Insulin for the treatment of women with gestational diabetes

Julie Brown; Luke Grzeskowiak; Kathryn Williamson; Michelle R Downie; Caroline A Crowther

doi:10.1002/14651858.CD012037.pub2

. 2017 Nov 5;2017(11):CD012037. doi: 10.1002/14651858.CD012037.pub2

Insulin for the treatment of women with gestational diabetes

Julie Brown ^1,^✉, Luke Grzeskowiak ², Kathryn Williamson ³, Michelle R Downie ⁴, Caroline A Crowther ^1,⁵

Editor: Cochrane Pregnancy and Childbirth Group

PMCID: PMC6486160 PMID: 29103210

Abstract

Background

Gestational diabetes mellitus (GDM) is associated with short‐ and long‐term complications for the mother and her infant. Women who are unable to maintain their blood glucose concentration within pre‐specified treatment targets with diet and lifestyle interventions will require anti‐diabetic pharmacological therapies. This review explores the safety and effectiveness of insulin compared with oral anti‐diabetic pharmacological therapies, non‐pharmacological interventions and insulin regimens.

Objectives

To evaluate the effects of insulin in treating women with gestational diabetes.

Search methods

We searched Pregnancy and Childbirth's Trials Register (1 May 2017), ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP) (1 May 2017) and reference lists of retrieved studies.

Selection criteria

We included randomised controlled trials (including those published in abstract form) comparing:

a) insulin with an oral anti‐diabetic pharmacological therapy;

b) with a non‐pharmacological intervention;

c) different insulin analogues;

d) different insulin regimens for treating women with diagnosed with GDM.

We excluded quasi‐randomised and trials including women with pre‐existing type 1 or type 2 diabetes. Cross‐over trials were not eligible for inclusion.

Data collection and analysis

Two review authors independently assessed study eligibility, risk of bias, and extracted data. Data were checked for accuracy.

Main results

We included 53 relevant studies (103 publications), reporting data for 7381 women. Forty‐six of these studies reported data for 6435 infants but our analyses were based on fewer number of studies/participants.

Overall, the risk of bias was unclear; 40 of the 53 included trials were not blinded. Overall, the quality of the evidence ranged from moderate to very low quality. The primary reasons for downgrading evidence were imprecision, risk of bias and inconsistency. We report the results for our maternal and infant GRADE outcomes for the main comparison.

Insulin versus oral anti‐diabetic pharmacological therapy

For the mother, insulin was associated with an increased risk for hypertensive disorders of pregnancy (not defined) compared to oral anti‐diabetic pharmacological therapy (risk ratio (RR) 1.89, 95% confidence interval (CI) 1.14 to 3.12; four studies, 1214 women; moderate‐quality evidence). There was no clear evidence of a difference between those who had been treated with insulin and those who had been treated with an oral anti‐diabetic pharmacological therapy for the risk of pre‐eclampsia (RR 1.14, 95% CI 0.86 to 1.52; 10 studies, 2060 women; moderate‐quality evidence); the risk of birth by caesarean section (RR 1.03, 95% CI 0.93 to 1.14; 17 studies, 1988 women; moderate‐quality evidence); or the risk of developing type 2 diabetes (metformin only) (RR 1.39, 95% CI 0.80 to 2.44; two studies, 754 women; moderate‐quality evidence). The risk of undergoing induction of labour for those treated with insulin compared with oral anti‐diabetic pharmacological therapy may possibly be increased, although the evidence was not clear (average RR 1.30, 95% CI 0.96 to 1.75; three studies, 348 women; I² = 32%; moderate‐quality of evidence). There was no clear evidence of difference in postnatal weight retention between women treated with insulin and those treated with oral anti‐diabetic pharmacological therapy (metformin) at six to eight weeks postpartum (MD ‐1.60 kg, 95% CI ‐6.34 to 3.14; one study, 167 women; low‐quality evidence) or one year postpartum (MD ‐3.70, 95% CI ‐8.50 to 1.10; one study, 176 women; low‐quality evidence). The outcomes of perineal trauma/tearing or postnatal depression were not reported in the included studies.

For the infant, there was no evidence of a clear difference between those whose mothers had been treated with insulin and those treated with oral anti‐diabetic pharmacological therapies for the risk of being born large‐for‐gestational age (average RR 1.01, 95% CI 0.76 to 1.35; 13 studies, 2352 infants; moderate‐quality evidence); the risk of perinatal (fetal and neonatal death) mortality (RR 0.85; 95% CI 0.29 to 2.49; 10 studies, 1463 infants; low‐quality evidence);, for the risk of death or serious morbidity composite (RR 1.03, 95% CI 0.84 to 1.26; two studies, 760 infants; moderate‐quality evidence); the risk of neonatal hypoglycaemia (average RR 1.14, 95% CI 0.85 to 1.52; 24 studies, 3892 infants; low‐quality evidence); neonatal adiposity at birth (% fat mass) (mean difference (MD) 1.6%, 95% CI ‐3.77 to 0.57; one study, 82 infants; moderate‐quality evidence); neonatal adiposity at birth (skinfold sum/mm) (MD 0.8 mm, 95% CI ‐2.33 to 0.73; random‐effects; one study, 82 infants; very low‐quality evidence); or childhood adiposity (total percentage fat mass) (MD 0.5%; 95% CI ‐0.49 to 1.49; one study, 318 children; low‐quality evidence). Low‐quality evidence also found no clear differences between groups for rates of neurosensory disabilities in later childhood: hearing impairment (RR 0.31, 95% CI 0.01 to 7.49; one study, 93 children), visual impairment (RR 0.31, 95% CI 0.03 to 2.90; one study, 93 children), or any mild developmental delay (RR 1.07, 95% CI 0.33 to 3.44; one study, 93 children). Later infant mortality, and childhood diabetes were not reported as outcomes in the included studies.

We also looked at comparisons for regular human insulin versus other insulin analogues, insulin versus diet/standard care, insulin versus exercise and comparisons of insulin regimens, however there was insufficient evidence to determine any differences for many of the key health outcomes. Please refer to the main results for more information about these comparisons.

Authors' conclusions

The main comparison in this review is insulin versus oral anti‐diabetic pharmacological therapies. Insulin and oral anti‐diabetic pharmacological therapies have similar effects on key health outcomes. The quality of the evidence ranged from very low to moderate, with downgrading decisions due to imprecision, risk of bias and inconsistency.

For the other comparisons of this review (insulin compared with non‐pharmacological interventions, different insulin analogies or different insulin regimens), there is insufficient volume of high‐quality evidence to determine differences for key health outcomes.

Long‐term maternal and neonatal outcomes were poorly reported for all comparisons.

The evidence suggests that there are minimal harms associated with the effects of treatment with either insulin or oral anti‐diabetic pharmacological therapies. The choice to use one or the other may be down to physician or maternal preference, availability or severity of GDM. Further research is needed to explore optimal insulin regimens. Further research could aim to report data for standardised GDM outcomes.

Plain language summary

Insulin for the treatment of women with gestational diabetes

What is the issue?

The aim of this Cochrane review was to find out the effectiveness and safety of insulin compared with oral medication or non‐pharmacological interventions for the treatment of gestational diabetes mellitus (GDM, which is diabetes diagnosed in pregnancy). It also looked at different timings for taking insulin during the day. We collected all the relevant studies (May 2017) and analysed the data.

Why is this important?

GDM can lead to both short‐ and long‐term complications for the mother and her baby.

Usually, diet and lifestyle advice is the first step, and women whose blood glucose remains too high may be treated with insulin, which is normally injected every day.

Finding out if other treatment options are as safe and effective as insulin, is important, as these other treatments may be preferred by women who do not want to inject themselves with insulin.

What evidence did we find?

We searched for evidence on 1 May 2017 and found 53 studies reporting data for 7381 mothers and 46 studies reported data for 6435 babies. Overall, the quality of the evidence ranged from very low to moderate. Studies were undertaken in a variety of countries, including low‐, middle‐ and high‐income countries. Three studies reported that financial support or drugs had been provided by a pharmaceutical company and 36 studies did not provide any statement about the source of funding.

For mothers with GDM, insulin was associated with an increased likelihood of hypertensive disorders of pregnancy (high blood pressure ‐ not defined) although there was no evidence of any difference in pre‐eclampsia (high blood pressure, swelling and protein in the urine), birth by caesarean section, developing type 2 diabetes, or postnatal weight when women who had been treated with insulin were compared with women who had been treated with oral anti‐diabetic medication.

Insulin appeared to possibly increase the likelihood of induction of labour, when compared with oral anti‐diabetic medication but these results are unclear. Damage to the perineum, return to pre‐pregnancy weight or postnatal depression were not reported by the included studies. For the baby, there was no evidence of a clear difference between groups in the risk of being born large‐for‐gestational age, death or serious illness after birth, low blood sugar, being overweight as a baby or as a child, having a hearing or visual impairment, or mild developmental delay at 18 months. None of the included studies looked at the baby’s health in childhood.

We also looked at comparisons for regular human insulin versus other insulin types, insulin versus dietary advice with standard care, insulin versus exercise, and we also looked at comparisons of different insulin dosages and frequency. However, there was not enough evidence for us to be certain of any differences for many of the key health outcomes.

What does this mean?

The available evidence suggests that there are very few differences in short‐term outcomes for the mother and baby between treatment with injected insulin and treatment with oral medication. There is not enough evidence yet for the long‐term outcomes. Decisions about which treatment to use could be based on discussions between the doctor and the mother. Further research is needed to explore optimal insulin regimens for women with GDM. Future studies could aim to report long‐term as well short‐term outcomes for mothers and their babies.

Summary of findings

Background

The original review by Alwan 2009 has been split into three new reviews due to the complexity of the included interventions. The new review protocols include the following.

Lifestyle interventions for the treatment of women with gestational diabetes (Brown 2017a)

Oral anti‐diabetic pharmacological therapies for the treatment of women with gestational diabetes (Brown 2017b)

Insulin for the treatment of women with gestational diabetes (this review).

There will be similarities in the background, methods and outcomes between these three systematic reviews. Portions of the methods section of this protocol 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 usually return to normal after the birth of the baby. However, there is currently no universally accepted diagnostic criteria (ACOG 2013; ADA 2013, Coustan 2010; HAPO 2008; Hoffman 1998; IADPSG 2010; Metzger 1998; NICE 2015) (Table 3). GDM may include previously undetected type 1 diabetes, type 2 diabetes, or diabetes presenting only during pregnancy depending on when the timing of when diagnosis is made (HAPO 2008; IADPSG 2010; Metzger 1998; Nankervis 2014; WHO 2014).

1. Examples of diagnostic criteria for gestational diabetes mellitus.

Organisation/professional body	Screening criteria	Diagnostic criteria
	One‐hour oral glucose challenge test	Oral glucose tolerance test	Fasting	1‐hour	2‐hour	3‐hour
ADA 2015b, IADPSG 2010, ADIPS 2014* (Nankervis 2014); WHO 2014*	‐	75 g	≥ 5.1 mmol/L (≥ 92 mg/dL)	≥ 10 mmol/L (≥ 180 mg/dL)	≥ 8.5 mmol/L (≥ 153 mg/dL)	‐
ADA 2015b	50 g (≥ 7.8 mmol/L; ≥ 140 mg/dL)	75 g	≥ 5.1 mmol/L (≥ 92 mg/dL)	≥ 10 mmol/L (≥ 180 mg/dL)	≥ 8.5 mmol/L (≥ 153 mg/dL)	‐
ACOG 2013 Carpenter and Coustan^ or National Diabetes Data Group^	50 g (> 7.2 mmol/L; > 130 mg/dL)	100 g	≥ 5.3 mmol/L (95 mg/dL)	≥ 10 mmol/L (180 mg/dL)	≥ 8.6 mmol/L (155 mg/dL)	≥ 7.8 mmol/L (140 mg/dL)
	50 g (> 7.8 mmol/L; > 140 mg/dL)	100 g	≥ 5.8 mmol/L (105 mg/dL)	≥ 10.6 mmol/L (190 mg/dL)	≥ 9.2 mmol/L (165 mg/dL)	≥ 8.0 mmol/L (145 mg/dL)
NICE 2008; WHO 1999*; ADIPS 1998 (Hoffman 1998)		75 g	≥ 7.0 mmol/L (≥ 126 mg/dL)	‐	≥ 11.1 mmol/L (≥ 200 mg/dL)	‐
NICE 2015	‐	75 g	≥ 5.6 mmol/L (≥ 101 mg/dL)	‐	≥7.8 mmol/L (140 mg/dL)	‐
New Zealand Ministry of Health 2014*	50 g if HbA1c < 41 mmol/mol (≥ 7.8 mmol/L; ≥ 140 mg/dL)	75 g	≥ 5.5 mmol/L (≥ 99 mg/dL)	‐	≥ 9.0 mmol/L (≥ 162 mg/dL)	‐

