Trial Outcomes & Findings for RCT Metformin for Reduction of Gestational Diabetes Mellitus Effects (NCT NCT02980276)

Last Updated: 2025-03-17

Results Overview

The primary efficacy outcome was achieved if any participant experienced: * Insulin initiation * Fasting glucose value \>5.1 mmol/l at 32weeks or 38 weeks gestation.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

535 participants

Primary outcome timeframe

Enrolment through delivery, an average of 16 weeks.

Results posted on

2025-03-17

Participant Flow

Participants were enrolled between June 2017 and September 2022. A total of 535 participants were randomised into the study, 502 at Galway University Hospital GUH and 33 at Portiuncula University Hospital PUH (the second site, PUH, did not start recruiting participants until February 2019).

Participant milestones

Participant milestones
Measure	Treatment Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Overall Study STARTED	268	267
Overall Study Included in Analysis of Primary Outcome	264	262
Overall Study COMPLETED	235	240
Overall Study NOT COMPLETED	33	27

Reasons for withdrawal

Reasons for withdrawal
Measure	Treatment Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Overall Study Withdrawal by Subject	4	4
Overall Study Physician Decision	0	1
Overall Study Lost to Follow-up	18	18
Overall Study Death	1	0
Overall Study Miscellaneous other	10	4

Baseline Characteristics

RCT Metformin for Reduction of Gestational Diabetes Mellitus Effects

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Treatment n=268 Participants Participants randomised to the treatment arm received active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg).	Control n=267 Participants Participants randomised to the placebo arm received placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group.	Total n=535 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	268 Participants n=5 Participants	267 Participants n=7 Participants	535 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	34.3 years STANDARD_DEVIATION 4.9 • n=5 Participants	34.3 years STANDARD_DEVIATION 4.7 • n=7 Participants	34.3 years STANDARD_DEVIATION 4.8 • n=5 Participants
Sex: Female, Male Female	268 Participants n=5 Participants	267 Participants n=7 Participants	535 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized African/Black	7 Participants n=5 Participants	6 Participants n=7 Participants	13 Participants n=5 Participants
Race/Ethnicity, Customized Asian	17 Participants n=5 Participants	29 Participants n=7 Participants	46 Participants n=5 Participants
Race/Ethnicity, Customized Irish Traveller	11 Participants n=5 Participants	2 Participants n=7 Participants	13 Participants n=5 Participants
Race/Ethnicity, Customized White	219 Participants n=5 Participants	209 Participants n=7 Participants	428 Participants n=5 Participants
Race/Ethnicity, Customized Other	14 Participants n=5 Participants	21 Participants n=7 Participants	35 Participants n=5 Participants
Region of Enrollment Ireland	268 Pregnancies n=5 Participants	267 Pregnancies n=7 Participants	535 Pregnancies n=5 Participants
BMI	31.2 kg per metre squared STANDARD_DEVIATION 7 • n=5 Participants	32.1 kg per metre squared STANDARD_DEVIATION 6.9 • n=7 Participants	31.7 kg per metre squared STANDARD_DEVIATION 7.1 • n=5 Participants
BMI Category >=30	160 Participants n=5 Participants	164 Participants n=7 Participants	324 Participants n=5 Participants
BMI <30	108 Participants n=5 Participants	103 Participants n=7 Participants	211 Participants n=5 Participants
Medical Card	63 Participants n=5 Participants	63 Participants n=7 Participants	126 Participants n=5 Participants
Private Health Insurance	126 Participants n=5 Participants	116 Participants n=7 Participants	242 Participants n=5 Participants
Unemployed	19 Participants n=5 Participants	27 Participants n=7 Participants	46 Participants n=5 Participants
Current Smoker	34 Participants n=5 Participants	17 Participants n=7 Participants	51 Participants n=5 Participants
History of Hypertension	12 Participants n=5 Participants	4 Participants n=7 Participants	16 Participants n=5 Participants
Nulliparous	84 Participants n=5 Participants	84 Participants n=7 Participants	168 Participants n=5 Participants
History of Macrosomia	57 Participants n=5 Participants	44 Participants n=7 Participants	101 Participants n=5 Participants
Previous Cesarian Section	70 Participants n=5 Participants	74 Participants n=7 Participants	144 Participants n=5 Participants
Previous Miscarriage	106 Participants n=5 Participants	93 Participants n=7 Participants	199 Participants n=5 Participants
Prevous Pre-eclampsia	24 Participants n=5 Participants	23 Participants n=7 Participants	47 Participants n=5 Participants
Previous Post-partum Hemorrhage	28 Participants n=5 Participants	20 Participants n=7 Participants	48 Participants n=5 Participants
Previous Polyhydramnios	10 Participants n=5 Participants	7 Participants n=7 Participants	17 Participants n=5 Participants
Previous Ante-partum Haemorrhage	20 Participants n=5 Participants	15 Participants n=7 Participants	35 Participants n=5 Participants
Previous Stillbirth	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Fasting glucose	5.2 mmol/L STANDARD_DEVIATION 0.45 • n=5 Participants	5.2 mmol/L STANDARD_DEVIATION 0.47 • n=7 Participants	5.2 mmol/L STANDARD_DEVIATION 0.46 • n=5 Participants
1hour Glucose Tolerance Test Result	9.4 mmol/L STANDARD_DEVIATION 1.9 • n=5 Participants	9.7 mmol/L STANDARD_DEVIATION 1.9 • n=7 Participants	9.5 mmol/L STANDARD_DEVIATION 1.9 • n=5 Participants
2hour Glucose Tolerance Test Result	7.1 mmol/L STANDARD_DEVIATION 1.6 • n=5 Participants	7.1 mmol/L STANDARD_DEVIATION 1.6 • n=7 Participants	7.1 mmol/L STANDARD_DEVIATION 1.6 • n=5 Participants
Gestational Age at Randomization	27 weeks n=5 Participants	27 weeks n=7 Participants	27 weeks n=5 Participants

