Preeclampsia prevention by timed birth at term

INTERVENTION: Randomisation will be provided by a computer‐generated programme hosted by King's Clinical Trials Unit, in random permuted blocks, using a minimisation algorithm to ensure balance in the treatment allocation stratified for participating site. Intervention group 1: Screening for PE at 35‐36 weeks’ gestation (by a combination of maternal factors, MAP, PlGF and sFlt‐1) and planned early‐term delivery if the risk for PE is increased, at a risk of at least 1 in 50. Screening for PE will be undertaken by the ‘competing‐risks model’ FMF algorithm that combines maternal demographics and medical history, MAP and maternal serum sFlt‐1 and PlGF, to provide a personalised risk of PE. MAP will be measured by validated automated devices and a standardised protocol. Serum sFlt‐1 and PlGF concentrations will be measured by an automated device (BRAHMS KRYPTOR compact PLUS, Thermo Fisher Scientific, Hennigsdorf, Germany). Women will have a planned initiation of early‐term delivery, according to their risk of PE, as follows: In the intervention arm, planned early‐term birth will be at 37, 38, 39, 40, or 41 weeks, depending on the women’s PE risk, and following induction or by caesarean, as appropriate. Initiation of birth will be by labour induction (by local protocol) or elective caesarean (if indicated or desired by the woman) within the first 2 days of the gestational week, according to local protocol. Control group 2: Usual care Birth will await the onset of spontaneous labour or development of a clinical need for delivery, as per relevant NICE or RCOG clinical guidance on the timing of birth in general (ng207) or specific to maternal or fetal conditions (e.g., NG133 for pregnancy hyp CONDITION: Pre‐eclampsia ; Pregnancy and Childbirth ; Pre‐eclampsia PRIMARY OUTCOME: ; Delivery with PE as defined by the International Society for the Study of Hypertension in Pregnancy (ISSHP) 2021.14. The definition of PE is chronic hypertension or new onset hypertension (systolic blood pressure (BP) should be =140 mm Hg and/or diastolic =90 mm Hg, on at least two occasions four hours apart BP >140/90 mm Hg) = 20 weeks of gestation together with any of the following:; 1. Proteinuria, defined as =300 mg in 24 hours or urinary creatinine ratio =30 mg/mmol (0.3 mg/mg) or two readings of at least ++ on dipstick analysis of midstream or catheter urine specimens if no 24‐hour collection is available; or; 2. Maternal organ dysfunction, defined as any one of the following:; 2.1. Acute kidney injury with creatinine >90 µmol/l or; 2.2. Liver involvement with elevated transaminases (alanine or aspartate aminotransferase [ALT or AST] >40 IU/L or twice the normal concentration) or; 2.3. Haematological complications (thrombocytopaenia with platelet count <150 x 109/L), disseminated intravascular coagulation or haemolysis, or; 2.4. Neurological complications, such as eclampsia, altered mental status, blindness, stroke, clonus, severe headaches, or persistent visual scotomata, or; 3. Uteroplacental dysfunction, defined as estimated fetal weight (EFW) <3rd percentile or EFW at the 3rd to 10th percentile in the presence of either of the following: uterine artery pulsatility index (UtA‐PI) >95th percentile, umbilical artery PI (UA‐PI) >95th percentile, or middle cerebral artery PI (MCA PI) <5th percentile; ; All outcome measures will be recorded during the routine care appointment and during childbirth. When the participants do not gIve birth at the chosen hospital, then the outcome is taken from their medical record.; SECONDARY OUTCOME: ; All outcome measures will be recorded during the routine care appointment and during childbirth. When the participants do not gIve birth at the chosen hospital, then the outcome is taken from their medical record.; ; 1. Emergency caesarean section, defined as any caesarean section after spontaneous onset or induction of labour. A caesarean section without prior labour will be considered as elective; 2. Neonatal care unit stay for =48 consecutive hours up to primary hospital discharge home or 28 days of life, whichever is earlier; ; Other secondary outcomes:; 1. GH, defined as systolic BP =140 mm Hg and/or diastolic =90 mm Hg, on at least two occasions 4 hours apart, and developing at =20 weeks’ gestation in previously normotensive women (i.e., BP <140/90 mm Hg); 