		Screen	Diagnostic test	Diagnostic criteria
Ashoush 2016	Not stated	Not stated	2‐hour, 75 g OGTT	Not stated	ADA 2004
Anjalakshi 2007	Not stated	Not stated	75 g OGTT	2‐hour ≥ 7.7 mmol/L (140 mg/dL)	WHO 1994
Ardilouze 2014	‐	‐	‐	‐	Canadian Diabetes Association (no details)
Balaji 2005	Not stated	Not stated	Not stated	Not stated	Not stated
Balaji 2012	12 to 28 weeks’	Not stated	2‐hour, 75 g OGTT	2‐hour ≥ 7.7 mmol/L (140 mg/dL)	WHO 1994
Behrashi 2016	11 to 33 weeks'	Not stated	3‐hour, 100 g OGTT	2 abnormal values of: Fasting blood glucose ≥ 5.3 mmol/L (95 mg/dL), 1‐hour glucose level 10.0 mmol/L (180 mg/dL), 2‐hour glucose level 8.6 mmol/L (155 mg/dL) 3‐hour glucose level 7.8 mmol/L (140 mg/dL),	Carpenter and Coustan criteria
Bertini 2005	11 to 33 weeks'	Not stated	2‐hour, 75 g OGTT	Fasting blood glucose ≥ 6.1 mmol/L (110 mg/dL) and 2‐hour glucose level ≥ 7.8 mmol/L (140 mg/dL)	WHO 1994
Beyuo 2015	20 to 28 weeks'	Not stated	2‐hour, 75 g OGTT	1 or more abnormal value from: Fasting blood glucose ≥ 5.1 mmol/L (92 mg/dL), 1‐hour glucose level 10.0 mmol/L (180 mg/dL), 2‐hour glucose level 8.5 mmol/L (153 mg/dL).	ADA 2012
Bung 1993	Not stated	Not stated	Not stated	Not stated	Not stated
Castorino 2011	Not stated	Not stated	Not stated	Not stated	Not stated
Coustan 1978	Not stated	Women with risk factors for GDM	3‐hour, 100 g OGTT	2 abnormal values of: Fasting blood glucose ≥ 5.3 mmol/L (95 mg/dL), 1‐hour glucose level 10.0 mmol/L (180 mg/dL), 2‐hour glucose level 8.9 mmol/L (160 mg/dL), 3‐hour glucose level 7.5 mmol/L (135 mg/dL).	Modified O'sullivan and Mahan (1964)
De Veciana 2002	Not stated	Not stated	Not stated	Not stated	Not stated
Di Cianni 2007	No details				Carpenter and Coustan criteria
Hague 2003	‐	‐	‐	‐	ADIPS (old criteria)
Herrera 2015					Carpenter and Coustan 1983 or IADPSG 2010
Hickman 2013	< 20 weeks'	Not stated	3‐hour 100 g OGTT	2 or more abnormal values	National Diabetes Data Group Criteria 1979
Hutchinson 2008	Not stated	Not stated	Not stated	Not stated	Not stated
Ijas 2011	Risk factor	Not stated	2‐hour, 75 g OGTT	Fasting blood glucose 5.3 mmol/L (95 mg/dL), 1‐hour glucose level 11.0 mmol/L, 2‐hour glucose level 9.6 mmol/L. There were to be 1 or more abnormal values.	Not stated
Ismail 2007	Not stated	Not stated	Not stated	Not stated	Not stated
Jovanovic 1999	14 to 32 weeks'				Carpenter and Coustan criteria modification of NDDG criteria
Lain 2009	24 to 34 weeks'	50 g 1‐hour oral glucose challenge test > 7.5 mmol/L (135 mg/dL)	100 g 3‐hour OGTT	2 abnormal values of: Fasting blood glucose 5.3 mmol/L (95 mg/dL), 1‐hour glucose level 10.0 mmol/L (180 mg/dL) 2‐hour glucose level 8.6 mmol/L (155 mg/dL) 3‐hour glucose level 7.8 mmol/L (140 mg/dL), An elevated fasting value of 3‐hour OGTT or 1‐hour OGTT > 11.1 mmol/L or 200 mg/dL diagnostic of diabetes.	Carpenter and Coustan criteria
Langer 2000	11 to 33 weeks'	50 g, 1‐hour oral glucose challenge test > 7.3 mmol/L (130 mg/dL)	100 g OGTT	Fasting blood glucose between 5.3 mmol/L (95 mg/dL) and 7.8 mmol/L (130 mg/dL). 2 or more abnormal values required	Carpenter and Coustan criteria.
Majeed 2015	Not reported	Not reported	Not reported	Not reported	Not reported
Martinez Piccole 2010	Not reported	Not reported	Not reported	Not reported	Not reported
Mecacci 2003	25 to 32 weeks'				Carpenter and Coustan criteria
Mesdaghinia 2013	24 to 34 weeks'	50 g, 1‐hour oral glucose challenge test	100 g 3‐hour OGTT	2 or more abnormal results required from Fasting blood sugar > 5.3 mmol/L or 95 mg/dL; 1‐hour glucose level > 9.99 mmol/L or 180 mg/dL; 2‐hour glucose level > 8.6 mmol/L or 150 mg/dL; 3‐hour glucose level > 7.8 mmol/L or 140 mg/dL.	Carpenter and Coustan criteria
Mirzamoradi 2015	24 to 28 weeks'	Not stated	Not stated	Fasting blood glucose > 5.3 mmol/L or 95 mg/dL, 1‐hour glucose level > 10.0 mmol/L or 180 mg/dL or 2‐hour glucose level > 8.6 mmol/L or 150 mg/dL.	Carpenter and Coustan criteria
Mohamed 2014	‐	‐	‐	Plasma glucose > 7.8 mmol/L (140 mg/dL)	Carpenter and Coustan criteria
Moore 2007	24 to 30 weeks'	1‐hour 50 g glucose challenge test	100 g 3‐hour OGTT	Fasting blood glucose > 105 mg/dL, 1‐hour glucose level > 190 mg/dL, 2‐hour glucose level > 165 mg/dL and 3‐hour glucose level > 145 mg/dL. 2 or more abnormal values required for diagnosis.	ADA criteria (old)
Mukhopadhyay 2012	20 to 28 weeks'	Not stated	2‐hour, 75 g OGTT	Fasting blood glucose ≥ 6.1 mmol/L (110 mg/dL) and 2‐hour glucose level ≥ 7.8 mmol/L (140 mg/dL)	WHO 1994
Nachum 1999	Not stated	Not stated	100 g 3‐hour OGTT	Fasting blood glucose 5.9 mmol/L 1‐hour glucose level 10.6 mmol/L 2‐hour glucose level 9.2 mmol/L 3‐hour glucose level 8.1 mmol/L	NDDG 1979
Niromanesh 2012	20 to 34 weeks'	1‐hour 50 g glucose challenge test	100 g 3‐hour OGTT	‐	Carpenter and Coustan criteria
Notelovitz 1971	Not reported	Not reported	2‐hour, 100 g OGTT	2‐hour glucose level ≥ 7.8 mmol/L (140 mg/dL)	Not reported
Ogunyemi 2007	Not reported	1‐hour 50 g glucose challenge test	3‐hour OGTT	Not reported	Not reported
O'Sullivan 1975a	Not reported	1‐hour 50 g glucose challenge test ‐ ≥ 130 mg/100 mL or presence of risk factors including history of macrosomia, fetal death, neonatal death, congenital anomaly.	3‐hour 100 g OGTT	2 or more abnormal readings from Fasting blood glucose ≥ 110 mg/100 mL 1‐hour blood glucose level ≥ 170 mg/100 mL, 2‐hour blood glucose level ≥ 120 mg/100 mL, 3‐hour blood glucose level ≥ 110 mg/100 mL.	Not reported
O'Sullivan 1975b	Not reported	1‐hour 50 g glucose challenge test ‐ ≥ 130 mg/100 mL	3‐hour 100 g OGTT	2 or more abnormal readings from Fasting blood glucose ≥ 110 mg/100 mL 1‐hour blood glucose level ≥ 170 mg/100 mL, 2‐hour blood glucose level ≥ 120 mg/100 mL, 3‐hour blood glucose level ≥ 110 mg/100 mL.	Not reported
Pavithra 2016	24 to 28 weeks'	1‐hour 50 g glucose challenge test	100 g OGTT	Fasting blood glucose > 5.3 mmol/L or 95 mg/dL, 1‐hour glucose level > 10.0 mmol/L or 180 mg/dL or 2‐hour glucose level > 8.6 mmol/L or 155 mg/dL. 3‐hour glucose level > 7.7 mmol/L or 140 mg/dL	Carpenter and Coustan criteria
Persson 1985	Not stated. Risk based selection	Not stated	3‐hour, 50 g OGTT	Not stated values but note that 2SD above normal	Gillmer 1975
Pettitt 2007	Not stated	Not stated	Not stated	Not stated	Not stated
Poyhonen‐Alho 2002	24 to 28 weeks'	OGTT based on risk factors (BMI > 25 kg/m2, age > 40 years, previous GDM, previous infant with macrosomia > 4500 g, glucosuria, current macrosomia)	2‐hour, 75 g OGTT	2 or more abnormal values from: Fasting ≥ 4.8 mmol/L 1‐hour glucose level ≥ 10.0 mmol/L 2‐hour glucose value ≥ 8.7 mmol/L	Finnish national guidelines (2008)
Prasad 2008	Not stated	Not stated	Not stated	Not stated	Not stated
Riaz 2014	Not stated	Not stated	75 g OGTT	Not stated	Not stated
Rowan 2008	20 to 33 weeks'	Not stated	75 g OGTT	1 or more of the following being abnormal Fasting plasma glucose level ≥ 5.1 mmol/L, 1‐hour venous plasma glucose ≥ 10.0 mmol/L (180 mg/dL), or 2‐hour venous plasma glucose ≥ 8.5 mmol/L.	ADIPS (1998)
Ruholamin 2014	24 to 28 weeks'				ADIPS 1998
Saleh 2016	26 to 34 weeks'	Not stated	2‐hour, 75 g OGTT	Fasting blood glucose ≥ 7.0 mmol/L (126 mg/dL) and 2‐hour glucose level ≥ 7.8 mmol/L (140 mg/dL)	IADPSG 2010
Silva 2007	11 to 33 weeks'	Not stated	2‐hour, 75 g OGTT	Fasting blood glucose ≥ 6.1 mmol/L (110 mg/dL) and 2‐hour glucose level ≥ 7.8 mmol/L (140 mg/dL)	WHO 1994
Spaulonci 2013	Not reported	Not stated	2‐hour 75 g or 3‐hour 100 g OGTT	2 or more abnormal results Fasting blood glucose > 5.3 mmol/L (95 mg/dL) 1‐hour glucose level ≥ 10.0 mmol/L (180 mg/dL) 2‐hour glucose level ≥ 8.6 mmol/L (155 mg/dL) 3‐hour glucose level ≥ 7.8 mmol/L (140 mg/dL)	ADA 2011
Tertti 2013	22 to 34 weeks'	Screening criteria based on risk changed during the study	2‐hour 75 g OGTT	Diagnostic cut‐off levels up to 2008 were: Fasting blood glucose ≥ 4.8 mmol/L (87 mg/dL) 1‐hour glucose level ≥ 10.0 mmol/L (180 mg/dL) and 2‐hour glucose level ≥ 8.7 mmol/L (157 mg/dL) and thereafter was fasting ≥ 5.3 mmol/L (95 mg/dL), 1‐hour ≥ 10 mmo/L (180 mg/dL) and 2‐hour ≥ 8.6 mmol/L (155 mg/dL).	Finnish national guidelines (2008)
Thompson 1990	28 weeks' or earlier	1‐hour 50 g glucose challenge test	100 g 3‐hour OGTT	Fasting blood glucose > 105 mg/dL, 1‐hour glucose level > 190 mg/dL, 2‐hour glucose level > 165 mg/dL and 3‐hour glucose level > 145 mg/dL. 2 or more abnormal values required for diagnosis.	ADA criteria (old)
Waheed 2013	14 weeks' or more	No details	No details	Fasting blood glucose > 5.5 mmol/L (100 mg/dL), and random blood sugar > 7.7 mmol/L (140 mg/dL).	Not stated
Wali 2015					IADPSG (2010)
Zangeneh 2014	24 weeks'	1‐hour 50 g glucose challenge test	100 g 3‐hour OGTT	Fasting blood glucose between 5.3 mmol/L (95 mg/dL) and 7.8 mmol/L (130 mg/dL). 2 or more abnormal values required	Carpenter and Coustan criteria.
Zawiejska 2016	No details	No details	No details	No details	No details

Trial ID
	Insulin	Glibenclamide
Anjalakshi 2007	27.5 ± 5.8 (n = 13)	24.9 ± 3.7 (n = 10)
Behrashi 2016	29.9 ± 7.0 (n = 129)	30.7 ± 7.2 (n = 120)
Bertini 2005	28.7 ± 6.0 (n = 27)	31.2 ± 4.5 (n = 24)
Lain 2009	31.2 ± 5.9 (n = 41)	32.2 ± 5.0 (n = 41)
Langer 2000	30 ± 6 (n = 203)	29 ± 7 (n = 201)
Mirzamoradi 2015	31.2 ± 5.0 (n = 59)	29.5 ± 4.1 (n = 37)
Mukhopadhyay 2012	26 ± 4.3 (n = 30)	26.3 ± 4.6 (n = 30)
Ogunyemi 2007	Not reported	Not reported
Pavithra 2016	27.9 ± 3.6 (n = 50)	28.2 ± 3.1 (n = 50)
Silva 2007	29.9 ± 6.0 (n = 36)	31.6 ± 4.2 (n = 32)
Zangeneh 2014	32.6 ± 6.2 (n = 46)	31.4 ± 5 (n = 44)

	Insulin	Metformin
Ashoush 2016	32.1 ± 3.2 (n = 48)	31.6 ± 2.8 (n = 47)
Beyuo 2015	33.1 ± 4.6 (n = 40)	33.5 ± 4.7 (n = 43)
Hague 2003	34.1 ± 3.7 (n = 14)	33.7 ± 4.44 (n = 16)
Hickman 2013	Median 31 (IQR 26, 33) (n = 14)	Median 36 (IQR 35, 37) (n = 14)
Ijas 2011	31.7 ± 6.1 (n = 50)	32.3 ± 5.6 (n = 47)
Mesdaghinia 2013	30.2 ± 5.9 (n = 100)	29.6 ± 5.3 (n = 100)
Moore 2007	27.7 ± 6.7 (n = 31)	27.1 ± 4.7 (n = 32)
Majeed 2015	Not reported	Not reported
Martinez Piccole 2010	Not reported	Not reported
Niromanesh 2012	31.8 ± 5.1 (n = 80)	30.7 ± 5.5 (n = 80)
Riaz 2014	Not reported	Not reported
Rowan 2008	33 ± 5.1 years (n = 370)	33.5 ± 5.4 (n = 363)
Ruholamin 2014	23.4 ± 2.5 (n = 50)	24.6 ± 6.3 (n = 50)
Saleh 2016	29.8 ± 2.2 (n = 70)	31.0 ± 3.4 (n = 67)
Spaulonci 2013	32.76 ± 4.66 (n = 47)	31.93 ± 6.02 (n = 47)
Tertti 2013	32.1 ± 5.4 (n =107)	31.9 ± 5.0 (n = 110)
Waheed 2013	29.82 ± 4.58 (n = 34)	29.35 ± 4.97 (n = 34)
Wali 2015	Not reported	Not reported
Zawiejska 2016	35 (30 to 38) (n = 43)	22 (29 to 39) (n = 35)