PRIMARY outcome

Timeframe: Enrolment through delivery, an average of 16 weeks.

Population: Population of pregnancies followed up until delivery. 268 were randomised to Treatment Group, of whom 264 received Metformin as randomised. Two participants delivered outside the country; delivery and neonatal information was available for the remaining 262 participants. Among those randomised to Treatment Group, 264 Pregnancies were included in the Primary Outcome Analysis. All 262 patients randomised to placebo were followed until delivery and included in Primary Outome Analysis.

The primary efficacy outcome was achieved if any participant experienced: * Insulin initiation * Fasting glucose value \>5.1 mmol/l at 32weeks or 38 weeks gestation.

Outcome measures

Outcome measures
Measure	Treatment n=264 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Primary Composite Outcome	150 Participants	167 Participants

PRIMARY outcome

Timeframe: Enrolment through delivery, an average of 16 weeks.

Initiation of insulin treatment at any time up to delivery.

Outcome measures

Outcome measures
Measure	Treatment n=264 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Insulation of Insulin	101 Participants	134 Participants

SECONDARY outcome

Timeframe: Time to Insulin Initiation, from date of randomization until the date of delivery, an average of 16 weeks..

Population: Pregnancies followed up until delivery.

Time to Insulin Initiation, from date of randomization until the date of delivery.

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Time to Insulin Initiation	68 days Standard Deviation 38.1	58.7 days Standard Deviation 37

SECONDARY outcome

Timeframe: Enrolment through delivery, an average of 16 weeks.

Population: Population of pregnancies followed up until delivery. 268 were randomised to Treatment Group, of whom 264 received Metformin as randomised. Two participants delivered outside the country; delivery and neonatal information was available for the remaining 262 participants. Among those randomised to Treatment Group, 264 Pregnancies were included in the Primary Outcome Analysis. Data for this outcome available for 263 in Treatment group.

Whether or not insulin was initiated at any time during the study.

Outcome measures

Outcome measures
Measure	Treatment n=263 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Insulin Initiated	94 Participants	106 Participants

SECONDARY outcome

Timeframe: Measured at 32 and 38 weeks' gestation.

