbose Outcome: 8 Small-for-gestational age

Study or subgroup

Glyburide

Acarbose

n/N

n/N

0/24

0/19

Not estimable

24

19

Not estimable

Bertini 2005

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.01

0.1

Favours glyburide

1

10

100

Favours acarbose


100

Analysis 3.9. Comparison 3 Glibenclamide versus acarbose, Outcome 9 Birth trauma (not specified). Review:


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

Study or subgroup

Glyburide

Acarbose

n/N

n/N

0/24

0/19

Not estimable

24

19

Not estimable

Bertini 2005

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.01

0.1

1

10

Favours glyburide

100

Favours acarbose

Analysis 3.10. Comparison 3 Glibenclamide versus acarbose, Outcome 10 Gestational age at birth (weeks). Review:


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

Study or subgroup

Glyburide

Bertini 2005

Total (95% CI)

Mean Difference

Acarbose

N

Mean(SD)

N

Mean(SD)

24

38.1 (1.2)

19

38.2 (1.2)

24

Weight

IV,Fixed,95% CI


19

100.0 %

-0.10 [ -0.82, 0.62 ]

100.0 %

-0.10 [ -0.82, 0.62 ]


-4

-2

Favours glyburide

0

2

4

Favours acarbose


101

Analysis 3.11. Comparison 3 Glibenclamide versus acarbose, Outcome 11 Preterm birth. Review:


Comparison: 3 Glibenclamide versus acarbose Outcome: 11 Preterm birth

Study or subgroup

Glyburide

Acarbose

n/N

n/N

0/24

0/19

Not estimable

24

19

Not estimable

Bertini 2005

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.01

0.1

1

10

Favours glyburide

100

Favours acarbose

Analysis 3.12. Comparison 3 Glibenclamide versus acarbose, Outcome 12 Birthweight (Kg). Review:


Comparison: 3 Glibenclamide versus acarbose Outcome: 12 Birthweight (Kg)

Study or subgroup

Glyburide

Bertini 2005

Total (95% CI)

Mean Difference

Acarbose

N

Mean(SD)

N

Mean(SD)

24

3395.6 (524.4)

19

3242.6 (400.6)

24

Weight

IV,Fixed,95% CI


100.0 %

153.00 [ -123.52, 429.52 ]

100.0 % 153.00 [ -123.52, 429.52 ]

19


-1000

-500

Favours glyburide

0

500

1000

Favours acarbose


102

Analysis 3.13. Comparison 3 Glibenclamide versus acarbose, Outcome 13 Neonatal hypoglycaemia. Review:


Comparison: 3 Glibenclamide versus acarbose Outcome: 13 Neonatal hypoglycaemia

Study or subgroup

Glyburide

Acarbose

n/N

n/N

8/24

1/19

100.0 %

6.33 [ 0.87, 46.32 ]

24

19

100.0 %

6.33 [ 0.87, 46.32 ]

Bertini 2005

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.01

0.1

1

Favours glyburide

10

100

Favours acarbose

Analysis 3.14. Comparison 3 Glibenclamide versus acarbose, Outcome 14 Respiratory distress syndrome. Review:


Comparison: 3 Glibenclamide versus acarbose Outcome: 14 Respiratory distress syndrome

Study or subgroup

Glyburide

Acarbose

n/N

n/N

0/24

0/19

Not estimable

24

19

Not estimable

Bertini 2005

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI



0.01

0.1

Favours glyburide

1

10

100

Favours acarbose


103

ADDITIONAL TABLES Table 1. Examples of diagnostic criteria for gestational diabetes

Organisation/ professional body

Screening and diagnostic criteria

1-hour oral glu- Oral glucose Fasting cose challenge tolerance test test

1 hour

2 hour

3 hour

ADA 2013a , IADPSG 2010a , ADIPS 2013 ( Nankervis 2014) a , WHO 2014a

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 Coustanb National Diabetes Data Groupb

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 100 g (> 7.8 mmol/L; > 140 mg/dL)

≥ 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 eithera orb

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)

-

≥ 5.5 mmol/L (≥ 99 mg/dL)

-

≥ 9.0 mmol/L (≥ 162 mg/dL)

-

New Zealand 50 g if HbA1c < 75 g Ministry of 41 mmol/mol (≥ 7.8 mmol/L; Health 2014a ≥ 140 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 a 1 abnormal result required for diagnosis Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes (Review) Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

104

b

2 or more abnormal results required for diagnosis

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



George 2015

33.4 ± 4.4 (n = 79), metformin


Moore 2010

31 ± 7.1 (n = 75) - metformin


Myers 2014


Not stated, standard care

Nachum 2015



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


Table 3. Maternal BMI kg/m2

Study ID

Intervention

Comparison

Timepoint BMI measured at

Bertini 2005


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


Baseline

Moore 2010

32.8 ± 5.8 (n = 75), metformin


Not stated


105

Table 3. Maternal BMI kg/m2

(Continued)

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


Not stated

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


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


25.4 ± 7.1 weeks’ (n = 96), glibenclamide

Table 5. Diagnostic criteria

Study ID

Timing

Screening

Diagnosis

Criteria

Casey 2015

24-28 weeks’

1 hour, 50 g OGCT(≥ 7.8 2 abnormal values National Diabetes Data Group mmol/L; 140 mg/dL) 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)


106

Table 5. Diagnostic criteria

(Continued)

Bertini 2005

11-33 weeks’

Not stated

75 g OGTT WHO criteria (old) Fasting ≥ 6.1 mmol/L (110 mg/dL); 2-hour value ≥ 7.8 mmol/L (140 mg/dL).

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 2 abnormal values Carpenter and Coustan mmol/L; 140 mg/dL) 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

George 2015

24-28 weeks’

Not stated

Moore 2010

11-33 weeks’

1 hour 50 g OGCT (≥ 7.2 3 hour 100 g OGTT using cri- Carpenter and Coustan mmol/L; 130 mg/dL) teria with 2 or more abnormal results

Myers 2014

Not stated

Not stated

Nachum 2015

11-33 weeks’

1 hour 50 g OGCT (≥ 7.2 3 hour 100 g OGTT using cri- Carpenter and Coustan mmol/L; 130 mg/dL) teria with 2 or more abnormal results

Notelovitz 1971

Not stated

Not stated

Not stated

Not stated

Silva 2012

Not stated

Not stated

Not stated

WHO criteria (1999)

2 abnormal values National Diabetes Data Group 100 g OGTT: (1979) fasting glucose ≥ 5.3 mmol/L, 1-hour ≥ 10 mmol/L, 2-hour ≥ 8.6 mmol/L, 3-hour ≥ 7.8 mmol/L

Fasting blood glucose 5.1 to 5. Not stated 4 mmol/L, 2 hour < 8.5 mmol/L

OGCT oral glucose tolerance test; OGTT oral glucose tolerance test


107

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


108

APPENDICES Appendix 1. Trial registry search strategy ClinicalTrials.gov and WHO ICTRP Search terms: oral anti-diabetic OR oral hypoglycaemic* OR oral hypoglycemic* OR metformin OR glibenclamide OR glyburide OR acarbose AND gestational diabetes OR GDM (In ICTRP, each term for medication was combined separately with each term for gestational diabetes)

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.

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

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.


109

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

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)


110