	Insulin	Acarbose
Bertini 2005	28.7 ± 6.0 (n = 27)	31.5 ± 5.8 (n = 19)
De Veciana 2002	Not reported	Not reported

	Insulin	Glyburide/metformin combined
Ardilouze 2014	30.7 ± 4.4 (n = 33)	31.1 ± 4.7 (n = 35)
Hutchinson 2008	Not reported	Not reported
Mohamed 2014	32.1 ± 5.7 (n = 42)	33.2 ± 4.9 (n = 42)

	Human insulin	Insulin aspart
Balaji 2005	31.0 ± 2.7 (n = 5)	30.6 ± 5.0 (n = 5)
Balaji 2012	29.6 ± 4.5 (n = 157)	29.2 ± 4.0 (n = 163)
Di Cianni 2007	Not reported	Not reported
Pettitt 2007	29.7 ± 6.9 (n = 13)	31.6 ± 5.9 (n = 14)
Prasad 2008	Not reported	Not reported


	Human insulin	Insulin lispro
Di Cianni 2007	Not reported	Not reported
Jovanovic 1999	29.8 ± 1.0 (n = 23)	34.2 ± 1.3 (n = 19)
Mecacci 2003	median 35 (range 28 to 41) (n = 24)	Median 34.5 (range 28 to 41) (n = 25)

	Human insulin	Neutral Protamine Hagedorn insulin
Poyhonen‐Alho 2002	Not reported	Not reported
Ismail 2007	Not reported	Not reported
Herrera 2015	Median 35 [ 31‐38] (n = 42)	Median 35 [IQR 32‐38] (n = 45)

	Insulin	Diet
Coustan 1978	Not reported	Not reported
Notelovitz 1971	31.8 (n = 47)	32.7 (n = 56)
Persson 1985	Median 30.5 (range 16 to 42) (n = 97)	Median 29 (range 18 to 46) (n = 105)
Thompson 1990	27 ± 5.4	26 ± 5.7

	Insulin	Exercise
Bung 1993	Not reported	Not reported

	Insulin	Standard care
O'Sullivan 1975a	Not reported	Not reported
O'Sullivan 1975b	Not reported	Not reported

	Insulin regimen A	Insulin regimen B
Castorino 2011	Not reported	Not reported
Nachum 1999	33 ± 5 (n = 136)	33 ± 5 (n = 138)

Trial ID	Ethnicity
Ashoush 2016	Not reported
Anjalakshi 2007	Not reported but likely to be Indian
Ardilouze 2014	Not reported
Balaji 2005	Not reported but likely to be Indian
Balaji 2012	Not reported but likely to be Indian
Behrashi 2016	Not reported
Bertini 2005	Not reported but likely to be Brazilian
Beyuo 2015	Not reported
Bung 1993	Not reported
Castorino 2011	86% Mexican
Coustan 1978	Not reported
De Veciana 2002	Not reported
Di Cianni 2007	Not reported
Hague 2003	Not reported
Herrera 2015	33% White, 14% Black, 31% Hispanic, 21% Native American/Alaskan
Hickman 2013	79% Hispanic, 14% Black
Hutchinson 2008	Not reported
Ijas 2011	Not reported
Ismail 2007	Not reported
Jovanovic 1999	95% Hispanic
Lain 2009	13% Black (no other details)
Langer 2000	83% were Hispanic and 12% non‐Hispanic Caucasian
Majeed 2015	Not reported but likely to be Indian
Martinez Piccole 2010	Not reported
Mecacci 2003	Caucasian
Mesdaghinia 2013	Not reported but likely to be Iranian
Mirzamoradi 2015	Not reported but likely to be Iranian
Mohamed 2014	Not reported
Moore 2007	50% African American, 44% Native American
Mukhopadhyay 2012	Not reported but likely to be Indian
Nachum 1999	56% were Jewish
Niromanesh 2012	Not stated but likely to be Iranian
Ismail 2007	Not reported
Notelovitz 1971	37% were Bantu (Zulu)
Ogunyemi 2007	80% were Hispanic and 15% African American
O'Sullivan 1975a	Not reported
O'Sullivan 1975b	Not reported
Pavithra 2016	Not reported
Persson 1985	Not reported
Pettitt 2007	75% were Hispanic and 19% were Caucasian
Poyhonen‐Alho 2002	Not reported
Prasad 2008	Not reported
Riaz 2014	Not reported but likely to be Pakistani
Rowan 2008	47% Caucasian, 21% Polynesian, 13% Indian
Ruholamin 2014	Not reported but likely to be Iranian
Saleh 2016	Not reported
Silva 2007	Not reported but likely to be Brazilian
Spaulonci 2013	Not reported
Tertti 2013	Not reported
Thompson 1990	41% 'Black', 49% 'White'
Waheed 2013	Not reported but likely to be Pakistani
Wali 2015	Not reported but likely to be Pakistani
Zangeneh 2014	Not reported but likely to Iranian
Zawiejska 2016	Not reported

Study ID	Fasting	1‐hour postprandial	2‐hour postprandial
Ashoush 2016	< 5.5 mmol/L (100 mg/dL)		< 7.7 mmol/L (140 mg/dL)
Anjalakshi 2007	‐	‐	< 6.7 mmol/L (120 mg/dL)
Ardilouze 2014	< 5.3 mmol/L (95 mg/dL)	‐	< 6.7 mmol/L (120 mg/dL)
Balaji 2005	< 5.0 mmol/L (90 mg/dL)		< 6.7 mmol/L (120 mg/dL)
Balaji 2012	> 4.4 mmol/L (> 80 mg/dL) and < 5.0 mmol/L (90 mg/dL)	‐	< 6.7 mmol/L (120 mg/dL)
Behrashi 2016	< 5.0 mmol/L (90 mg/dL)	‐	< 6.7 mmol/L (120 mg/dL)
Bertini 2005	< 5.0 mmol/L (90 mg/dL)	‐	< 5.6 mmol/L (100 mg/dL)
Beyuo 2015	< 5.5 mmol/L (99 mg/dL)		< 7.0 mmol/L (126 mg/dL)
Bung 1993	> 5.8 mmol/L (105 mg/dL) to < 7.2 mmol/L (< 130 mg/dL)	‐	‐
Castorino 2011	< 5.0 mmol/L (90 mg/dL)	< 6.7 mmol/L (120 mg/dL	‐
Coustan 1978	Not reported	Not reported	Not reported
De Veciana 2002	</= 5.3 mmol/L (95 mg/dL)		</= 6.7 mmol/L (120 mg/dL)
Di Cianni 2007	‐	< 7.2 mmol/L (< 130 mg/dL)	‐
Hague 2003	Not reported
Herrera 2015	< 5.0 mmol/L (90 mg/dL)	‐	< 6.7 mmol/L (120 mg/dL)
Hickman 2013	< 5.3 mmol/L (95 mg/dL)	< 7.2 mmol/L (< 130 mg/dL)
Hutchinson 2008	Not reported	Not reported	Not reported
Ijas 2011	< 5.3 mmol/L (95 mg/dL)	‐	1.5 hours postprandial < 6.7 mmol/L (120 mg/dL)
Ismail 2007	< 5.5 mmol/L (100 mg/dL)	‐	‐
Jovanovic 1999	< 5.0 mmol/L (90 mg/dL)	‐	< 6.7 mmol/L (120 mg/dL)
Lain 2009	< 5.3 mmol/L (95 mg/dL)	‐	< 6.7 mmol/L (120 mg/dL)
Langer 2000	3.4 to 5.0 mmol/L (80 to 95 mg/dL)	‐	< 6.7 mmol/L (120 mg/dL)
Majeed 2015	Not reported	‐	Not reported
Martinez Piccole 2010	Not reported	‐	Not reported
Mecacci 2003	< 5.0 mmol/L (90 mg/dL)	< 6.7 mmol/L (120 mg/dL)	‐
Mesdaghinia 2013	< 5.3 mmol/L (95 mg/dL)		< 6.7 mmol/L (120 mg/dL)
Mirzamoradi 2015	3.3 to 5.0 mmol/L (60 to 90 mg/dL)	‐	< 6.7 mmol/L (120 mg/dL)
Moore 2007	< 5.3 mmol/L (95 mg/dL)	‐	< 6.7 mmol/L (120 mg/dL)
Mukhopadhyay 2012	< 5.0 mmol/L (90 mg/dL)	‐	< 6.7 mmol/L (120 mg/dL)
Nachum 1999	3.3 to 5.3 mmol/L	</= 6.7	</= 6.7 mmol/L (120 mg/dL)
Niromanesh 2012	< 5.3 mmol/L (95 mg/dL)	‐	< 6.7 mmol/L (120 mg/dL)
Ismail 2007	< 5.5 mmol/L
Notelovitz 1971		8.3 mmol/L (150 mg/dL)
Ogunyemi 2007	Not reported	Not reported	Not reported
O'Sullivan 1975a	Not reported	Not reported	Not reported
O'Sullivan 1975b	Not reported	Not reported	Not reported
Pavithra 2016	< 5.0 mmol/L (90 mg/dL)		</= 6.7 mmol/L (120 mg/dL)
Persson 1985	< 5.0 mmol/L	< 6.5 mmol/L	‐
Poyhonen‐Alho 2002	Not reported	Not reported	Not reported
Pettitt 2007	Not reported	Not reported	Not reported
Prasad 2008	Not reported	Not reported	Not reported
Riaz 2014	Not reported	Not reported	Not reported
Rowan 2008	< 5.3 mmol/L (95 mg/dL)	‐	< 6.7 mmol/L (120 mg/dL)
Ruholamin 2014	< 5.3 mmol/L (95 mg/dL)	‐	< 6.7 mmol/L (120 mg/dL)
Saleh 2016	≤5.5mmol/L (<100 mg/dL)		< 7.0 mmol/L (126 mg/dL)
Silva 2007	< 5.0 mmol/L (90 mg/dL)	‐	< 5.6 mmol/L (100 mg/dL)
Spaulonci 2013	≤ 5.3 mmol/L (95 mg/dL)	‐	≤ 6.7 mmol/L (120 mg/dL)
Tertti 2013	≤5.5mmol/L (100 mg/dL)	‐	≤ 7.8 mmol/L
Thompson 1990	< 5.8 mmol/L (105mg/dL)	‐	< 6.7 mmol/L (120 mg/dL)
Waheed 2013	3.5 to 5.5 mmol/L (63 to 100 mg/dL)	‐	‐
Wali 2015	Not reported	‐	Not reported
Zangeneh 2014	< 5.3 mmol/L (95 mg/dL)	‐	< 6.7 mmol/L (120 mg/dL)
Zawiejska 2016	Not reported	‐	Not reported