Population: Participants having fasting glucose levels measured at 32 and/or 38 weeks' gestation. Data available for 255 in the Treatment group and 248 in the Control group.

Number of women with fasting hyperglycemia at 32wks or at 38wks gestation.

Outcome measures

Outcome measures
Measure	Treatment n=255 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=248 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Fasting Hyperglycemia	94 Participants	106 Participants

SECONDARY outcome

Timeframe: Enrolment through delivery, an average of 16 weeks.

Insulin dose required in any participant requiring insulin.

Outcome measures

Outcome measures
Measure	Treatment n=264 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Insulin Dose Required	20.4 IU Standard Deviation 19.8	2.2 IU Standard Deviation 22.8

SECONDARY outcome

Timeframe: Enrolment through delivery, an average of 16 weeks.

Change in weight (kg) from randomization until last visit before delivery

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Gestational Weight Gain	0.88 kg Standard Deviation 3.31	1.96 kg Standard Deviation 3.53

SECONDARY outcome

Timeframe: 12 weeks post-partum

Population: Participants followed until 12 weeks postpartum who contributed samples for analysis.

Impaired fasting glucose at 12 weeks postpartum

Outcome measures

Outcome measures
Measure	Treatment n=230 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=235 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Postpartum Impaired Fasting Glucose	51 Participants	52 Participants

SECONDARY outcome

Timeframe: 12 weeks postpartum

Population: Participants followed until 12 weeks postpartum who contributed samples.

Outcome measures

Outcome measures
Measure	Treatment n=229 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=235 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Postpartum Impaired Glucose Tolerance	15 Participants	16 Participants

SECONDARY outcome

Timeframe: 12 weeks postpartum

Population: Participants followed until 12 weeks postpartum who contributed samples

Outcome measures

Outcome measures
Measure	Treatment n=222 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=231 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Postpartum Metabolic Syndrome	20 Participants	25 Participants

SECONDARY outcome

Timeframe: At delivery, an average of 16 weeks after enrolment

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Gestational Age at Delivery	39.1 weeks Standard Deviation 1.5	39.1 weeks Standard Deviation 1.6

SECONDARY outcome

Timeframe: At delivery, an average of 16 weeks after enrolment

Delivered by Cesarian section.

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Mode of Delivery - Cesarian Delivery	114 Participants	100 Participants

SECONDARY outcome

Timeframe: At delivery, an average of 16 weeks after randomization.

Population: Among those having cesarian section, count of emergency procedures.

Among those having cesarian section, count of emergency procedures.

Outcome measures

Outcome measures
Measure	Treatment n=114 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=100 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Mode of Delivery - Emergency Cesarian Section	53 Participants	53 Participants

SECONDARY outcome

Timeframe: At time of labor, an average of 16 weeks after enrolment.

Labor induced.

Outcome measures

Outcome measures
Measure	Treatment n=259 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Mode of Delivery - Induced	73 Participants	87 Participants

SECONDARY outcome

Timeframe: From enrolment through 6 weeks postpartum, an average of 22 weeks.

Population: Participants followed from randomisation through to 12 weeks postpartum. 268 participants were randomised to Treatment Group; 264 received Metformin as randomised. Two of those participants delivered outside the country; delivery and neonatal information was available for the remaining 262 participants. 267 were randomised to Placebo, of which 262 received Placebo as randomised and were followed through to delivery.

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Maternal Morbidity - Pregnancy-induced Hypertension	31 Participants	28 Participants

SECONDARY outcome

Timeframe: Enrolment through 6 weeks postpartum, an average of 22 weeks.

Population: Participants followed from randomisation through delivery.

Pre-eclampsia diagnosed during study participation

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Maternal Morbidity - Pre-eclampsia	10 Participants	5 Participants

SECONDARY outcome

Timeframe: From enrolment through delivery, an average of 16 weeks.

Any vaginal bleeding prior to delivery

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Maternal Morbidity - Antepartum Hemorrhage	15 Participants	27 Participants

SECONDARY outcome

Timeframe: From delivery through 6 weeks postpartum.