2. Components of the 2021 ISSHP definition of PE (as above); 2.1. PE as defined by ACOG 201915:; 2.2. GH (as above) or severe hypertension (as below), and either; 2.3. Proteinuria (as above) or; 2.4. In absence of proteinuria, one/more of:; 2.4.1. Pulmonary edema; 2.4.2. Platelet count <100 X10e9/litre); 2.4.3. Serum creatinine >97 µmol/L or a doubling in its value; 2.4.4. Abnormal liver enzymes (ALT or AST >67 IU/litre); 3. ‘Severe features’ of PE (one or more), and its components, according to ACOG 201915 and without alternative diagnoses:; 3.1. Severe hypertension (as defined below); 3.2. Platelet count <100 X10e9/L; 3.3. ALT or AST raised to twice normal (>67 IU/L) and persistent severe right upper quadrant abdominal or epigastric pain unresponsive to medication and not otherwise accounted for by alternative diagnoses; 3.4. Serum creatinine >97 µmol/L or a doubling of value in the absence of other renal disease; 3.5. Pulmonary edema; 3.6. New‐onset headache unresponsive to medication; 3.7. Visual disturbances; 4. Preeclampsia Integrated Estimate of Risk Score (PIERS) combined adverse maternal outcome, and its components, derived from Delphi consensus (with the exception of the Glasgow coma score <13):; 4.1. Maternal death; 4.2. Central nervous system complications (one or more of):; 4.2.1. Stroke (acute neurological event with deficits lasting > 24 hr, not due to a post‐ictal state); 4.2.2. Eclampsia (generalized convulsion in the absence of a history of epilepsy); 4.2.3. Blindness (either retinal or cortical, defined as loss of visual acuity in the presence of intact pupillary response to light); 4.3. Cardiorespiratory complications (one or more of):; 4.3.1. Uncontrolled hypertension (requiring administration of 3 or more different parenteral [intravenous or intramuscular] antihypertensive agents within a 12‐hour period); 4.3.2. Inotropic support (use of vasopressors to keep systolic BP >90 mmHg or a MAP >70 mmHg); 4.3.3. Pulmonary oedema (diagnosed clinically with one/more of oxygen saturation < 95%, diuretic treatment or x‐ray confirmation); 4.3.4. Respiratory failure (intubation, ventilation by endotracheal tube or non‐invasively, or need for > 50% oxygen for > 1 hr which is not due to caesarean delivery); 4.3.5. Myocardial ischemia or myocardial infarction (by characteristic ECG changes and markers of myocardial necrosis); 4.3.6. SpO2 <90%; 4.4. Haematological complications (one or more of):; 4.4.1. Platelet count <50 X10e9/L; 4.4.2. Transfusion (of any blood product); 4.5. Hepatic complications (one or more of):; 4.5.1. Dysfunction (INR>1.2 in the absence of DIC or treatment with warfarin, OR, in the presence of DIC or treatment with warfarin: either mixed hyperbilirubinemia >17 µM or hypoglycemia <2.5 mM) in the absence of insulin); 4.5.2. Hepatic haematoma or rupture (presence of a blood collection under the hepatic capsule as confirmed by imaging or at laparotomy); 4.6. Acute kidney injury:; 4.6.1. Acute serum creatinine >200 µM with pre‐existing renal disease; 4.6.2. Acute serum creatinine >150uM with no pre‐existing renal disease; 4.6.3. Dialysis; 4.7. Placental abruption (clinically or on placental examination); 4.8. Other (as detailed, with appropriate information from hospital records); 5. Core maternal outcome set for PE17 (one or more of) and its components:; 5.1. Maternal mortality; 5.2. Central nervous system complications: eclampsia, stroke, blindness that is retinal or cortical (as defined for PIERS); 5.3. Cardiorespiratory complications: pulmonary edema, respiratory failure (as defined for PIERS); 5.4. Platelet count <100 X10e9/L; 5.5. Hepatic complications: AST or ALT raised to twice normal, or haematoma (as for PIERS); 5.6. Acute kidney injury (as for PIERS); 5.7. Placental abruption; 5.8. Postpartum haemorrhage (defined as blood loss =1 L within the first 24 hours after birth); 5.9. Maternal admission to intensive care or high dependency unit; 6. Severe hypertension (defined as systolic BP =160 mm Hg and/or diastolic BP =110 mm Hg, on at least one occasion); 7. Caesarean section (any); 8. Labour onset, classified as spontaneous, induced, or no labour. (Spontaneous rupture of membranes without labour will be considered as spontaneous labour onset); XX INCLUSION CRITERIA: 1. Singleton pregnancy 2. Live fetus at 35+0‐36+6 weeks’ gestation 3. Able to provide informed and documented consent