Insulin compared to anti‐diabetic agent for the treatment of women with gestational diabetes (maternal outcomes)
Patient or population: the treatment of women (maternal outcomes) with gestational diabetes  Setting: primary and secondary care (Canada, Egypt, USA, Brazil, Finland, Iran, Australia, New Zealand, India)  Intervention: Insulin  Comparison: Oral anti‐diabetic pharmacological therapy
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Risk with oral anti‐diabetic agent	Risk with insulin	Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Hypertensive disorders of pregnancy (pre‐eclampsia)	77 per 1000	88 per 1000  (66 to 117)	RR 1.14  (0.86 to 1.52)	2060  (10 RCTs)	⊕⊕⊕⊝  MODERATE ¹	No data were reported for eclampsia
Hypertensive disorders of pregnancy (not defined)	36 per 1000	69 per 1000 (42 to 114)	RR 1.89 (1.14 to 3.12)	1214 (4 RCTs)	⊕⊕⊕⊝  MODERATE ¹	There were no definitions for hypertensive disorders in pregnancy in the trials reporting this outcome.
Caesarean section	394 per 1000	405 per 1000  (366 to 449)	RR 1.03  (0.93 to 1.14)	1988  (17 RCTs)	⊕⊕⊕⊝  MODERATE ¹
Development of type 2 diabetes	52 per 1000	73 per 1000  (42 to 128)	RR 1.39  (0.80 to 2.44)	754  (2 RCTs)	⊕⊕⊕⊝  MODERATE ²	These 2 trials compared insulin with metformin. No other trials reported this long‐term outcome.
Perineal trauma/tearing ‐ not measured	‐	‐	‐	‐	‐	None of the included trials in this review pre‐specified or reported perineal trauma as an outcome.
Postnatal weight retention or return to pre‐pregnancy weight ‐ Maternal weight six to eight weeks postpartum ‐ Maternal weight one year postpartum	The mean weight at six to eight weeks postpartum was 80.8 kg The mean weight at one year postpartum was 81.8 kg	MD 1.6 kg lower  (6.34 lower to 3.14 higher) MD 3.7 kg lower (8.5 lower to 1.1 higher)	MD 1.60 kg (‐6.34 to 3.14) MD 3.70 kg (‐8.50 to 1.10)	167 (1 RCT) 176 (1 RCT)	⊕⊕⊝⊝^2,3   LOW ⊕⊕⊝⊝^2,3   LOW
Postnatal depression ‐ not reported	‐	‐	‐	‐	‐	None of the included trials in this review pre‐specified or reported postnatal depression as an outcome.
Induction of labour	408 per 1000	535 per 1000  (424 to 669)	average RR 1.30, 95%CI 0.96,to 1.75	348  (3 RCTs)	⊕⊕⊕⊝  MODERATE ²	These 3 trials compared insulin with metformin. No other trials reported this outcome.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; MD: mean difference; RR: Risk ratio
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Insulin compared to anti‐diabetic agent for the treatment of women with gestational diabetes
Patient or population: Infants of women with gestational diabetes.  Setting: Primary and secondary care (Canada, Egypt, USA, Brazil, Finland, Iran, Australia, New Zealand, India)  Intervention: Insulin  Comparison: Oral anti‐diabetic pharmacological therapy.
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Risk with oral anti‐diabetic agent	Risk with insulin	Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Large‐for‐gestational age (birthweight > 90th centile)	159 per 1000	161 per 1000  (121 to 215)	Average RR 1.01  (0.76 to 1.35)	2352  (13 RCTs)	⊕⊕⊕⊝  MODERATE ¹
Perinatal (fetal and neonatal death) and later infant mortality	8 per 1000	7 per 1000  (2 to 20)	RR 0.85  (0.29 to 2.49)	1463  (10 RCTs)	⊕⊕⊝⊝  LOW ^1,2	Event rates are low 5/728 for the group whose mothers were treated with insulin and 6/735 for the group whose mothers were treated with anti‐diabetic pharmacological therapies. No data were reported for later infant mortality.
Death or serious morbidity composite	319 per 1000	329 per 1000  (268 to 402)	RR 1.03  (0.84 to 1.26)	760  (2 RCTs)	⊕⊕⊕⊝  MODERATE ¹	These 2 trials compared insulin with metformin. No other trials reported this outcome. One trial included: resuscitation in the delivery room, preterm birth (< 37 weeks), neonatal intensive care unit admission, birth injury or diagnosis of neonatal complication, glucose infusion, antibiotics or phototherapy. One trial included: hypoglycaemia ‐< 2.6 mmol/L, RDS, phototherapy, birth trauma, Apgar < 7 at 5 minutes, preterm birth (< 37 weeks)
Neonatal hypoglycaemia	111 per 1000	126 per 1000  (94 to 169)	Average RR 1.14  (0.85 to 1.52)	3892  (24 RCTs)	⊕⊕⊝⊝  LOW ^1,5
Adiposity at birth ‐ percentage fat mass	The mean percentage fat mass was 12.8%	MD 1.6% lower  (3.77 lower to 0.57 higher)	MD ‐1.60 (‐3.77, 0.57)	82  (1 RCT)	⊕⊕⊕⊝  MODERATE ⁴
Adiposity at birth ‐ skinfold sum (mm)	The mean skinfold sum was 16 mm	MD 0.8 mm lower (0.49 lower to 0.73 higher)	MD ‐0.80 mm (‐2.33, 0.73)	82  (1 RCT)	⊕⊝⊝⊝  VERY LOW ^2,4,7
Adiposity in childhood up to 2 years ‐ total fat mass (%)	The mean childhood Total fat mass (%) ‐ Metformin was 16.4%	MD 0.5% higher  (0.49 lower to 1.49 higher)	MD 0.50 % (‐0.49, 1.49)	318  (1 RCT)	⊕⊕⊝⊝  LOW ^1,4
Childhood/adulthood diabetes (type 1, type 2) ‐ not reported	‐	‐	‐	‐	‐	No data were pre‐specified or reported for type 1 or type 2 diabetes in childhood or adulthood in the included trials in this review.
Neurosensory disability in later childhood (18 months) Mild developmental delay Hearing impairment Visual impairment	104 per 1000 0 per 1000 21 per 1000	111 per 1000 (34 to 358) 0 per 1000 (0 to 0) 6 per 1000 (1 to 60)	RR 1.07, (0.33 to 3.44) RR 0.31; (0.01 to 7.49) RR 0.31, (0.03 to 2.90)	93 (1 RCT)	⊕⊕⊝⊝  LOW ^4,6
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; MD: mean difference; RDS: respiratory distress syndrome; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Study ID	Outcome	Insulin (A)	Comparison
Hickman 2013	Fasting blood glucose (mg/dL)	Median 85.2 (IQR 86, 115) (n = 8)	Metformin Median 89.5 (IQR 90, 98) (n = 10)
Coustan 1978	Fasting blood glucose (mg/dL)	86.8 ± 12.7 (n = 33 observations)	Diet 94.7 ± 9.1 (n = 14 observations)
Waheed 2013	Fasting blood glucose	30/34 women within treatment target	Metformin 27/34 women within treatment target
Hickman 2013	1‐hour postprandial blood glucose (mg/dL)	Median 125.3 (IQR 112, 138) (n = 8)	Metformin Median 122.3 (IQR 118, 130) (n = 10)
Coustan 1978	2‐hour postprandial blood glucose (mg/dL)	99.9 ± 27.6 (n = 32 observations)	102.6 ± 12.4 (n = 13 observations)
Hickman 2013	HbA1c (%)	Median 5.6 (IQR 5.3, 6.4) (n = 13)	Metformin Median 5.9 (IQR 5.5, 6.0) (n = 13)
Ismail 2007	HbA1c (%)	Human insulin Median 6.0 (IQR 1.20) (n = 30)	Neutral Protamine Hagedorn insulin Median 5.90 (IQR 0.80) (n = 31)
Waheed 2013	HbA1c (%)	27/34 women within treatment target	Metformin 28/34 women within treatment target
Hickman 2013	Gestational weight gain (kg)	Median 0.30 (IQR 0.18, 0.47) (n = 13)	Metformin Median 0.28 (IQR 0.11, 0.38) (n = 13)
Mecacci 2003	Gestational weight gain (kg)	Regular insulin ‐ Median 11.1 (range 8 to 14) (n = 24)	Insulin lispro ‐ Median 10.9 (range 7 to 17) (n = 25)
Riaz 2014	Glycaemic control	Insulin 56/100	Metformin 72/100