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Maternal Morbidity - Postpartum Hemorrhage	51 Participants	63 Participants

SECONDARY outcome

Timeframe: At birth

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Birthweight	3393 grams Standard Deviation 527	3505 grams Standard Deviation 510

SECONDARY outcome

Timeframe: At birth

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Neonatal Head Circumference	34.7 cm Standard Deviation 1.6	34.7 cm Standard Deviation 1.8

SECONDARY outcome

Timeframe: At birth

Population: Pregnancies followed until delivery

Height in cm (crown-heel length)

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Neonatal Height	51 cm Standard Deviation 3.2	51.7 cm Standard Deviation 3.2

SECONDARY outcome

Timeframe: At birth

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Neonatal Abdominal Circumference	33.4 cm Standard Deviation 2.4	33.3 cm Standard Deviation 2.8

SECONDARY outcome

Timeframe: At birth

Ponderal index is calculated as 100 x weight(grams)/(crown-heel length).

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Neonatal Ponderal Index	2.6 grams/cm Standard Deviation 0.4	2.6 grams/cm Standard Deviation 0.5

SECONDARY outcome

Timeframe: At birth

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Birth Weight >4000g	20 Participants	39 Participants

SECONDARY outcome

Timeframe: At birth

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Birth Weight >90th Percentile	17 Participants	39 Participants

SECONDARY outcome

Timeframe: At birth

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Birth Weight <2500g	16 Participants	9 Participants

SECONDARY outcome

Timeframe: At birth

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Birth Weight <10th Percentile	15 Participants	7 Participants

SECONDARY outcome

Timeframe: From birth until 6 weeks of life.

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Neonatal Morbidity - Need for NICU Care	41 Participants	33 Participants

SECONDARY outcome

Timeframe: At birth

Delivery at gestational age \<37 weeks.

Outcome measures

Outcome measures
Measure	Treatment n=261 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=260 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Neonatal Morbidity - Preterm Birth	24 Participants	17 Participants

SECONDARY outcome

Timeframe: From birth until 6 weeks of life.

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Neonatal Morbidity - Respiratory Distress Syndrome Requiring Respiratory Support	24 Participants	18 Participants

SECONDARY outcome

Timeframe: From birth until 6 weeks of life.

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Neonatal Morbidity - Jaundice Requiring Phototherapy	1 Participants	0 Participants

SECONDARY outcome

Timeframe: From birth until 6 weeks of life.

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Neonatal Morbidity - Major Congenital Anomalies	10 Participants	7 Participants

SECONDARY outcome

Timeframe: At 5 minutes after birth

The Apgar score comprises five components: 1) color, 2) heart rate, 3) reflexes, 4) muscle tone, and 5) respiration, each of which is given a score of 0, 1, or 2. (for example see: https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2015/10/the-apgar-score#:\~:text=The%20Apgar%20score%20comprises%20five,0%2C%201%2C%20or%202)

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Neonatal Morbidity - Apgar Score <7 at 5 Minutes	1 Participants	1 Participants

SECONDARY outcome

Timeframe: First hour of life.

serum glucose \<2.6mmol/l on at least one occasion \<60 minutes after delivery

Outcome measures

Outcome measures
Measure	Treatment n=262 Participants Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg). Metformin Hydrochloride: Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.	Control n=262 Participants Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group. Placebo: Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.
Neonatal Morbidity - Neonatal Hypoglycemia	36 Participants	34 Participants

Adverse Events

Treatment - Mother

Serious events: 79 serious events

Other events: 225 other events

Deaths: 2 deaths

Control - Mother

Serious events: 72 serious events

Other events: 247 other events

Deaths: 1 deaths

Treatment - Fetus/Neonate

Serious events: 107 serious events

Other events: 157 other events

Deaths: 1 deaths

Control - Fetus/Neonate

Serious events: 123 serious events

Other events: 172 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

Professor Fidelma Dunne

University of Galway

Phone: +35391492117

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place