Understanding the impact of metformin on maternal health and fetal growth in pregnancies complicated by maternal diabetes

Third trimester fetal growth velocity will be assessed by change in fetal growth zscore between 20-26 weeks (average) and birth.
(At each scan the estimated fetal weight (EFW) will be calculated using standard 2D biometry and fractional thigh volume (TVol) measurements using a standard formula and converted to a zscore (WHO). The delta change in zscore between the average zscore of scans performed between 20-26 weeks and the birthweight zscore will be calculated. In order to verify the primary outcome, the eCRF will capture the TVol measurement and the EFW at each scan as well as recording the 2nd trimester and 3rd trimester deviation scores. The source data (scan report) will verify the 2D biometry.)

1. Adherence/Acceptability
1.1. Number of missed doses– calculated as an average over pregnancy from the number of missed doses reported in the 7 days prior to each study visit (adjusted for number of study visits)
1.2. Undesirable effects of allocated treatment (number of women reporting undesirable effects associated with metformin and/or insulin/number of women receiving metformin or insulin treatment)
1.3. Treatment satisfaction with allocated medication regime (questionnaire)
1.4. Acceptability of allocated medication regime (questionnaire)
1.5. Secondary fetal growth outcomes:
1.6. Distribution of fetal growth zscores between treatment groups and within prespecified subgroups
1.7. Comparison of fetal growth zscores (conventional Hadlock formula EFW without TVol measurement) between treatment groups and within prespecified subgroups
1.8. Fetal growth velocity measured by growth potential realisation index (GPRI). (IGAP). https://igap.research.bcm.edu/ This online tool uses second trimester growth measurements to predict 3rd trimester growth for an individual fetus. The percentage deviation from the predicted growth is calculated and reported as GPRI.
1.9. Number of small and large for gestational age infants (defined using birthweight zscore)
2. Secondary maternal outcomes
2.1. Gestational weight gain (difference between baseline and 30-34 week visit weight adjusted for number of weeks)
2.2. Episodes of severe hypoglycaemia (blood glucose < 3mmol/L) – (total number reported over the treatment duration reported at each study visit)
2.3. Mean (fasting and 1 hour post meal) daily glucose and % time in target – captured from HBGM and/or CGM sensors at each study visit and summarised for each trimester
2.4. Maximum achieved dose of metformin (standard care arm only)
2.5. Total insulin dose (units/kg/day) at final study visit (short and long acting insulin reported separately)
2.6. Mean change in insulin dose (units/day) from baseline to last study visit
2.7. Need for antihypertensive therapy – study visits and pregnancy outcome case note review
2.8. Pre-eclampsia (defined according to ISSHP guidelines) - study visits and pregnancy outcome case note review
2.9. Indicated delivery (induction of labour or prelabour rupture of membranes (PROM) with stimulation of labour or pre-labour Caesarean section)- pregnancy outcome case note review
2.10. Mode of onset of birth (spontaneous, induction of labour, PROM with stimulation of labour, pre-labour Caesarean section) - pregnancy outcome case note review
2.11. Indication for onset of birth - pregnancy outcome case note review
2.12. Mode of birth - pregnancy outcome case note review
2.13. Post-partum haemorrhage (blood loss >1000mls) - pregnancy outcome case note review
2.14. Shoulder dystocia - pregnancy outcome case note review
2.15. Maternal skinfold measurements (delta change from baseline visit adjusted for gestation)
2.16. HOMA-IR (measured at 30-34 weeks) - measured in research blood samples (real time in the biochemistry lab)
3. Neonatal outcomes – clinical birth outcomes obtained from case note review
3.1. Fetal loss prior to 24 weeks’ gestation
3.2. Fetal loss from 24+0 weeks’ gestation (stillbirth)
3.3. Known early neonatal death (up to 7 days from birth)
3.4. Known late neonatal death (between 7 and up to 28 days from birth)
3.5. Gestational age at birth
3.6. Birthweight
3.7. Birthweight centile
3.8. Birthweight zscore
3.9. Neonatal unit admission (separation of baby from mother)
3.10. Principal recorded indication for neonatal unit admission
3.11. Length of stay in neonatal unit (and level of care) ,
3.12. Apgar score (5minutes)
3.13. Umbilical arterial pH at birth
3.14. Need for additional resuscitation at birth: intubation in the delivery room, resuscitation drugs or chest compressions
3.15. Need for respiratory support
3.16. Type of respiratory support needed
3.17. Need for treatment for neonatal hypoglycaemia
3.18. Type of treatment for hypoglycaemia
3.19. Lowest blood glucose measurement
3.20. Neonatal seizures
3.21. Intracranial haemorrhage
3.22. Necrotising enterocolitis
3.23. Time to reach full feeds without intravenous /parenteral nutrition support
4. Exploratory outcomes – additional research outcomes
4.1. Longitudinal changes in angiogenic markers (sFlt, PlGF) – measured in research blood samples (batch analysis end of study)
4.2. Maternal metabolic/inflammatory markers (hsCRP, IL-6, adiponectin) - measured in research blood samples (batch analysis end of study)
4.3. Total number of antenatal hospital inpatient days - pregnancy outcome case note review
4.4. Total number of postnatal hospital inpatient days - pregnancy outcome case note review
4.5. Ponderal index (fetal weight in grams X 100/(fetal length in centimeters) – measurement after birth
4.6. Neonatal measurements within 72 hours of birth (Crown-rump, crown-heel lengths, weight, arm, thigh, head, abdominal circumferences, biceps, triceps, subscapular skinfold thicknesses)
4.7. Cord blood C-peptide – measured in cord blood (batch analysis)
4.8. Erythropoietin (marker of intrauterine stress) - measured in cord blood (batch analysis)