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Hypertensive disorders of pregnancy ‐ Pre‐eclampsia	10	2060	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.86, 1.52]
1.1 Glibenclamide	3	590	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.62, 2.00]
1.2 Metformin	7	1470	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.83, 1.60]
2 Hypertensive disorders of pregnancy ‐ not defined	4	1214	Risk Ratio (M‐H, Fixed, 95% CI)	1.89 [1.14, 3.12]
2.1 Glibenclamide	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.38, 10.43]
2.2 Metformin	3	1114	Risk Ratio (M‐H, Fixed, 95% CI)	1.88 [1.11, 3.18]
3 Caesarean section	17	1988	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.93, 1.14]
3.1 Glibenclamide	7	892	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.93, 1.28]
3.2 Metformin	9	995	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.87, 1.13]
3.3 Acarbose	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.39, 1.71]
3.4 Combined metformin‐glibenclamide	1	68	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.41, 2.15]
4 Development of type 2 diabetes	2	754	Risk Ratio (M‐H, Fixed, 95% CI)	1.39 [0.80, 2.44]
5 Perinatal (fetal and neonatal death) and later infant mortality	10	1463	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.29, 2.49]
5.1 Glibenclamide	5	668	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.25, 3.91]
5.2 Metformin	4	678	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.3 Acarbose	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.4 Combined metformin/glibenclamide	1	84	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.12, 3.79]
6 Large‐for‐gestational age	13	2352	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.76, 1.35]
6.1 Glibenclamide	5	651	Risk Ratio (M‐H, Random, 95% CI)	0.45 [0.19, 1.07]
6.2 Metformin	8	1668	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.94, 1.44]
6.3 Acarbose	1	33	Risk Ratio (M‐H, Random, 95% CI)	0.27 [0.01, 5.15]
7 Death or serious morbidity composite (variously defined by trials, e.g. perinatal or infant death, shoulder dystocia, bone fracture or nerve palsy)	2	760	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.84, 1.26]
8 Neurosensory disability in later childhood (18 to 24 months)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
8.1 Hearing impairment	1	93	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.01, 7.49]
8.2 Visual impairment	1	93	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.03, 2.90]
8.3 Any mild developmental delay	1	93	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.33, 3.44]
9 Use of additional pharmacotherapy	19	2761	Risk Ratio (M‐H, Fixed, 95% CI)	0.03 [0.02, 0.06]
9.1 Glibenclamide	7	893	Risk Ratio (M‐H, Fixed, 95% CI)	0.10 [0.03, 0.31]
9.2 Metformin	10	1676	Risk Ratio (M‐H, Fixed, 95% CI)	0.02 [0.01, 0.04]
9.3 Acarbose	2	124	Risk Ratio (M‐H, Fixed, 95% CI)	0.10 [0.01, 0.74]
9.4 Metformin/glibenclamide	1	68	Risk Ratio (M‐H, Fixed, 95% CI)	0.04 [0.00, 0.63]
10 Maternal hypoglycaemia	10	998	Risk Ratio (M‐H, Random, 95% CI)	3.01 [0.74, 12.27]
10.1 Glibenclamide	7	779	Risk Ratio (M‐H, Random, 95% CI)	2.80 [0.29, 26.99]
10.2 Metformin	3	186	Risk Ratio (M‐H, Random, 95% CI)	3.01 [0.91, 9.94]
10.3 Acarbose	1	33	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
11 Glycaemic control during/end treatment (fasting)	19	2812	Std. Mean Difference (IV, Random, 95% CI)	0.05 [‐0.09, 0.19]
11.1 Glibenclamide	9	1185	Std. Mean Difference (IV, Random, 95% CI)	0.03 [‐0.21, 0.27]
11.2 Metformin	8	1441	Std. Mean Difference (IV, Random, 95% CI)	0.03 [‐0.18, 0.24]
11.3 Combined metformin‐glyburide	1	68	Std. Mean Difference (IV, Random, 95% CI)	0.33 [‐0.15, 0.81]
11.4 Acarbose	2	118	Std. Mean Difference (IV, Random, 95% CI)	0.10 [‐0.60, 0.79]
12 Glycaemic control during/end treatment (postprandial)	18	2508	Std. Mean Difference (IV, Random, 95% CI)	0.12 [‐0.05, 0.29]
12.1 Glibenclamide	9	959	Std. Mean Difference (IV, Random, 95% CI)	0.00 [‐0.25, 0.26]
12.2 Metformin	7	1363	Std. Mean Difference (IV, Random, 95% CI)	0.33 [0.07, 0.59]
12.3 Combined metformin‐glyburide	1	68	Std. Mean Difference (IV, Random, 95% CI)	0.20 [‐0.28, 0.67]
12.4 Acarbose	2	118	Std. Mean Difference (IV, Random, 95% CI)	‐0.30 [‐0.67, 0.07]
13 Glycaemic control during/end of treatment (HbA1c)	9	1963	Std. Mean Difference (IV, Random, 95% CI)	0.01 [‐0.12, 0.15]
13.1 Glibenclamide	3	487	Std. Mean Difference (IV, Random, 95% CI)	0.04 [‐0.31, 0.39]
13.2 Metformin	5	1392	Std. Mean Difference (IV, Random, 95% CI)	0.05 [‐0.14, 0.24]
13.3 Combined metformin/glibenclamide	1	84	Std. Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.55, 0.30]
14 Weight gain in pregnancy	10	2336	Mean Difference (IV, Random, 95% CI)	1.06 [0.63, 1.48]
14.1 Glibenclamide	3	509	Mean Difference (IV, Random, 95% CI)	0.63 [‐0.42, 1.67]
14.2 Metformin	7	1794	Mean Difference (IV, Random, 95% CI)	1.11 [0.62, 1.61]
14.3 Acarbose	1	33	Mean Difference (IV, Random, 95% CI)	0.90 [‐1.56, 3.36]
15 Induction of labour	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
15.1 Metformin	3	348	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.96, 1.75]
16 Postpartum haemorrhage	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
16.1 Metformin	2	91	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.01, 8.13]
17 Breastfeeding at discharge, six weeks postpartum, six months or longer	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
17.1 Metformin	2	411	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.86, 1.23]
18 Relevant biomarker changes associated with the intervention	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
18.1 HOMA‐IR	1	78	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐2.92, 2.92]
18.2 Total Cholesterol	1	78	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.49, 0.69]
18.3 HDL Cholesterol	1	78	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.13, 0.33]
18.4 Triglycerides	1	78	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐0.68, 0.08]
19 Body mass index (BMI)	1	733	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐1.29, 0.89]
19.1 Metformin	1	733	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐1.29, 0.89]
20 Postnatal weight retention	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
20.1 Six to eight weeks postpartum	1	167	Mean Difference (IV, Fixed, 95% CI)	‐1.60 [‐6.34, 3.14]
20.2 One year postpartum	1	176	Mean Difference (IV, Fixed, 95% CI)	‐3.70 [‐8.50, 1.10]
21 Impaired glucose tolerance	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
21.1 six weeks postpartum	3	841	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.80, 1.68]
21.2 one year postpartum	1	179	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.56, 1.26]
22 Stillbirth	3	653	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.08, 4.52]
22.1 Glibenclamide	1	404	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.06, 15.72]
22.2 Metformin	2	249	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.01, 8.17]
23 Neonatal death	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
23.1 Glibenclamide	2	503	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.06, 15.72]
24 Macrosomia (> 4000 g)	19	2305	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.77, 1.78]
24.1 Glibenclamide	9	1186	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.31, 1.94]
24.2 Metformin	10	1086	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.88, 1.81]
24.3 Acarbose	1	33	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
25 Small‐for‐gestational age	9	1812	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.79, 1.69]
25.1 Glibenclamide	2	136	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.17, 4.20]
25.2 Metformin	7	1643	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.77, 1.71]
25.3 Acarbose	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	4.0 [0.17, 91.48]
26 Birth trauma	12		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
26.1 Birth trauma not defined	5	1107	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.53, 2.03]
26.2 Shoulder dystocia	8	968	Risk Ratio (M‐H, Fixed, 95% CI)	1.44 [0.62, 3.34]
26.3 Clavicular fracture	2	196	Risk Ratio (M‐H, Fixed, 95% CI)	4.71 [0.23, 95.53]
26.4 Brachial nerve injury	2	320	Risk Ratio (M‐H, Fixed, 95% CI)	5.05 [0.24, 103.90]
27 Gestational age at birth	18	2834	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.20, 0.18]
27.1 Glibenclamide	7	1025	Mean Difference (IV, Random, 95% CI)	‐0.21 [‐0.67, 0.26]
27.2 Metformin	8	1533	Mean Difference (IV, Random, 95% CI)	0.17 [0.04, 0.30]
27.3 Acarbose	2	124	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.52, 0.49]
27.4 Combined metformin/glibenclamide	2	152	Mean Difference (IV, Random, 95% CI)	‐0.07 [‐0.56, 0.42]
28 Preterm birth (< 37 weeks)	11	2417	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.64, 1.88]
28.1 Glibenclamide	2	182	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.51, 1.74]
28.2 Metformin	9	2235	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.58, 2.39]
29 Congenital abnormality	15	2671	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.88, 2.08]
29.1 Glibenclamide	6	922	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.50, 2.54]
29.2 Metformin	7	1574	Risk Ratio (M‐H, Fixed, 95% CI)	1.40 [0.81, 2.41]
29.3 Acarbose	1	91	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
29.4 Combined metformin/glibenclamide	1	84	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.39, 10.34]
30 Five minute Apgar less than seven	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
30.1 Metformin	4	1170	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.09, 2.64]
31 Birthweight (g)	22	3183	Mean Difference (IV, Random, 95% CI)	‐20.14 [‐83.58, 43.29]
31.1 Glibenclamide	9	1116	Mean Difference (IV, Random, 95% CI)	‐75.73 [‐230.46, 78.99]
31.2 Metformin	10	1791	Mean Difference (IV, Random, 95% CI)	22.00 [‐33.67, 77.67]
31.3 Acarbose	2	124	Mean Difference (IV, Random, 95% CI)	22.17 [‐154.08, 198.42]
31.4 Combined metformin‐glyburide	2	152	Mean Difference (IV, Random, 95% CI)	‐46.17 [‐199.60, 107.26]
32 Head circumference (cm) at birth	3	975	Mean Difference (IV, Random, 95% CI)	0.14 [‐0.26, 0.53]
32.1 Glibenclamide	1	82	Mean Difference (IV, Random, 95% CI)	‐0.40 [‐1.08, 0.28]
32.2 Metformin	2	893	Mean Difference (IV, Random, 95% CI)	0.27 [‐0.12, 0.65]
33 Length (cm) at birth	3	975	Mean Difference (IV, Random, 95% CI)	0.11 [‐0.50, 0.71]
33.1 Glibenclamide	1	82	Mean Difference (IV, Random, 95% CI)	‐0.60 [‐1.64, 0.44]
33.2 Metformin	2	893	Mean Difference (IV, Random, 95% CI)	0.29 [‐0.38, 0.97]
34 Ponderal index at birth	2	815	Mean Difference (IV, Random, 95% CI)	0.03 [‐0.13, 0.19]
34.1 Glibenclamide	1	82	Mean Difference (IV, Random, 95% CI)	‐0.07 [‐0.22, 0.08]
34.2 Metformin	1	733	Mean Difference (IV, Random, 95% CI)	0.10 [0.06, 0.14]
35 Adiposity at birth (Triceps skinfold (mm))	2	815	Mean Difference (IV, Fixed, 95% CI)	‐0.07 [‐0.25, 0.10]
35.1 Glibenclamide	1	82	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.35, 0.35]
35.2 Metformin	1	733	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.31, 0.11]
36 Adiposity at birth (Subscapular skinfold (mm))	2	815	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.50, 0.24]
36.1 Glibenclamide	1	82	Mean Difference (IV, Random, 95% CI)	‐0.40 [‐0.90, 0.10]
36.2 Metformin	1	733	Mean Difference (IV, Random, 95% CI)	0.0 [‐0.20, 0.20]
37 Adiposity at birth (Skin fold sum (mm))	1	82	Mean Difference (IV, Fixed, 95% CI)	‐0.80 [‐2.33, 0.73]
38 Adiposity at birth (Percentage fat mass)	1	82	Mean Difference (IV, Fixed, 95% CI)	‐1.60 [‐3.77, 0.57]
39 Neonatal hypoglycaemia	24	3892	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.85, 1.52]
39.1 Glibenclamide	10	1283	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.41, 1.19]
39.2 Metformin	12	2424	Risk Ratio (M‐H, Random, 95% CI)	1.58 [1.16, 2.16]
39.3 Acarbose	1	33	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.02, 10.16]
39.4 Combined hypoglycaemia	2	152	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.49, 1.18]
40 Respiratory distress syndrome	10	1894	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.83, 1.99]
40.1 Glibenclamide	3	409	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.45, 3.91]
40.2 Metformin	7	1485	Risk Ratio (M‐H, Fixed, 95% CI)	1.28 [0.80, 2.06]
41 Neonatal jaundice (hyperbilirubinaemia)	16	2183	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.83, 1.19]
41.1 Glibenclamide	6	999	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.61, 1.02]
41.2 Metformin	9	1100	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.89, 1.56]
41.3 Combined metformin/glibenclamide	1	84	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.69, 1.78]
42 Hypocalcaemia	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
42.1 Glibenclamide	5	939	Risk Ratio (M‐H, Fixed, 95% CI)	1.95 [0.49, 7.78]
43 Polycythaemia	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
43.1 Glibenclamide	3	590	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.38, 3.57]
44 Relevant biomarker changes associated with the intervention (Cord blood C‐peptide)	1	59	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.82, 0.42]
44.1 Glibenclamide	1	59	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.82, 0.42]
45 Relevant biomarker changes associated with the intervention (Cord blood insulin)	3		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only
45.1 Glibenclamide	3	486	Std. Mean Difference (IV, Fixed, 95% CI)	0.03 [‐0.15, 0.21]
46 Childhood weight (kg)	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
46.1 6 months	1	93	Mean Difference (IV, Fixed, 95% CI)	‐0.35 [‐0.75, 0.05]
46.2 12 months	1	93	Mean Difference (IV, Fixed, 95% CI)	‐0.62 [‐1.18, ‐0.06]
46.3 18 months to 2 years	2	411	Mean Difference (IV, Fixed, 95% CI)	‐0.44 [‐0.83, ‐0.05]
47 Childhood height (cm)	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
47.1 6 months	1	93	Mean Difference (IV, Random, 95% CI)	‐0.70 [‐2.05, 0.65]
47.2 12 months	1	93	Mean Difference (IV, Random, 95% CI)	‐1.30 [‐2.60, 0.00]
47.3 18 to 24 months	2	411	Mean Difference (IV, Random, 95% CI)	‐0.65 [‐2.61, 1.31]
48 Childhood adiposity (ponderal index (kg/m³))	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
48.1 6 months	1	93	Mean Difference (IV, Fixed, 95% CI)	‐1.0 [‐3.43, 1.43]
48.2 12 months	1	93	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐1.12, 0.72]
48.3 18 months to 2 years	1	93	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.88, 0.68]
49 Childhood adiposity (Total fat mass (%))	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
49.1 Metformin	1	318	Mean Difference (IV, Fixed, 95% CI)	0.5 [‐0.49, 1.49]
50 Childhood blood pressure (2 years)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
50.1 Systolic BP	1	170	Mean Difference (IV, Fixed, 95% CI)	‐2.24 [‐5.02, 0.54]
50.2 Diastolic BP	1	170	Mean Difference (IV, Fixed, 95% CI)	‐0.5 [‐16.75, 15.75]
51 Number of antenatal visits or admissions	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
51.1 Glibenclamide	1	404	Mean Difference (IV, Fixed, 95% CI)	1.0 [‐0.08, 2.08]
52 Admission to neonatal care unit/nursery	18	3441	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [1.19, 1.59]
52.1 Glibenclamide	7	1018	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.74, 1.92]
52.2 Metformin	10	2306	Risk Ratio (M‐H, Fixed, 95% CI)	1.44 [1.22, 1.71]
52.3 Acarbose	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
52.4 Combined metformin/glibenclamide	1	84	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.82, 1.52]
53 Duration of stay in neonatal intensive care unit or special care baby unit	3	401	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐1.79, 1.39]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Caesarean section	2	133	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.50, 1.42]
2 Development of type 2 diabetes	2	653	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.79, 1.21]
3 Perinatal (fetal and neonatal death) and later infant mortality	4	1137	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.41, 1.33]
4 Large‐for‐gestational age	1	202	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.41, 1.78]
5 Use of additional pharmacotherapy	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6 Maternal hypoglycaemia	1	95	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Glycaemic control during/end of treatment	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
7.1 HbA1c	1	161	Mean Difference (IV, Fixed, 95% CI)	0.10 [0.04, 0.16]
7.2 Fasting blood glucose	1	68	Mean Difference (IV, Fixed, 95% CI)	1.60 [‐2.97, 6.17]
7.3 Postprandial blood glucose	1	68	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐5.32, 5.92]
8 Weight gain in pregnancy	1	38	Mean Difference (IV, Fixed, 95% CI)	1.73 [‐3.31, 6.77]
9 Neonatal death	1	611	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.23, 2.23]
10 Macrosomia	3	717	Risk Ratio (M‐H, Fixed, 95% CI)	0.30 [0.18, 0.50]
11 Small‐for‐gestational age	2	240	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.05, 2.40]
12 Birth trauma	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
12.1 Shoulder dystocia	2	133	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.2 Nerve palsy	1	38	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
13 Gestational age at birth	2	106	Mean Difference (IV, Fixed, 95% CI)	‐0.66 [‐1.37, 0.06]
14 Preterm birth (less than 37 weeks' gestation)	1	611	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.64, 1.85]
15 Birthweight	2	106	Mean Difference (IV, Fixed, 95% CI)	‐342.85 [‐561.11, ‐124.60]
16 Ponderal Index	1	68	Mean Difference (IV, Fixed, 95% CI)	‐0.18 [‐0.34, ‐0.02]
17 Neonatal hypoglycaemia	3	176	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.34, 2.24]
18 Neonatal jaundice (Hyperbilirubinaemia)	1	68	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
19 Hypocalcaemia	1	68	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
20 Polycythaemia	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	0.9 [0.30, 2.67]
21 Relevant biomarker changes associated with the intervention (Cord C‐peptide)	1	202	Mean Difference (IV, Fixed, 95% CI)	0.03 [0.02, 0.04]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Caesarean section	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	1.5 [0.29, 7.87]
2 Macrosomia	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.42, 9.50]
3 Gestational age at birth	1	34	Mean Difference (IV, Fixed, 95% CI)	‐0.80 [‐2.05, 0.45]
4 Birthweight (g)	1	34	Mean Difference (IV, Fixed, 95% CI)	103.0 [‐245.40, 451.40]
5 Length at birth (cm)	1	34	Mean Difference (IV, Fixed, 95% CI)	1.60 [‐0.01, 3.21]
6 Neonatal hypoglycaemia	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	0.5 [0.05, 5.01]
7 Respiratory distress syndrome	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Neonatal jaundice (Hyperbilirubinaemia)	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Hypocalcaemia	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Methods	Parallel randomised controlled trial. Single centre.
Participants	256 women were screened and 35 were eligible, 26 women were randomised and 23 were analysed. Inclusion criteria: diagnosis of GDM using a 75g OGTT and diagnosis based on World Health Organization criteria of > 140 mg/dL at 2 hours, a singleton pregnancy and having failed to maintain blood glucose on medical nutrition therapy alone after 2 weeks. Exclusion criteria: no details. Setting: women attending antenatal clinic in Chennai, India. Timing: dates not specified.
Interventions	Insulin (n = 13) starting dose 0.1 units/kg and increased weekly as required. Glibenclamide (n = 10) starting dose 0.625 mg titrated weekly to maintain 2‐hour plasma glucose ≤ 120 mg/dL.
Outcomes	No outcomes were prespecified but reported on birthweight, glycaemic control and cord blood insulin.
Notes	Published correspondence article only. Sample size calculation: none stated. ITT analysis: no. Funding: not stated. Conflicts of interest: no details were stated in the manuscript.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"assigned randomly" no other details.
Allocation concealment (selection bias)	Unclear risk	No details.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No evidence of blinding and it is unlikely to have occurred due to different modes of administration.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details.
Incomplete outcome data (attrition bias)   All outcomes	High risk	3 women lost to follow‐up all from the glibenclamide group. No details for losses were provided.
Selective reporting (reporting bias)	High risk	Outcomes were not prespecified and were very limited. The evidence is published as correspondence only and no full publication could be identified.
Other bias	High risk	The evidence is published as correspondence only and no full publication could be identified.

Methods	Parallel randomised controlled trial.
Participants	68 women diagnosed with GDM (Canadian Diabetes Association criteria). Inclusion criteria: ≥ 18 years, diagnosed with GDM between 24 and 28 weeks' gestation, failure to achieve glycaemic control with diet and exercise alone, able to understand and read French or English. Exclusion criteria: known type 1 or type 2 diabetes, treatment interfering with glucose metabolism, allergies to 1 of the components of treatment, hepatic or haematologic diseases. Setting: Quebec, Canada. Timing: no details in abstract.
Interventions	Combined metformin and glyburide ‐ metformin 250 mg per day and glyburide 5 mg per day with an incremental increase in dosages to a maximum of 750 mg metformin and 10 mg glyburide. If treatment targets (capillary glucose fasting < 5.3 mmol/L; 2‐hour postprandial < 6.7 mmol/L) not met over a 2‐week period, then insulin was added. versus Insulin (Insulin aspart/lispro and Neutral Protamine Hagedorn insulin).
Outcomes	Primary outcomes: glycaemic control at end of treatment. Secondary outcomes: acceptability of treatment.
Notes	Additional information was found from the NIH trials register NCT01215331. Estimated enrolment is for 275 women. Funding: Fonds de recherche sante Quebec Conflicts of interest: no details
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomised". No further details.
Allocation concealment (selection bias)	Unclear risk	No details.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	"open label", masking is difficult due to insulin being given by subcutaneous injection and metformin and glyburide by oral medication.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details.
Incomplete outcome data (attrition bias)   All outcomes	High risk	Interim report only.
Selective reporting (reporting bias)	High risk	Published as a conference abstract only.
Other bias	Low risk	No differences at baseline.

