PI4 - A Trial Assessing Metformin to Prolong Gestation in Preterm Preeclampsia

Length of pregnancy from diagnosis of preeclampsia to delivery

Time for neonatal care from birth to discharge

Birth wight measured in grams

Occurrence of maternal death

Occurrence of Eclampsia

Occurrence of Cerebral vascular event

Occurrence of posterior reversible encephalopathy syndrome

Occurrence of pulmonary edema

Occurrence of left ventricular failure

Occurrence of renal dialysis

Occurrence of renal failure:≥ 90 µmol/L or no urinary output for 6 hours

Occurrence of elevated liver transaminases: ALT or AST ≥ 2 times highest normal value (ALAT >1.5 µkat/L and ASAT > 1.2 µkat/L)

Occurrence of HELLP (Haemolysis, elevated liver enzymes and low platelets) syndrome

Occurrence of thrombocytopenia (platelets <100 X 109/L)

Occurrence of liver haematoma or rupture

Occurrence of admission to an intensive care unit

Occurrence of severe hypertension (BP>160/110 mm Hg)

Occurrence of disseminated intravascular coagulation

Occurrence of caesarean section

Occurrence of major postpartum hemorrhage (>1000 ml)

Occurrence of thromboembolic disease: deep venous thrombosis or pulmonary embolism

Duration of maternal postpartum hospital stay (days)

Number of antihypertensive drugs at discharge after delivery

Duration of antihypertensive medication (days)

Occurrence of intrauterine fetal demise

Occurrence of neonatal death

Occurrence of growth restriction at birth (less than 2 standard deviations from median weight from Swedish birth weight growth curves).

Occurrence of grade 3 or 4 intraventricular hemorrhage

Occurrence of necrotizing enterocolitis

Occurrence of reversed a-wave in the ductus venosus

Occurrence of persistent reversed flow in the umbilical artery

Occurrence of redistribution in the middle cerebral artery

Occurrence of low APGAR score, defined as less than 4 at 5 minutes

Occurrence of umbilical artery pH below 7.1

Occurrence of invasive ventilation, intubation and mechanical ventilation or non-invasive ventilation; continuous positive airway pressure (CPAP) support or high flow nasal oxygen

Occurrence of grade III/IV hyaline membrane disease

Occurrence of surfactant use

Occurrence of retinopathy of prematurity

Occurrence of neonatal sepsis

Severity of nausea measured by PHASE-20 Severity of vomiting measured by PHASE-20 Severity of diarrhoea measured by PHASE-20 Severity of headache measured by PHASE-20

Occurrence of lactic acidosis (blood pH< 7.35 or blood lactate> 5 mM)

Drug adherence (measured by treatment diary)

Concentrations of Soluble Fms-like tyrosine kinase-1 Concentrations of Placental growth factor Concentrations of Soluble endoglin

Omics-based analysis of the microbiome

Breastfeeding initiation (measured by unvalidated breastfeeding questionnaire with no score)

Depressive symptoms (measured by the Edinburgh Postnatal Depression Scale; 0-30, with higher scores indicating higher self-esteem)

Self-esteem (measured by The Rosenberg Self-Esteem Scale; 0-30, higher scores indicating higher self-esteem)

Perceived stress (measured by the 10-item Perceived Stress Scale; 0-40, with higher scores indicating greater perceived stress)

Breastfeeding self-efficacy (measured by the Breastfeeding Self-Efficacy Scale-Short Form; 14-70, higher score= greater breastfeeding self-efficacy)

Health-related quality of life (measured using the EQ-5D-5L and reported as the EQ-5D-5L index value and the EQ VAS [0-100]). EQ-5D-5L index values will be derived using country-specific value sets where available; higher index values indicate better health-related quality of life. The EQ VAS ranges from 0 to 100, with higher scores indicating better self-rated health)

Parental-infant bonding (measured by the Postpartum Bonding Questionnaire; 0-125, higher score= greater impairment/difficulties in parent-infant bonding)

Cost-effectiveness short-term: direct healthcare costs (based on drug and healthcare use) for mother and child from enrolment until discharge, will be compared to incremental effects measured as prolongation of gestation

Cost-effectiveness long-term: societal costs (based on drug and healthcare use, and social insurance transactions) for mother and child from enrolment until two years postpartum, will be compared to incremental effects measured as prolongation of gestation and health-related quality of life

Risk of autism spectrum disorder (evaluated by the Modified Checklist for Autism in Toddlers, Revised (M-CHAT/R); 20 questions resulting in score 0-20 where 0-2 indicates no risk, 3-7 moderate risk and 8-20 high risk for autism).

Developmental screening (based on parental questionnaire Ages and Stages Questionnaire, Third Edition 24-months (ASQ-3);questions covering five key developmental domains; communication, gross motor, fine motor, problem-solving and personal-social skills; answers scored from 0-60 with age-specific cut-off levels at -2 and -1SD indicating clear or suspect developmental delay)

Comprehensive developmental assessment (evaluated by the Bayley Scales of Infant Development-4 (BSID-4), with main scores for motor, language and cognitive function. Results expressed as age-corrected developmental scores in each domain with clear developmental delay at scores < 70 (-2SD) and suspect developmental delay at scores < 85 (-1SD).