Clinical consequences of poor placentation I

Question 1

What is pre-eclampsia?

Answer 1

• Disease of pregnancy
• It can lead to severe maternal complications, including death, and also for baby, including severe prematurity. This is because the baby has to be delivered as soon as possible following PE diagnosis before the mum becomes too sick.
• Only effective treatment is delivery
• While the effective treatment is delivery, there are still long-standing sequelae of PE for the mum going forward into her later life. This includes an increased risk of CVD and stroke.

Question 2

Why is PE important?

Answer 2

• 6th leading cause of direct maternal deaths (6 deaths over 3 years)
• Commonest medical problem in pregnancy:
  1) Gestational hypertension = 10%
  2) PE = 2-5%
  3) Severe PE= 1%
  4) Eclampsia (2% death rate)
• Leading cause of iatrogenic prematurity. Iatrogenic because the prematurity is induced by early delivery early. To reduce prematurity, preventing PE would play a big role.
• Immediate risks of eclampsia, stroke and heart failure (cardiomyopathy)
• Life-long risk of cardiovascular disease
• MBRRACE = mothers and babies: reducing risk through audits and confidential enquiries across the UK. Important to go to the website and look at this report which is given every year. It discusses themes in obstetrics about why women die.
• The severity of PE causing death has decreased because prevention, management and timely delivery before complications arise has improved.
• Direct maternal deaths = it is the pregnancy that causes the death, rather than an indirect cause (a condition that has been exacerbated by pregnancy).
• Hypertension is an umbrella term and it is the most common problem during pregnancy. Hypertension during pregnancy (gestational hypertension) does not cause end-organ damage. When it begins to cause end-organ damage, it is called PE. About 2 to 5% of women can get preeclampsia. About 1% of women get severe PE. The end-stage is eclampsia. About 2% of women who have eclampsia will die. It has to be taken seriously to manage it effectively.
• Prematurity is very dangerous for babies. If they are born early, they can have problems with their lungs, cerebral palsy, disability and long-term neurodevelopmental problems.
• There are many associated risks to high blood pressure.

Question 3

What are the high- and moderate-risk factors for PE?

Answer 3

What are the risk factors for PE?

• Previous PE increases the risk of getting it again.
• Chronic hypertension, because pregnancy puts a huge strain on the cardiovascular system so existing damage can be exacerbated
• Diabetes mellitus, which again affects the CVS. The arteries get stiffened, there is glycation of the artery walls, which makes them stiff and leads to PE.
• Chronic kidney disease can again cause high blood pressure. End-organ damage from kidney disease increases risk of PE.
• Autoimmune disease

What are the moderate risk factors?

• Older mum (40+) or large pregnancy interval (similar to being an older mum). Likely due to cardiovascular ageing.
• Never had a baby before as there is no evidence to predict how the patient will respond to pregnancy.
• High BMI strains the CVS already (works hard to perfuse tissue) and it will be exacerbated by pregnancy.
• Studies have shown that a mother with PE has an increased chance of having a baby who develops PE. This is likely due to programming of the baby changing their gene expression in the womb due to the environment they are in that makes their cardiovascular system more susceptible to being abnormal when they grow up.
• The strains of pregnancy are prolonged with additional pregnancies
• These risk factors have been described in relation to the cardiovascular system without mentioning the placenta. This is why it makes sense for PE to be a cardiovascular disease, rather than a placental pathology.

Question 4

What is the cardiovascular theory of PE pathophysiology?

Answer 4

• Traditionally, PE is thought to be a problem with spiral artery remodelling. Thinking about placental perfusion, a good CVS with low resistance that is pumping blood adequately around the body means the placenta is going to be well perfused. However, if there is a poor cardiovascular reserve and the placenta does not get as much oxygen/nutrients, as well as increased demand on the placenta, e.g. multiple pregnancies or overweight, there will be placental hypoperfusion. The placenta will then give out cytokines which will cause endothelial dysfunction seen in PE. This makes the blood vessels very stiff with high resistance and then causing the preeclampsia.
• There is vasoconstriction, endothelial dysfunction, then end organ damage. The liver gets damaged, the kidneys get damaged and the blood vessels. This is how preeclampsia is defined when looking at the clinical definitions.

Question 5

What is the traditional theory of placentation and what happens if it goes wrong?

Answer 5

• The trophoblasts invade the maternal blood vessels, which are normally very narrow, muscle-bound and high resistance.
• Narrow spiral arteries remodelled = Wide-bore low-resistance vessels deliver large amounts of maternal blood. They are changed into low resistance vessels so that large amounts of blood can go to the uterus (placenta) and deliver nutrients/oxygen.
• Nutrient and oxygen delivery to foetus
• If this trophoblast invasion does not happen efficiently, the spiral arteries are not remodelled, they remain high resistance (High-resistance placental bed) and there is a poorly perfused, hypoxic placenta.
• The placenta releases inflammatory cytokines (IL, TNF etc), because it is hypoxic, and this causes the maternal endothelial dysfunction.
  1) Increased vascular reactivity and vasospasm
  2) Increased capillary permeability and reduced intravascular volume

Question 6

Is the placenta the villain or the victim?