Methods	Parallel randomised controlled trial
Participants	100 women enrolled Inclusion criteria: Women with GDM, singleton pregnancy, failure of satisfactory glycaemic control for at least one week after diagnosis. Exclusion criteria: Presence of fetal anomaly, pregnancy complications other than GDM, known intolerance to metformin or risk of lactic acidosis. Setting: Antenatal care clinics, Ain Shams University Maternity Hospital, Cairo; Egypt. Timing: From January to November 2014
Interventions	Insulin (n = 50) Regular insulin and NPH insulin ratio of 3:7 at a starting dose of 0.7 units/kg/day, with two thirds before breakfast and one‐third before dinner (evening). vs Metformin (n = 50) 1000 mg daily with meals and increased by 500 mg or 850 mg every 1 or 2 weeks up to maximum of 2500 mg until birth. Insulin could be added if required.
Outcomes	Primary outcome ‐ maternal glycaemic control Secondary outcomes ‐ BMI, pre and post‐prandial glucose concentration, supplemental insulin, birthweight, gestational weight gain, side effects of metformin, mode of birth, gestational age at birth, macrosomia, neonatal hypoglycaemia, admission to NICU, neonatal death, congential abnormalities,
Notes	Funding: No details. Conflicts of interest: The authors declare there were no conflicts of interest.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"selected randomly" no other details. Looks as though drawn by lots.
Allocation concealment (selection bias)	Unclear risk	'200 closed, mixed and identical envelopes containing 50 'selected for insulin', 50 'selected for metformin' and '100 'non‐selected cards, left in the office of the head nurse of the clinic. No details on who placed details in envelopes or if envelopes were sealed.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label. Blinding not possible because of type of intervention.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Five women excluded for discontinuing study and withdrawal of consent before starting treatment (two from insulin and three from metformin). Unrelated to treatment. 47 analysed in metformin group and 48 in the insulin group. No women were lost to follow‐up.
Selective reporting (reporting bias)	Low risk	All pre‐specified outcomes appear to be reported.
Other bias	Low risk	Groups seemed balanced at baseline.

Methods	Parallel randomised controlled trial.
Participants	10 women Inclusion criteria: Women with GDM failing to respond to diet alone. No details on diagnostic criteria. Exclusion criteria: No details Setting: India Timing: Not stated
Interventions	Human insulin (n = 5) before breakfast, and lunch and pre‐mixed insulin before dinner versus Insulin aspart (n = 5) before breakfast and lunch and 70/30 mixture of aspart protamine and soluble aspart before dinner.
Outcomes	Fasting and 2‐hour blood glucose levels, birthweight.
Notes	Sample size calculation – no details. ITT – yes. Funding – none stated. Conflicts of interest ‐ no details in abstract.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomly assigned", no other details.
Allocation concealment (selection bias)	Unclear risk	No details provided.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No details.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Data reported for all women.
Selective reporting (reporting bias)	High risk	Not all outcomes reported.
Other bias	High risk	Conference abstract only. Groups balanced at baseline.

Methods	Single‐centre randomised controlled trial.
Participants	345 women eligible. 323 women randomised. Inclusion criteria: ≥ 20 and ≤ 30 years of age, 12 to 28 weeks’ gestation. BMI ≤ 35 kg/m² at first visit, GDM confirmed by 75 g OGTT unable to maintain treatment targets after 2 weeks of medical nutrition therapy. Exclusion criteria: pre‐gestational diabetes, type 1 diabetes, ketoacidosis, severe kidney disease, cardiovascular disease, stroke, cancer, severe psychological disorder, hypothyroidism, anaemia,taking antibiotics or insulin. Setting: Diabetes care and research institute, Chennai, India. Timing: April 2008 to September 2009.
Interventions	Biphasic insulin aspart BIAsp 30 (n = 163) initial dose 6 IU versus Biphasic human insulin BHI 30 (n = 160) initial dose 6 IU. Dosage adjusted after contact with women every 3 days; seen in clinic every 2 weeks or monthly depending on degree of glycaemic control. Self‐monitoring 6 times daily before and 2 hours after each meal.
Outcomes	Primary outcome: macrosomia (> 90^th percentile). Secondary outcome: achievement of FPG and PPG targets, adverse events, maternal hypoglycaemia, newborn length, birthweight and Apgar scores at 1 and 5 minutes.
Notes	Sample size calculation – no details. ITT – yes. Funding – none stated. Conflicts of interest ‐ authors declared no known conflicts of interest in manuscript.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomly allocated.
Allocation concealment (selection bias)	Low risk	Using sealed random allocation slips that were opened serially.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label as there were differences in injection devices.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	3 women in BHI group lost to follow‐up as they moved out of area.
Selective reporting (reporting bias)	High risk	More outcomes are reported in the results than listed in the methods section.
Other bias	Low risk	Groups were balanced at baseline.

Methods	Single‐centre open‐label randomised controlled trial.
Participants	70 women diagnosed with gestational diabetes using WHO criteria.  Inclusion criteria: GDM diagnosed as ≥ 6.1 mmol/L or 110 mg/dL fasting plasma glucose and ≥ 7.8 mmol/L or 140 mg/dL OGTT after 2 hours 75 g of glucose. Exclusion criteria: presence of a pathology requiring faster glucose control, such as corticoid therapy. Other concomitant pathologies that could affect therapy or perinatal results. Setting: Maternity institution in Brazil. Timing: October 2003 to July 2004.
Interventions	1) Insulin as conventional therapy (n = 27), 0.7 IU/kg in the first trimester, 0.8 IU/kg in the 2nd trimester and 0.9 IU/kg in the 3rd trimester. Regular human insulin and Neutral Protamine Hagedorn insulin used. 2) Glyburide (n = 24) initial dose 5 mg daily increasing every 7 days until glucose control achieved (max 20 mg), and 3) Acarbose (n = 19) initial dose 50 mg increasing by 50 mg every 7 days to a maximum dose of 300 mg. All women received diet and exercise programmes. Treatment targets ‐ fasting plasma glucose 5.0 mmol/L or 90 mg/dL and 2‐hour postprandial 5.6 mmol/L or 100 mg/dL.
Outcomes	Primary outcomes: neonatal hypoglycaemia, birthweight. Gestational age at birth, Apgar scores, neonatal hypoglycaemia, macrosomia (> 4000 g), LGA (> 90th centile), fasting and postprandial glucose levels, severe maternal hypoglycaemia requiring admission, BMI, weight gain in pregnancy, mode of birth, other outcomes (not specified).
Notes	Gestational age at diagnosis range from 11 to 33 weeks'. All women had planned birth at 39 weeks' gestation. ITT analysis: 1 woman was excluded from the study data. Sample size calculation: no details. Funding: no details. Conflicts of interest: not reported in paper. See also Silva 2005.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomized". Telephone randomisation.
Allocation concealment (selection bias)	Unclear risk	"brown envelopes, containing outside the randomization number and in the inside a sheet defining which therapy, the patient was to be allocated to".
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No blinding.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	1 woman was excluded due to severe asthma and data were not included in the analysis.
Selective reporting (reporting bias)	Low risk	All outcomes were reported between both papers.
Other bias	Low risk	No evidence of other bias. Groups were balanced at baseline. The manuscript provides no acknowledgements or details of funding at yet in the text it is stated that acarbose was provided free of charge by the pharmaceutical company whereas insulin and glyburide were free of charge within the public health system.

Methods	Randomised controlled trial.
Participants	104 pregnant women. Inclusion criteria: age 18 to 45 years, singleton pregnancy, gestational age 20 to 30 weeks', diagnosed with type 2 diabetes or GDM, meeting hospital criteria for starting insulin therapy, not meeting treatment targets with diet and exercise. Exclusion criteria: type 1 diabetes, type 2 diabetes who previously failed to meet treatment targets with metformin, allergic reaction to metformin. Setting: Ghana. Timing: January 2013 to October 2013.
Interventions	Insulin (n = 52) soluble and premixed insulin used. Total daily dose of premixed insulin was usually calculated as 0.3 IU/kg body weight versus Metformin (n = 52) initial dose 500 mg daily and increased to a maximum daily dose of 2500 mg. Insulin was added if glycaemic targets not met.
Outcomes	Glycaemic control, gestational age at birth, mode of birth, birthweight, neonatal intensive care admissions.
Notes	Sample size calculation: yes. ITT analysis: yes. Funding: there was no source of funding. Conflicts of interest: authors declare no conflicts.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"randomized", ballot.
Allocation concealment (selection bias)	Low risk	Picking randomly 1 paper with an inscription from an opaque envelope. The sequencing of picking was in the order in which they reported to clinic.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	"open‐label."
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	No details, but glycaemic control was analysed by laboratories who were unlikely to be aware of the patients' allocation.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	In the insulin group 6 women delivered outside the hospital area, 5 were lost to follow‐up and 1 discharged from the clinic against advice (40 were analysed). In the metformin group 1 woman delivered outside the hospital area, 3 were lost to follow‐up and 1 withdrew consent. 4 women who had been allocated metformin received insulin, they were analysed in the metformin group (47 were analysed).
Selective reporting (reporting bias)	Unclear risk	32 of the 43 women analysed had GDM in the metformin group and 23/40 in the insulin group had GDM. Only glycaemic control data is reported although other neonatal outcomes were listed in the methods section of the report. In the trial protocol viewed on ACTRN12614000942651 the primary outcome was glycaemic control and the secondary outcome was maternal weight gain. The authors note in the results section that fasting blood glucose, 1 hour postprandial glucose, maternal weight gain, pregnancy and neonatal outcomes were also recorded but were not discussed in this publication.
Other bias	Low risk	Groups appear to be balanced at baseline.

Methods	Randomised trial.
Participants	40 women with GDM unable to achieve fasting glucose < 90 mg/dL and 1‐hour postprandial glucose < 120 mg/dL after at least 1 week lifestyle intervention. No other details available.
Interventions	50/50 mixture of Neutral Protamine Hagedorn insulin/lispro delivered as 3 pre‐meal injections (n = 20) versus Neutral Protamine Hagedorn insulin and lispro as 6 injections pre‐meal (n = 20).
Outcomes	Included fasting glucose and HbA1c.
Notes	Conference abstract only. Funding: No details Conflicts of interest: No details
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomised" no other details.
Allocation concealment (selection bias)	Unclear risk	No details.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No details but is unlikely to have occurred.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	2 women in the 50/50 mix group and 1 in the 6 injection group dropped out of the study.
Selective reporting (reporting bias)	High risk	Conference abstract only, no full publication identified.
Other bias	Unclear risk	States that groups were balanced at baseline although the 50/50 mix group was younger. 86% of the included women were Mexican.

Methods	Partly randomised and partly quasi‐randomised controlled trial.
Participants	72 women from USA. Inclusion criteria: women identified with GDM. Exclusion criteria: none stated. Setting: California, USA. Timing: July 1973 to February 1975.
Interventions	Insulin (n = 27) also received the diet advice plus 20 units of Neutral Protamine Hagedorn insulin and 10 units regular insulin given 30 minutes before breakfast versus Diet (n = 11) 30 to 35 calories/kg ideal body weight/day (24% at breakfast, 30% at lunch, 33% at dinner, 13% at bedtime snack). 125 g of protein but the rest equally divided between carbohydrates and fat versus No therapy (n = 34) ‐ usual dietary counselling with 90 g of protein and a weight gain of 6.8 to 11.3 kg.
Outcomes	No outcomes prespecified apart from testing for diabetes postpartum.
Notes	Sample size calculation: not reported. ITT analysis: yes. Funding: not reported. Conflicts of interest: not reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	The first 20 women were assigned treatment based on time of gestation (10 diagnosed before 36 weeks' and given insulin and diet, 10 diagnosed after 35 weeks' and were control participants with no therapy). After this point women were randomly assigned to 1 of 3 groups (a diet group was added).
Allocation concealment (selection bias)	High risk	The first 20 women were assigned based on time of gestation and therefore there was no allocation, for the remaining 52 women there are no details.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No details but unlikely.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All women randomised appear to have been analysed.
Selective reporting (reporting bias)	High risk	No outcomes were prespecified apart from diabetes postpartum.
Other bias	High risk	The data for those women quasi‐randomised cannot be separated from the truly randomised.

Methods	Parallel, randomised controlled trial.
Participants	30 women.  Inclusion criteria: GDM diagnosed by the criteria of the Australasian Diabetes in Pregnancy Society.  Exclusion criteria: not stated.  Setting: Australia, no further details. Timing: not stated.
Interventions	Insulin ‐ n = 14 (no further details) versus Metformin ‐ n = 16 (no further details).
Outcomes	Outcomes: mode of delivery, pre‐eclampsia, gestational age at birth, cord C‐peptide, cord glucose, birthweight, requiring intravenous dextrose, median time in SCBU, neonatal jaundice, need for neonatal phototherapy.
Notes	This data comes from a letter to the editor. ITT analysis: not stated. Funding: not stated. Conflicts of interest: not reported in the letter to the editor.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"women randomised".
Allocation concealment (selection bias)	Unclear risk	Unclear, no details.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Not stated but unlikely to be blinded.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not stated.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Insufficient details provided.
Selective reporting (reporting bias)	High risk	This is a letter to a journal editor.
Other bias	Unclear risk	Unable to make judgements due to lack of data, groups appeared to be balanced at baseline.

