Supplementary table 1. Search strategy

Transcription

1 Table of contents Supplementary table 1. Search strategy Supplementary figure 1. Flow chart of articles through the selection process.. 4 Supplementary table 2. Characteristics and baseline data of the individual studies 5 Supplementary table 3. Quality assessment of studies included in the meta-analyses.. 6 Supplementary figure 2. Forest plots of primary outcome variables with significant differences Supplementary table 4. Baseline characteristics Supplementary table 5. Sensitivity analysis for the comparison glyburide insulin... 9 Supplementary table 6. Sensitivity analysis for the comparison metformin insulin

2 Supplementary table 1. Search strategy MEDLINE (PubMed) #1 [MeSH] 5415 #2 ""[MeSH] 6142 #3 oral diabetes agent*[tiab] 12 #4 oral antidiabetic agent*[tiab] 658 #5 oral hypoglycemic agent*[tiab] 1406 #6 metformin[tiab] 8079 #7 glyburide[tiab] 1212 #8 glibenclamide[tiab] 6634 #9 glimepiride[tiab] 744 #10 glipizide[tiab] 830 #11 sulfonylurea[tiab] 4029 #12 sulphonylurea[tiab] 1331 #13 (((((((((((#1) OR #2) OR #3) OR #4) OR #5) OR #6) OR #7) OR #8) OR #9) OR #10) OR #11) OR # #14 Pregnancy [MeSH] #15 Diabetes, Gestational [MeSH] 6200 #16 pregnan*[tiab] #17 gestation*[tiab] #18 GDM[tiab] 2545 #19 ((((#14) OR #15) OR #16) OR #17) OR # #20 (#13) AND # #21 (randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR placebo[tiab] OR drug therapy[sh] OR randomly[tiab] OR trial[tiab] OR groups[tiab]) NOT (animals[mh] NOT (humans[mh] AND animals[mh])) #22 (#20) AND # Cochrane Central Register of Controlled Trials (The Cochrane Libray: Issue 4 of 12) #1 MeSH descriptor: [] explode all trees 473 #2 MeSH descriptor: [] explode all trees 1334 #3 oral diabetes agent*:ti,ab 872 #4 oral antidiabetic agent*:ti,ab 159 #5 oral hypoglycemic agent*:ti,ab 552 #6 metformin:ti,ab 1728 #7 glyburide:ti,ab 194 #8 glibenclamide:ti,ab 474 #9 glimepiride:ti,ab 215 #10 glipizide:ti,ab 179 #11 sulfonylurea:ti,ab 475 #12 sulphonylurea:ti,ab 258 #13 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or # #14 MeSH descriptor: [Pregnancy] explode all trees 5310 #15 MeSH descriptor: [Diabetes, Gestational] explode all trees 276 #16 pregnan*:ti,ab #17 gestation*:ti,ab 6261 #18 GDM:ti,ab 118 #19 #14 or #15 or #16 or #17 or # #20 #13 and # (164 in Clinical Trials) EMBASE (OVID Embase Classic+Embase 1 exp glibenclamide/ (19156) 2 exp metformin/ (29677) 3 oral diabetes agent*.ti,ab. (19) 4 oral antidiabetic agent*.ti,ab. (1112) 5 oral hypoglycemic agent*.ti,ab. (2069) 6 metformin.ti,ab. (12825) 7 glyburide.ti,ab. (1573) 8 glibenclamide.ti,ab. (8721) 9 glimepiride.ti,ab. (1186) 10 glipizide.ti,ab. (1252) 11 sulfonylurea.ti,ab. (5443) 12 sulphonylurea.ti,ab. (2032) 2

3 13 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 (52632) 14 exp pregnancy/ (652287) 15 exp pregnancy diabetes mellitus/ (19212) 16 pregnan*.ti,ab. (480705) 17 gestation*.ti,ab. (179763) 18 GDM.ti,ab. (3864) or 15 or 16 or 17 or 18 (856454) and 19 (2280) 21 random:.tw. or placebo:.mp. or double-blind:.mp. ( ) and 21 (540) 3