Summarise the alternative hypothesis of PE.

Answer 6

• The alternative hypothesis is that if there is poor maternal cardiovascular reserve, poor adaptation to pregnancy and excessive demands to meet that placenta, it will be underperfused. This will lead to cytokines and antivascular factors being released and causing endothelial dysfunction. Results in PE in the mum and growth restriction in the baby. This has been summarised in the diagram.
• Diagram illustrating the interaction between maternal cardiovascular function and placental function, maternal health, and fetal well-being. Placental oxidative stress or hypoxia is related to the relative balance of cardiovascular functional reserve and the cardiovascular volume/resistance load of pregnancy. The final common pathway that results in the signs and symptoms of preeclampsia involves the release of placental vasoactive substances. PIGF indicates placenta growth factor; and sFLT, soluble fms-like tyrosine kinase.
• There is a common end pathway in all of this, which is endothelial injury and vasoconstriction. It is debated how this point is reached, but once it is reached, there is end organ damage.

Question 7

What two factors make up the common end pathway?

Answer 7

• There is a common end pathway in all of this, which is endothelial injury and vasoconstriction. It is debated how this point is reached, but once it is reached, there is end organ damage.

Question 8

What are the maternal and foetal effects of PE?

Answer 8

• PE has effects on both the mother and the baby.
• From the mother’s perspective, it can affect anything that is lined with endothelium. This includes the brain, the arteries, the kidneys, the liver etc.
  1) Leaky blood vessels in the brain cause cerebral oedema, leading to eclampsia.
  2) Vasospasm causes high vascular resistance, resulting in hypertension. In the kidneys, this will result in renal failure.
  3) Endothelial injury can affect anything lined with endothelium = low platelets, disseminated intravascular coagulopathy (DIC). For example, the spleen has a role in coagulation, haemopoiesis and the immune function of the body. Therefore, consumption of the platelets can occur (low platelets). There can also be consumption of other coagulation factors, causing disseminated intravascular coagulopathy. This means that all of the coagulation factors are used up, which may result in bleeding to death.
  4) As the blood vessels are dysfunctional and leaky, there can be leakage of albumin. This causes proteinuria in the kidneys. If this occurs in vasculature of the lungs, it can result in fluid in the lungs (pulmonary oedema). These women tend to be very dry intravascularly (since their blood vessels are leaky). When trying to remove the fluid in the lungs, traditionally diuretics are given to cause urination. As these women can be intravascularly deplete, as well as having pulmonary oedema, so they can die from this.

1) With regards to the baby, there can be growth restriction due to inadequate oxygenation and nutritional supply to the baby.
2) There can also be prematurity due to delivering the baby early to save the mum.
3) Placental abruption = The placenta may separate from the womb before there baby is born (abruption). This is bad because the placenta acts as the baby’s lungs and so the baby can die in the womb (foetal stillbirth).
4) Fetal death

Question 9

How do the current guidelines (NICE) advocate using a risk factor-based assessment to try and screen for PE in women who are going to develop it in the first trimester?

Answer 9

• Prevention is always better than cure.
• The current guidelines (NICE) advocate using a risk factor-based assessment to try and screen for PE in women who are going to develop it in the first trimester. There is medication that can reduce PE. This is aspirin.
  Women with one high risk factor or two moderate risk factors are eligible to have aspirin from 12 weeks until delivery. This screening programme is not very sensitive because risk factor based assessment is not very good at identifying all of the cases that will go on to develop PE.
• High risk factors =
  1) Previous PE
  2) Chronic HTN
  3) Autoimmune disease
  4) Diabetes Mellitus
  5) Chronic kidney disease
• Moderate-risk factors =
  1) Nulliparity
  2) Age >40
  3) Pregnancy interval >10yr 4) BMI >35
  5) FH PE
  6) Multifetal gestation
• Indication for aspirin = 1 high or >1 moderate
• Aspirin dose = 75-150mg from 12w
• Aspirin duration = daily until delivery

Question 10

What risk assessment did the ASPRE study use?