Methods	Randomised controlled trial ‐ 2 centres.
Participants	31 women randomised. Inclusion criteria: presenting for antenatal care < 20 weeks' gestation, women with type 2 diabetes, GDM (A2) diagnosed < 20 weeks', failing to achieve glycaemic control with medical nutrition therapy. Exclusion criteria: taking insulin before pregnancy, < 18 years of age at randomisation, not speaking fluent English or Spanish, having a triplet or higher order pregnancy, known fetal anomaly, evidence of end organ damage or major comorbidity associated with diabetes, contraindications to metformin including hepatic or renal disease, allergy, adverse reaction, history of diabetic ketoacidosis. Setting: 2 hospitals in Carolina, USA. Timing: 2008 to 2010.
Interventions	Insulin ‐ regular insulin (twice daily) and Neutral Protamine Hagedorn insulin. Insulin dose was weight based and initial dose was 0.7 U/kg per day given twice a day versus Metformin ‐ initial dose 500 mg once or twice a day up to maximum daily dose of 2500 mg. If treatment targets not met then regular or Neutral Protamine Hagedorn insulin were added. All women received dietary advice and were asked to self‐monitor blood glucose fasting and 1‐hour post‐prandial.
Outcomes	HbA1c, maternal hypoglycaemia, glycaemic control, c‐peptide, neonatal hypoglycaemia, satisfaction.
Notes	Sample size calculation ‐ yes based on change in mean fasting blood glucose. ITT analysis ‐ yes. Funding ‐ Bowles‐Cefalo Young Researcher Award Grant. Conflicts of interest ‐ no statement of conflicts of interest in the manuscript. Data are presented for type 2 diabetes and GDM combined and cannot be separated. However as 50% of the women had GDM these data have been included. The authors have been contacted to see if the GDM data alone are available.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated, block randomisation.
Allocation concealment (selection bias)	Low risk	A nurse not involved in the study prepared opaque, sequentially numbered envelopes.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No blinding of participants due to differences in administration of drugs.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not stated.
Incomplete outcome data (attrition bias)   All outcomes	High risk	Due to only randomising 31 of 230 women the trial is underpowered to detect differences in primary outcome. Of the 31 randomised 16 were allocated to insulin and 14 were analysed (1 inadequate mental capacity, 1 fetal demise). 15 were allocated to metformin 14 analysed (1 withdrew consent).
Selective reporting (reporting bias)	High risk	Several outcomes are reported that were not listed a priori.
Other bias	High risk	3 months after recruitment had started the authors became aware that they would not reach the target enrolment within the funded timeframe but continued to recruit and added another site. Trial includes GDM and pre‐existing diabetes and data cannot be currently separated.

Methods	Multicentre (2 sites) randomised trial.
Participants	128 eligible women approached and 100 consented and randomised. Inclusion criteria: singleton pregnancy, 12 to 34 weeks' gestation, normal liver and renal function. Diagnosis of GDM. Exclusion criteria: pre‐eclampsia, essential hypertension requiring medication, fetal growth restriction. Setting: tertiary level hospitals in Finland. Timing: June 2005 to June 2009.
Interventions	1) Insulin (n = 50) ‐ long acting insulin (Neutral Protamine Hagedorn insulin) according to hospital guidelines to normalise fasting and rapid‐acting insulin lispro to normalise post‐prandial glucose concentrations. Self‐monitoring twice a week (4 to 6 times in 1 day). Treatment targets were fasting < 5.3 mmol/L; 1.5 hours post‐prandial < 6.7 mmol/L. 2) Metformin (n = 50) 750 mg once daily for first week, twice daily for second week and 3 times daily from week 3 onwards ± supplementary insulin if normoglycaemia not achieved within 1 to 2 weeks. versus All women were followed up until 6 to 8 weeks postpartum.
Outcomes	Primary outcome: macrosomia (birthweight > 4000 g or LGA). Secondary outcomes: admission to NICU, neonatal hypoglycaemia needing intravenous glucose, hyperbilirubinaemia treated with phototherapy, birth injury (clavicular fracture or brachial nerve injury), Apgar score, cord pH, need for supplementary insulin, preterm delivery, mode of birth, hypertension, weight gain during pregnancy, HbA1c.
Notes	Power calculation: yes based on the outcome of macrosomia. ITT analysis: yes. Funding: Alma and K.A. Snellman, Oulu, Finland. Conflicts of interest: the authors declared there were no conflicts of interest associated with this trial. Ijäs 2014 reported on follow‐up of the cohort at 18 months of age in 45 children from the metformin group and 48 children from the insulin group.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation code generated manually in blocks of 10.
Allocation concealment (selection bias)	Low risk	Opaque, numbered, sealed envelopes.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No blinding due to different routes of administration of the interventions. "Open label".
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No blinding due to different routes of administration of the interventions.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Insulin: no losses in insulin group (50 randomised and 50 analysed). Metformin: 2 women withdrew consent, 1 woman was excluded as they had abnormal liver function, 3 women discontinued metformin due to gastrointestinal side effects (50 randomised and 47 analysed).
Selective reporting (reporting bias)	Unclear risk	The authors report on subgroups of the supplementary insulin group but this is not listed prospectively and the trial is not powered to look at the effects of this.
Other bias	Low risk	There was no evidence of other sources of bias, groups did not differ at baseline.

Methods	Prospective randomised trial.
Participants	99 women randomised. Inclusion criteria: 24‐34 weeks' gestation, singleton pregnancy, no fetal abnormality, no intrauterine growth restriction, no use of medication that could affect glycaemic control. Diagnosis of GDM using a 50 g 1‐hour oral glucose challenge test. If > 7.5 mmol/L or 135 mg/dl then received a 100 g 3‐hour OGTT. Diagnosis by 2 abnormal values (5.3 mmol/L or 95 mg/dL, 10.0 mmol/L or 180 mg/dL, 8.6 mmol/L or 155 mg/dL and 7.8 mmol/L or 140 mg/dL Carpenter and Coustan criteria), an elevated fasting value of 3‐hour OGTT or 1‐hour OGTT> 11.1 mmol/L or 200 mg/dL. Exclusion criteria: no details. Setting: Magee Women's Hospital. Pittsburgh, USA. Timing: 2002 to 2005.
Interventions	Medical therapy was commenced if blood sugars were ≥ 5.3 mmol/L or 95 mg/dL (fasting) or 6.7 mmol/L or 120 mg/dL (2‐hour postprandial). All women had education for diet and blood sugar monitoring. 1) Insulin (n = 50) 0.8 U/kg in multiple daily injections with long‐acting insulin and short‐acting insulin and increased up to twice weekly versus 2) Glibenclamide (n = 49) 2.5 mg daily increasing to 2.5 to 5 mg increments weekly. Taken once or twice daily. Transitioned to insulin if maximum dose of 20 mg per day did not achieve therapeutic goal.
Outcomes	Primary outcome: percentage fat mass. Secondary outcomes: glycaemic control, anthropometry, timing and mode of delivery, metabolic biomarkers (maternal and neonatal), gestational age, birthweight, fat free mass, neonatal complications.
Notes	Power calculation: yes based on percentage fat mass. ITT analysis: yes but not for all outcomes. Funding: American Association of Obstetricians and Gynecologists Foundation, Magee Women's Health Foundation. Conflicts of interest: not reported in the manuscript.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation using permuted block design.
Allocation concealment (selection bias)	Low risk	Sequentially numbered, opaque, sealed envelopes.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Unlikely that the women or the clinicians were blinded to the treatment but this is not stated.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Assays performed in a blinded fashion. Research team performing neonatal measurements were masked to the group assignment.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Insulin: 2 withdrawals, no reasons specified. Glibenclamide: 4 withdrawals (no reasons specified) and 1 stillbirth. Some outcomes were assessed by ITT but overall only analysed 41 women in each group and less for some outcomes.
Selective reporting (reporting bias)	High risk	There were limited maternal outcomes and mode of delivery was not reported.
Other bias	High risk	The trial was stopped early due to discontinuation of maintenance of equipment used for the primary outcome. No differences at baseline.

Methods	Randomised trial no further details.
Participants	100 women treated for gestational diabetes. Inclusion criteria: no details. Exclusion criteria: no details. Setting: Turkey. Timing: no details.
Interventions	Insulin (no other details) versus Metformin (no other details).
Outcomes	Neonatal hypoglycaemia, birthweight, respiratory problems, admission to NICU.
Notes	Conference abstract only. No details available to contact authors. Funding: no details Conflicts of interest: no details
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomly assigned" no other details.
Allocation concealment (selection bias)	Unclear risk	No details.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No details but unlikely to be blinded.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	No details.
Selective reporting (reporting bias)	High risk	No details, conference abstract only.
Other bias	High risk	Conference abstract only.

PERMALINK

Insulin for the treatment of women with gestational diabetes

Julie Brown

Luke Grzeskowiak

Kathryn Williamson

Michelle R Downie

Caroline A Crowther

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

1. Examples of diagnostic criteria for gestational diabetes mellitus.

Screening and diagnosis of GDM

Pathophysiology of GDM

Risk factors associated with GDM

Clinical outcomes for women with pregnancy hyperglycaemia

Neonatal, infant and later outcomes related to pregnancy hyperglycaemia

Description of the intervention

Types of insulin used during pregnancy

Rapid‐acting insulin

Short‐acting insulin

Intermediate‐acting insulin

Long‐acting insulin

Other formulations of insulin

Insulin regimens

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Maternal

Neonatal

Secondary outcomes

Maternal

Long‐term outcomes for mother

Fetal/neonatal outcomes

Later infant/childhood outcomes

Child as an adult outcomes

Health service use

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

1.

Data extraction and management

Assessment of risk of bias in included studies

(1) Random sequence generation (checking for possible selection bias)

(2) Allocation concealment (checking for possible selection bias)

(3.1) Blinding of participants and personnel (checking for possible performance bias)

(3.2) Blinding of outcome assessment (checking for possible detection bias)

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

(5) Selective reporting (checking for reporting bias)

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

(7) Overall risk of bias

Assessing the quality of the body of evidence using the GRADE approach

Measures of treatment effect

Dichotomous data

Continuous data

Unit of analysis issues

Cluster‐randomised trials

Other unit of analysis issues

Multiple pregnancy

Multiple‐arm studies

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Methods	Parallel, randomised controlled trial ‐ single centre.
Participants	200 women. Inclusion criteria: 18 to 45 years, singleton pregnancy, no documented history of diabetes prior to pregnancy, gestational age 24 to 32 weeks'. Exclusion criteria: no details. Setting: hospital in Isfahan, Iran. Timing: not stated.
Interventions	All women initially taught lifestyle modification. Treatment targets: fasting < 5.3 mmol/L or 95 mg/dL and 2‐hour post‐prandial < 6.7 mmol/L or 120 mg/dL. if failed to reach treatment targets then randomised to: Insulin (n = 100) initial dose 0.5 IU/kg/day divided as 2/3 of dose in morning (Neutral Protamine Hagedorn insulin) and 1/3 in the afternoon (regular insulin). Dose was increased in 1 IU intervals if treatment target levels not reached versus Metformin (n = 100) initial dose 500 mg daily and if required adjusted to a maximum of 2500 mg per day.
Outcomes	Primary and secondary outcomes not specified. HbA1c, mode of birth, hypertension, pre‐eclampsia, birthweight, shoulder dystocia, Apgar at 1 and 5 minutes, neonatal sepsis, jaundice, hypoglycaemia, respiratory distress, fetal anomalies, admission to NICU, neonatal liver function.
Notes	Power calculation: yes but outcome that it was based on was not detailed. ITT analysis: yes. Funding: funded by University. Conflicts of interest: manuscript states no conflicts of interest.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"randomized"; "random number tables".
Allocation concealment (selection bias)	Low risk	Generated by a third party physician.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	"blinded", Care providers were blinded.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Outcome assessors were blinded.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Women who failed to maintain treatment targets on metformin and required insulin were excluded (n = 22) and replaced with new women. No further exclusions or losses.
Selective reporting (reporting bias)	Unclear risk	Very few maternal outcomes reported. No raw data reported for cord liver function although this was not an outcome of the review.
Other bias	Low risk	No other evidence of bias, the groups were matched at baseline.

Methods	Randomised controlled trial ‐ single centre.
Participants	96 women randomised. Inclusion criteria: age 18 to 45 years, singleton pregnancy, 24 to 36 weeks' gestation; diagnosed with GDM. Not meeting treatment targets for dietary control (fasting > 5.0 mmol/L or 90 mg/dL; 2‐hour postprandial 6.66 mmol/L or 120 mg/dL. Exclusion criteria: previous diabetes mellitus, fetal anomalies/aneuploidy, vascular disorders or substance/alcohol abuse. Setting: tertiary teaching hospital, Iran. Timing: March 2012 to March 2013.
Interventions	All women had dietary advice and educated about how to measure blood glucose levels 4 times per day. Insulin (n = 59) ‐ initial dose 0.4 unit/kg. 50% from Neutral Protamine Hagedorn insulin and 50% from regular insulin in divided doses adjusted every 2 days. Glyburide (n = 37) ‐ initial dose of 1.25 mg with morning meal. If required dose was increased by 1.25 mg every 3 to 7 days up to a maximum dose of 20 mg per day. If treatment targets not met at maximum dose for 2 weeks then switched to insulin. Self‐monitoring of blood glucose 4 times daily. Treatment targets: fasting 5.0 to 5.8 mmol/L or 90 to 105 mg/dL, 2‐hour postprandial < 6.7 mmol/L or 120 mg/dL.
Outcomes	Primary outcome ‐ effective glycaemic control. Secondary outcomes ‐ LGA, SGA, macrosomia (≥ 4000 g), hypoglycaemia, hyperbilirubinaemia, hypocalcaemia, admission to NICU, need for oxygen therapy more than 1 hour after birth, need for assisted ventilation and intubation, RDS, transient tachypnoea, adverse effects associated with drug.
Notes	ITT analysis: yes.. Power calculation: yes, unclear for which outcome this was based. Funding: no details reported in manuscript. Conflicts of interest: no details reported in manuscript.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised by block randomisation method based on computer generated blocks of 4.
Allocation concealment (selection bias)	Low risk	Sequentially coded sealed opaque envelopes.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No evidence of blinding.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No evidence of blinding of outcome assessors.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All women randomised had data reported.
Selective reporting (reporting bias)	Unclear risk	Some neonatal outcomes reported are not listed a priori and no data on adverse drug effects was reported.
Other bias	Unclear risk	Groups were balanced at baseline. There are however more women randomised to insulin than glyburide and the reason is not clear.

