IMproved PRegnancy Outcome by Early Detection (IMPROvED)

• Pre-eclampsia. [ Time Frame: 7 days after birth ] [ Designated as safety issue: No ]
  Preeclampsia is defined as gestational hypertension defined as systolic BP ≥140mmHg and/or diastolic BP ≥90mmHg (Korotkoff V) on at least 2 occasions 4h apart after 20 weeks' gestation, but before the onset of labour or postpartum systolic BP ≥140mmHg and/or diastolic BP ≥90mmHg on at least 2 occasions 4h apart with either proteinuria ≥300mg/24h or spot urine protein:creatinine ratio ≥30mg/mmol creatinine or urine dipstick protein ≥++.
  
  
• Spontaneous pre-term birth [ Time Frame: Up to 37+0 weeks´ gestation ] [ Designated as safety issue: No ]
  Spontaneous pre-term birth is defined as spontaneous preterm labour or preterm premature rupture of the membranes resulting in preterm birth at <37+0 weeks' gestation.
  
  
• Small for gestational age (SGA) [ Time Frame: Within 24 hours after birth ] [ Designated as safety issue: No ]
  The birth weight is converted to a customized centile, adjusting for gestation, maternal weight, height, parity, ethnicity and infant sex. SGA is defined as <10th customised centile.
  
  

• Early onset pre-eclampsia [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
  Pre-eclampsia resulting in delivery at <34+0 weeks' gestation.
  
  
• Multisystem complications of pre-eclampsia [ Time Frame: Between 20 weeks´gestation and 6 weeks after birth ] [ Designated as safety issue: No ]

  Defined as one or more of the following:

  • Acute renal insufficiency defined as new increase in serum creatinine to >100μmol/L antepartum or >130μmol/L postpartum.
  • Liver disease defined as raised aspartate transaminase and/or alanine transaminase >45 IU/L and/or severe right upper quadrant or epigastric pain or liver rupture.
  • Neurological problems defined as eclampsia, imminent eclampsia (severe headache with hyperreflexia and persistent visual disturbance) or cerebral haemorrhage.
  • Haematological abnormalities including thrombocytopenia (platelets <100x109/L), disseminated intravascular coagulation or haemolysis, diagnosed by features on blood film (such as fragmented cells, helmet cells) and reduced haptoglobin.
  
  
• Pre-eclampsia with severe fetal or neonatal complications [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
  Pre-eclampsia resulting in either delivery at < 32+0 weeks' gestation or major neonatal morbidity or stillbirth or neonatal death or post-neonatal death.
  
  
• Major neonatal morbidity in preterm infants [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]

  One or more of the following amongst babies delivered before 37 weeks' gestation:

  Grade III or IV intraventricular haemorrhage; Chronic lung disease; Necrotizing enterocolitis; Retinopathy of prematurity stage 3 or 4; Sepsis (blood or CSF culture proven); Or cystic periventricular leukomalacia. These conditions will be defined using the Australian and New Zealand neonatal network definitions.

  
  
• Major neonatal morbidity in term infants [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]

  One or more of the following amongst babies delivered at or after 37 weeks' gestation:

  Grade II or III hypoxic ischaemic encephalopathy; Ventilation >24 hours; Neonatal unit care admission >4 days; Apgars < 4 at 5 minutes; Cord arterial pH <7.0 and/or base excess >-15; Or neonatal seizures.

  
  
• Pre-eclampsia with severe maternal complications [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]

  The development of pre-eclampsia with one or more of the following:

  Maternal death; Persistent severe hypertension (systolic blood pressure ≥170mmHg or diastolic blood pressure ≥110mmHg on more than one occasion antepartum or postpartum); Or multi-system complication (as defined in outcome above.

  
  
• Preeclampsia with either severe maternal complication or severe fetal or neonatal complications [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
  Pregnancies affected by severe maternal or severe fetal or neonatal complications (as defined in Major neonatal morbidity in preterm infants or Major neonatal morbidity term infants).
  
  
• Early onset SGA [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
  SGA resulting in delivery at <34+0 weeks' gestation.
  
  
• SGA with severe fetal or neonatal complications [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
  SGA and either delivery at <32+0 weeks' gestation or major neonatal morbidity (as defined in Major neonatal morbidity in preterm infants) or stillbirth or neonatal death or post-neonatal death.
  
  
• Early onset spontaneous preterm birth [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
  Spontaneous pre-term birth resulting in delivery < 34+0 weeks' gestation.
  
  
• Spontaneous preterm birth with severe fetal or neonatal complications [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
  Spontaneous preterm birth (PTB) resulting in either delivery at <32+0 weeks' or spontaneous PTB resulting in major neonatal morbidity (as defined in Major neonatal morbidity in preterm infants) or stillbirth or neonatal death or post-neonatal death.
  
  
• Spontaneous preterm birth with PPROM [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
  Spontaneous PTB following preterm premature rupture of the membranes (PPROM).
  
  
• Spontaneous preterm birth without PPROM [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
  Spontaneous PTB with intact membranes at the onset of labour.
  
  

Sample size calculations have been considered extensively and given the complexity of the study; there is no single simple solution. For the purpose of sample size estimation in the overall study, we used a binary outcome and associated measures of sensitivity and likelihood ratio as determinants of the value of these tests. Although the predictive algorithms will produce a continuous risk score, the use of a categorical outcome fits with the final binary decision process (to treat or not to treat) based on the risk score. Based on the lowest estimated prevalence of pre-eclampsia of 3% and a test sensitivity of 93% and a test specificity of 97%, then to be 90% certain that the true specificity of the patient population is no less than 95%, a sample size of 4,800 participants is required. Thus, allowing for patient dropout, a study population of 5,000 women is needed.