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5 Supplementary table 2. Characteristics and baseline data of the individual studies included in the meta-analyses Author/ Country GDM criteria Blood glucose criteria for drug treatment (mmol/l) Drug Number of patients Age (years) Prepregnancy BMI (Kg/m2) OGTT fasting/ 2h blood glucose (mmol/l) GA at entry (weeks) HbA1c at entry (%) Langer Silva Anjalakshi Ogunyemi Lain Mukhopadhyay Tempe Local 5.3 fasting 6.7 2h postprandial 5.0 fasting 5.6 2h postprandial WHO 6.7 2h postprandial t given t given WHO >5.3 fasting >6.7 2h postprandial 5.0 fasting 6.7 2h postprandial 5.0 fasting 6.7 2h postprandial Ns / / / */ 9.94* 5.64/ / * * Moore Rowan Australia- New Zealand Ijäs Finland Niromanesh Iran Tertti Finland Spaulonci NDDG ADIPS Local Local 5.8 fasting 6.7 2h postprandial >5.4 fasting >6.7 2h postprandial >5.3 fasting > h postprandial >5.3 fasting >6.7 2h postprandial >5.5 fasting >7.8 1h postprandial >5.3 fasting >6.7 2h postprandial * / / / / / / / / Moore Silva WHO 5.8 fasting 6.7 2h postprandial 5.0 fasting 6.7 1h postprandial / / GDM=Gestational Diabetes Mellitus; BMI=body mass index; OGTT=oral glucose tolerance test; HbA 1c =glycated haemoglobin; GA=gestational age; =Carpenter and Coustan; WHO=World Health Organization; Ns=non-significant; NDDG=National Diabetes Data Group; ADIPS=Australasian Diabetes In Pregnancy Society. * significant differences between groups 5

6 Supplementary table 3. Quality assessment of studies included in the meta-analyses Author/ Country Randomization Allocation concealment Blinding of patients and healthcare professionals Published protocol / Selective outcomes reporting Sample size calculation/ Attrition rates Intention to treat Comparability in baseline characteristics Excluded in sensitivity analysis Langer t found All but SGA t described 0 0% Yes Balanced Silva Anjalakshi Ogunyemi Lain Mukhopadhyay Tempe t described Envelopes t found All but Apgar t described t described t found t predefined Random permuted block Table of random numbers t found t found t described t found t described t described t found All but delivery type 5.56% total t described % t described % % t described 0 0% t described % Yes Balanced Yes Balanced Yes Yes Unbalanced Yes Stated Balanced Yes Unbalanced Yes Balanced Moore t found 0 0% Yes Unbalanced Height >1.60 Height <1.40 Yes Rowan Australia- New Zealand Block size 4, stratified by site t described Published % Yes Stated Balanced Ijäs Finland Niromanesh Iran Tertti Finland Spaulonci Generated manually t described Single blind (Obstetrician) Published Published Published t described Published 6 0% 7 7% % % Yes Balanced Yes Balanced Yes Balanced Yes Stated Balanced Moore Silva Brown Published t published All but macrosomia 0 0% t described 0 0% Yes Balanced Yes Balanced SGA= Small-for-gestational age newborns 6

7 Supplementary figure 2. Forest plot of primary outcome variables with significant differences* in women with gestational diabetes mellitus requiring drug treatment A) Weight gain GA at delivery Preterm birth Macrosomia LGA MD= I 2 =21% ns MD= 0.05 I 2 =14% ns RR= 0.87 I 2 =0% ns RR= 2.62 I 2 =34% p=0.004 RR= 1.87 I 2 =52% ns B) Weight gain GA at delivery Preterm birth Macrosomia LGA MD= I 2 =64% p=0.04 MD=-0.16 I 2 =0% p=0.03 RR=1.50 I 2 =0% p=0.03 RR=0.96 I 2 =13% ns RR=0.88 I 2 =22% ns C) Weight gain GA at delivery Preterm birth Macrosomia LGA MD=-2.06 p=0.04 MD=-0.11 I 2 =0% ns RR=1.15 ns RR=0.33 I 2 =0% p=0.02 RR=0.44 p=0.03 *Forest plots for birthweight and any neonatal hypoglycemia are depicted in figures 1 and 2 of the main text 7

8 Supplementary table 4. Baseline patient characteristics in randomized controlled trials comparing glyburide or metformin insulin or each other in women with gestational diabetes mellitus studies patients treated with glyburide patients treated with insulin Maternal age (years) Prepregnancy BMI (Kg/m 2 ) Gestational age at entry (weeks) Fasting plasma glucose at OGTT (mmol/l) h postprandial glucose at OGTT (mmol/l) HbA 1c e at entry (%) prior pregnancies (per patient) Mean difference Relative risk P I (-1.09 to 0.45) (-0.64 to 1.50) ( to 1.20) * (-0.53 to 0.12) * (-0.83 to 0.41) * (-0.88 to 0.11) (-1.20 to 0.40) % of prior pregnancies * (0.38 to 3.63) Maternal age (years) (-0.55 to 0.58) Prepregnancy BMI (Kg/m 2 ) (0.15 to1.41) Gestational age at entry (weeks) (-0.31 to 0.32) Fasting plasma glucose at OGTT (mmol/l) (-0.15 to 0.02) * 2h postprandial glucose at OGTT (mmol/l) (-0.26 to 0.49) HbA 1c at entry (%) (-0.10 to 0.02) prior pregnancies (per patient) (-1.01 to 0.34) % of prior pregnancies (0.83 to 1.07) Maternal age (years) (0.07 to 2.64) Prepregnancy BMI (Kg/m 2 ) (-1.16 to 1.33) * Gestational age at entry (weeks) (-2.91 to 1.64) Fasting plasma glucose at OGTT (mmol/l) (-0.19 to 0.39) h postprandial glucose at OGTT (mmol/l) (-0.05 to 0.57) HbA 1c at entry (%) prior pregnancies (per patient) (0.20 to 0.72) % of prior pregnancies I 2 =Heterogeneity; BMI=Body mass index; OGTT=Oral glucose tolerance test; HbA 1c=Glycated haemoglobin * Estimated using a random effects model because I 2 >50%, 8