Methods	Single‐centre, parallel, randomised controlled trial.
Participants	63 women.  Inclusion criteria: women diagnosed with GDM.  Exclusion criteria: insulin‐dependent diabetes mellitus, liver/kidney disease, chronic hypertension or seizure disorders, less than 11 weeks or more than 36 weeks' gestation.  Setting: Medical Centre in Mississippi, USA. Timing: 2001 to 2004.
Interventions	All women received dietary counselling. If they failed to maintain glycaemic control (fasting < 105 mg/dL, 2 hours postprandial < 120 mg/dL) then commenced on treatment. 1) Insulin ‐ 0.7 units/kg subcutaneously (n = 31).  2) Metformin ‐ 500 mg twice daily (n = 32) ‐maximum dose 1000 mg twice daily (if glycaemic control not maintained then started on insulin). Target was postprandial glucose of < 120 mg/dL, or 60 to 90 mg/dL fasting.
Outcomes	Primary: glycaemic control, mode of delivery, shoulder dystocia, PPH. Gestational age at birth, birthweight, Apgar score at 5 minutes, NICU admission, hypoglycaemia, RDS, hyperbilirubinaemia, perinatal death.
Notes	Sample size calculation: yes. ITT analysis: unclear but all women randomised were analysed. Funding: no details. Conflicts of interest: authors state that there were no financial conflicts of interest.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"randomized" "computer generated list".
Allocation concealment (selection bias)	Low risk	Sequentially numbered sealed opaque envelopes.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Unclear, no details but unlikely to be blinded due to different modes of administration. Neonatologist was not blinded.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Unclear, no details.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	There were no dropouts.
Selective reporting (reporting bias)	Unclear risk	All outcomes appear to be reported but there are some outcomes not listed and that have no data in the text of the paper such as induction of labour.
Other bias	High risk	Report that groups equal at baseline. Only half the sample that had been estimated to be appropriate had been recruited after 32 months and as such an interim report on 63 women was undertaken. There is no evidence of a full report.

Methods	Prospective open‐label parallel randomised trial.
Participants	60 women with singleton pregnancy, diagnosed with GDM, not maintaining glycaemic control with medical nutrition therapy. Inclusion criteria: GDM diagnosed as above, singleton pregnancy. Exclusion criteria: pre‐gestational diabetes, severe anaemia, heart disease, renal disease, taking steroids. Setting: Department of Obstetrics and Gynecology, Kolkata, India. Timing: January 2010 to December 2010.
Interventions	All women received medical nutrition therapy for 2 weeks to include 3 meals and 3 snacks per day. If glycaemic control (fasting 5.0 mmol/L (90 mg/dL) and postprandial (timing not specified) 6.7 mmol/L (120 mg/dL) was not maintained then randomised to: Insulin (n = 30) commenced on 0.7 units per kg subcutaneously 3 times daily and increasing weekly as required versus Glibenclamide (n = 30) 2.5 mg orally in the morning, increased weekly by 2.5 mg up to a maximum of 20 mg. Women were switched to insulin if glycaemic targets not achieved in 2 weeks. Self‐monitoring of blood glucose occurred 7 times per day. Followed up for 7 days after delivery.
Outcomes	No primary outcomes specified. Birthweight, LGA (≥ 90th centile), macrosomia (≥ 4000 g), glycaemic control, hyperbilirubinaemia,maternal and neonatal hypoglycaemia (≤ 2.4 mmol/L), congenital abnormalities, perinatal death, respiratory distress, gestational age at delivery, HbA1c.
Notes	Sample size calculation: no. ITT analysis: unclear but all women randomised were analysed. Funding: no funding relating to this trial. Conflicts of interest: states that there were no conflicts of interest in the manuscript. All deliveries were planned between 37 to 38 weeks' gestation.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number tables.
Allocation concealment (selection bias)	Unclear risk	No details provided.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	There was no blinding of staff or participants due to mode of delivery of drug.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Outcome assessors were not blinded.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All women appear to have been randomised and analysed. No losses to follow‐up were reported.
Selective reporting (reporting bias)	High risk	The original protocol was no viewed. Outcomes are not listed a priori in the methods section. Not all of the outcomes reported in the results were identified in the methods section.
Other bias	Low risk	Unclear if there were other biases. No differences in baseline demographics.

Methods	Randomised single‐blind parallel controlled trial.
Participants	172 women. Inclusion criteria: aged 18‐40 years, singleton pregnancy with gestational age between 20 and 34 weeks. All women attending clinic were screened using a 50 g glucose challenge test. Exclusion criteria: history of systemic disease, substance abuse, pre‐gestational diabetes, major fetal malformation. Setting: Women's Hospital Tehran, Iran. Timing: 2010 to 2012.
Interventions	All women received counselling and dietary and exercise advice with caloric restriction based on BMI. Women who failed to maintain glucose control for 1 week (FPG > 95 mg/dL or 2‐hour postprandial blood glucose > 120 mg/dL) were randomised. Insulin (n = 86) Neutral Protamine Hagedorn insulin with initial dose of 0.2 units/kg. Adjustments were made depending on whether fasting and or postprandial values were high versus Metformin (n = 86) initial dose of 500 mg twice daily and increased by 500 mg to 1000 mg weekly up to am maximum daily dose of 2500 mg divided by meals. Insulin was added if glycaemic control was not achieved.
Outcomes	Side effects of treatment, HbA1c, weight gain, pre‐eclampsia, pregnancy‐induced hypertension, abruption, PPROM, shoulder dystocia, mode of delivery, preterm birth, neonatal anthropometry, birthweight, birthweight centile, macrosomia, admission to NICU, perinatal death, hospitalisation, umbilical artery PH, 5 minute Apgar, hyperbilirubinaemia, phototherapy, RDS, minor birth defects.
Notes	Elective delivery was planned at 38.5 weeks by induction or caesarean section. Sample size calculation: yes based on birthweight. ITT analysis: yes. Funding: none stated. Conflicts of interest: manuscript states that there were no conflicts of interest.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"assigned randomly", "computer generated list".
Allocation concealment (selection bias)	Low risk	Sequentially‐labelled, opaque, sealed envelopes.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Participants were not blinded but obstetricians were.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details on outcome assessors.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	160 out of 172 women who were randomised were analysed. In the metformin group, 1 woman withdrew consent, 2 were lost to follow‐up, 3 discontinued due to adverse effects. In the insulin group there were 6 women lost to follow‐up.
Selective reporting (reporting bias)	Low risk	All important infant and maternal outcomes appear to have reported.
Other bias	Low risk	No evidence of other bias.

Methods	Randomised parallel trial.
Participants	207 women from South Africa. Inclusion criteria: women who had been screened using a 2‐hour 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	Insulin (n = 47) Dietary restriction alone (n = 56) Chlorpropramide (n = 58) Tolbutamide (n = 46)
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	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"random sample basis", no other details.
Allocation concealment (selection bias)	Unclear risk	No details.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No details.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All women randomised appear to have data.
Selective reporting (reporting bias)	High risk	There are no pre‐specified outcomes for the mother or the infant.
Other bias	High risk	Paper states that there were no differences between interventions at baseline. The data for GDM and other diabetes cannot be separated. The proportion of women with GDM cannot be determined and the data have therefore not been included in any meta‐analysis.

Methods	Randomised parallel controlled trial.
Participants	615 women. Inclusion criteria: women with GDM. Exclusion criteria: pre‐gestational diabetes, blood sugar > 300 mg/100 mL, classic diabetic symptoms and abnormal blood sugars, enrolling after 37 weeks' gestation with GDM. Setting: Boston, USA. Timing: April 1954 to June 1960.
Interventions	Insulin plus diet (n = 307) ‐ 10 Units Neutral Protamine Hagedorn insulin in the morning plus 30/cal/kg ideal body weight as 1.5 g to 2.0 g protein/kg with 40% total calories from carbohydrates versus Routine prenatal care (n = 308) ‐ not defined further.
Outcomes	Perinatal death, LGA, subsequent maternal diabetes.
Notes	Also included a group of women without GDM who were selected at random at regular intervals. The data for these women are not included in this review. Power calculation ‐ no details. ITT ‐ appears to be conducted. Funding ‐ not stated. Conflicts of interest ‐ not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomly allocated", no other details.
Allocation concealment (selection bias)	Unclear risk	No details.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Blinding not reported and unlikely to have occurred due to different treatment interventions.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All women randomised appear to have data.
Selective reporting (reporting bias)	High risk	Outcomes very limited. Only report on LGA, perinatal death and subsequent maternal diabetes.
Other bias	Unclear risk	No details of demographics at baseline, unable to judge. 12/305 (4%) did not receive insulin in the treatment group.

Methods	Randomised controlled trial, parallel design.
Participants	97 women with a diagnosis of GDM (1‐hour 50 g glucose challenge test followed by a 3‐hour OGTT). 80% were Hispanic and 15% African American. Inclusion criteria: diagnosis of GDM, dietary interventions alone had not been effective in maintaining glycaemic control. Exclusion criteria: not specified. Setting: prenatal clinics in Los Angeles, USA. Timing: 2002 to 2005.
Interventions	1) Insulin (n = 49) no other details versus 2) Glibenclamide (n = 48) no other details.
Outcomes	Primary outcomes: maternal glycaemic control and neonatal birthweight.
Notes	Unable to contact authors by email. Funding: no details Conflicts of interest: no details
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"computer generated list."
Allocation concealment (selection bias)	Low risk	Sealed sequentially number opaque envelopes.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label trial.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No evidence of attrition. ITT analysis conducted.
Selective reporting (reporting bias)	High risk	Only published as a conference abstract and as a letter to the editor.
Other bias	High risk	No evidence of other sources of bias. No differences reported at baseline for demographic variables but the fasting, 1‐hour and 2‐hour glucose levels from the OGTT and the HbA1c were all significantly higher in the insulin group.

Methods	Single‐centre, randomised controlled trial.
Participants	27 women with GDM at 18 to 28 weeks' gestation. Inclusion/exclusion criteria: not stated. Setting: California USA. Timing: no details.
Interventions	Insulin aspart 5 minutes before a meal + Neutral Protamine Hagedorn insulin as the basal insulin versus Regular human insulin 30 minutes before a meal + Neutral Protamine Hagedorn insulin as the basal insulin Initial treatment was 2 daily doses (morning and bedtime) of Neutral Protamine Hagedorn insulin and 3 daily doses of either insulin aspart or regular human insulin. Initial dose of insulin was 0.8 U/kg per day if < 26 weeks' gestation or 0.9 U/kg if ≥26 weeks' gestation. Given dietary advice and self‐monitored 7 times per day.
Outcomes	HbA1c, maternal hypoglycaemia, insulin antibodies, blood glucose values, cord blood insulin and insulin antibody binding.
Notes	Sample size calculation ‐ no details. ITT analysis ‐ yes. Funding ‐ the study was funded in part through a contract with Novo Nordisk Inc. Conflicts of interest ‐ One of the authors was an employee of the funding body.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomized", no other details.
Allocation concealment (selection bias)	Unclear risk	No details.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	"open label."
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	13/14 women in the insulin aspart group completed the study and 9/13 in the human insulin group. 4 participants discontinued as they gave birth early and 1 participant due to the inability to complete the meal test. The authors do not specify which groups the participants belonged to.
Selective reporting (reporting bias)	High risk	Data on birth outcome including weight and length, macrosomia and congenital anomalies were not prespecified.
Other bias	Low risk	No differences at baseline.

Methods	Randomised controlled pilot trial, single‐centre.
Participants	23 women. Inclusion criteria: insulin requiring GDM. Exclusion criteria: not stated. Setting: Department of Obstetrics and Gynaecology, Helsinki, Finland. Timing: not stated.
Interventions	Individualised diet planned with a dietician. Daily energy intake 1800 kcal of which 50% was carbohydrates. Short‐acting insulin ‐ Actrapid (human insulin). 3 daily injections with starting doses of 4, 6 and 4 IU before breakfast, lunch and dinner. Dose was increased if 1 of the postprandial glucose values > 7.8 mmol/L (n = 11) versus Long‐acting insulin ‐ Protaphan (Neutral Protamine Hagedorn insulin). 1 injection in the morning with an initial dose of 14 IU. Dose was increased if 2 of daily preprandial values > 5.5 mmol/L. (n = 12) Doses were individually adjusted and women followed up in clinics every 2 to 4 weeks. Self‐monitoring of blood glucose before breakfast and pre‐ and postprandial at least twice a week.
Outcomes	None prespecified but reported on insulin requirements,timing of birth, birthweight, macrosomia, nerve palsy, fetal hypoglycaemia, hyperbilirubinaemia, transient tachypnoea, need for insulin postpartum, mode of birth, malformations, Apgar < 7 at 1 minute, maternal HbA1c.
Notes	Sample size calculation ‐ no. ITT analysis ‐ yes. Funding: not stated. Conflicts of interest ‐ not reported in manuscript.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomized", no other details.
Allocation concealment (selection bias)	Unclear risk	No details.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No details but blinding unlikely due to different protocols and targets.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All women randomised were analysed.
Selective reporting (reporting bias)	High risk	No outcomes were prespecified. A number of outcomes were reported in the results section. Some outcomes were not associated with any data and the authors state that there was no difference between groups.
Other bias	High risk	These data are published as a brief report of a pilot study. There is no full publication and no indication that a larger trial was undertaken.