9 Supplementary table 5. Meta-analysis of randomized controlled trials comparing glyburide insulin in women with gestational diabetes mellitus Sensitivity analysis Primary outcomes Secondary outcomes studies patients treated with glyburide patients treated with insulin Mean difference Relative risk P I 2 End 3rd trimester HbA 1c (%) * (-0.24 to 0.25) Severe maternal hypoglycaemia (%) t estimable (0 0) - - Preeclampsia (%) (0.51 to 1.68) Weight gain (kg) (-1.62 to 0.62) Caesarean section (%) (0.68 to 1.10) Gestational age at delivery (weeks) (-0.18 to 0.28) Preterm birth (%) (0.55 to 1.29) Birth weight (g) (33.2 to 183) Macrosomia (%) (1.35 to 5.08) Large-for-gestational age (%) * (0.80 to 5.77) Small-for-gestational age (%) (0.51 to 1.85) Any neonatal hypoglycaemia (%) (1.30 to 3.20) Perinatal mortality (%) (0.29 to 7.21) Fasting blood glucose 0.06 (mmol/l) (-0.06 to 0.19) Postprandial blood glucose 0.07 (mmol/l) (-0.11 to 0.25) Weight gain since entry (kg) Pregnancy-induced hypertension (%) Induction (%) Cord C-peptide 0.07 (nmol/l) (-0.14 to 0.27) Cord insulin (pmol/l) (-24.5 to 17.2) min Apgar <7 (%) min Apgar <7 (%) Obstetric trauma (%) Severe neonatal hypoglycaemia 5.31 (%) (0.63 to 44.9) Neonatal jaundice 1.72 (%) (0.75 to 3.94) Neonatal respiratory distress syndrome 0.61 (%) (0.19 to 1.92) Stillbirth 1.32 (%) (0.33 to 5.22) Neonatal mortality 1.01 (%) (0.06 to 16.0) NICU admission 0.97 (%) (0.56 to 1.69) I 2 =Heterogeneity; HbA 1c= Glycated haemoglobin * Estimated using a random effects model because I 2 >50% Defined by authors or requiring intravenous glucose and/or NICU admittance 9

10 Supplementary table 6. Meta-analysis of randomized controlled trials comparing metformin insulin in women with gestational diabetes. Sensitivity analysis Primary outcomes Secondary outcomes studies patients treated with metformin patients treated with insulin Mean difference Relative risk P I 2 End 3rd trimester HbA 1c (%) (-0 09 to 0 02) Severe maternal hypoglycaemia (%) t estimable (0 0) Preeclampsia 0.82 (0.56 to 1.20) Weight gain (kg) * (-2.22 to -0.06) Caesarean section 0.99 (0.86 to 1.14) Gestational age at delivery (weeks) (-0.30 to -0.02) Preterm birth 1.50 (1.04 to 2.16) Birth weight (g) (-86.8 to 24.8) Macrosomia 0.99 (0.75 to 1.31) Large-for-gestational age 0.88 (0.69 to 1.11) Small-for-gestational age 0.88 (0.58 to 1.33) Any neonatal hypoglycaemia (%) (0.61 to 1.03) Perinatal mortality (%) (0.14 to 7.12) Fasting blood glucose 0.06 (mmol/l) (-0.01 to 0.13) Postprandial blood glucose -0.12* (mmol/l) (-0.28 to 0.04) Weight gain since entry -1.23* (kg) (-1.72 to -0.73) - < Pregnancy-induced hypertension 0.53 (%) (0.31 to 0.90) Induction 0 91 (%) (0.81 to 1.02) Cord C-peptide (nmol/l) Cord insulin 7.64 (pmol/l) (-92.7 to 108) min Apgar <7 - (%) min Apgar < (%) (0.32 to 29.3) Obstetric trauma 0.86 (%) (0.45 to 1.63) Severe neonatal hypoglycaemia 0.62 (%) (0.42 to 0.94) Neonatal jaundice 0.93 (%) (0.67 to 1.28) Neonatal respiratory distress syndrome 1.21 (%) (0.62 to 2.37) Stillbirth 1.00 (%) (0.14 to 7.12) Neonatal mortality t estimable (%) (0 0) - - NICU admission 0 89 (%) (0.71 to 1.10) I 2 = Heterogeneity; HbA 1c=Glycated haemoglobin * Estimated using a random effects model because I 2 >50% Defined by authors or requiring intravenous glucose and/or NICU admittance 10