Answer 10

• Focusing on the bit highlighted in red, the NICE risk factor screening method can detect about 40% of preterm PE.
• It is important to differentiate between preterm PE (<37w) and PE. Preterm PE means the baby may have to be delivered prematurely and can cause problems with the baby. The answer to term PE is just to deliver the baby. Term PE tends to be milder as it is stopped from getting too far and the baby can be delivered sooner.
• The ASPRE study (aspirin for the prevention of preeclampsia by giving it to high risk women) used a slightly different risk assessment. Instead of just using risk factors, which this algorithm does, it uses other markers for PE. This includes maternal blood pressure, maternal blood flow (maternal uterine dopplers measuring blood flow to the womb) and hormones produced by the placenta, e.g. placental growth factor and pregnancy associated plasma protein-A. When using an algorithm that combines all of these different factors, the combined test for PE, the sensitivity of the screening tool can be increased by double.
• Looking at the way it has been presented, using the algorithm with maternal factors only, it is comparable to the NICE risk factor based assessment. The additional factors increase the sensitivity to 80% (double).
• This allows aspirin to be targeted to the right women to help reduce PE.
• Maternal risk factors
  1) Age: every 10 years above 30 y
  2) Weight: every 10 kg above 70 kg
  3) Racial origin = Afro-Caribbean, South Asian
  4) Obstetric history
• First pregnancy
• Previous PE
• Family history of PE
  5) Conception by IVF
  6) Chronic hypertension
  7) Diabetes mellitus
  8) Autoimmune: SLE/APS

Question 11

Summarise the ASPRE trial.

Answer 11

• This is the ASPRE trial. It included ~11 centres around Europe and the UK. 26,000 women were screened and 2,971 women were high risk for preterm PE.
• 11 - screening n= 26,49113w FMF PE algorithm
• They were randomised into either aspirin or placebo.
• There was some discrepancy between the numbers that were eligible for randomisation and the number who did get randomised. Women who were traditionally screened by the traditional risk factor based approach may have been given aspirin anyway and they would not have been eligible for the trial. This is why there was some drop out.
• The results showed a reduction in early PE (<34 weeks) by 82% and preterm PE (<37 weeks) by 62%. Effective screening and targeted aspirin saves lives and prevents the baby from being born prematurely.

Question 12

How was the ASPRE trial implemented at St. George’s?

Summarise the findings.

Answer 12

• The ASPRE trial was implemented into a routine healthcare setting at St. George’s and this is now the only way used to assess the risk of PE. This study was conducted last year. By being more sensitive picking women who are high risk, the risk was reduced from 16% to 8%. Traditionally, 16% of women would be classified as high risk, whereas now it is 8%. This 8% of women are now on a low risk pathway without detriment to their health, e.g. can have less visits, a birth centre delivery (midwifery led unit without doctor involvement). This is less of a burden for these women.
• While the risk was deescalated in about half of the women, the detection of PE was almost doubled (in keeping with the results of the ASPRE trial).
• Another note was that the traditional screening was only giving 29% of women aspirin that were eligible. Now, this combined screening that is carried out at the same time as the Down’s syndrome screening means everyone who is eligible for aspirin is prescribed it (the 1% remaining accounts for allergies, gastritis etc.).
• It was found that giving women aspirin reduced preterm PE by 80%. It also did not worsen PE severity, growth restriction or stillbirth.
• Hopefully, this will be introduced nationwide in the next few years.

1) Two-fold de-escalation of maternal risk (16% vs 8%)
2) Two-fold increase of preeclampsia detection (41% vs 76%)
3) Almost complete physician compliance with aspirin prophylaxis (29% vs 99%)
4) Reduction the prevalence of preterm PE (80% reduction)
5) No evidence of worsening preeclampsia clinical severity or FGR rate

Question 13

What happens if PE is not prevented?

How is hypertension classified in pregnancy?

Answer 13

• Have to consider how high blood pressure in pregnancy is classified. If someone has high blood pressure less than 20 weeks, it is classified as pre-existing hypertension. - Some women may not know this as they only visited the doctor after getting pregnant where they found they have high blood pressure. Therefore, they are treated like a chronic hypertensive, perhaps given medication, but that factor will go into the algorithm and incorporated into their risk assessment of whether they need aspirin or not.
• If the woman has significant protein in her urine before 20 weeks, it would be likely that her hypertension is due to kidney disease. She will be referred to a nephrologist to help manage this because she may not know about it and may have underlying renal disease. They may need other medication to help preserve renal function.
• However, after reaching the 20 week mark, any new blood pressure changes will be classified as gestational hypertension. If there is any evidence of end-organ damage, such as proteinuria, it will be classified as PE. Proteinuria is quite a traditional way of diagnosing PE. Endothelia lining lines lots of different structures and there are lots of organs that can be damaged. Therefore, NICE changed their criteria in 2019.

Summary:

1) No proteinuria
- Pre-existing HTN (<20/40)
- Gestational HTN (>20/40)
2) Significant proteinuria
- Pre-existing HTN secondary to renal disease (<20/40)
- PE (>20/40)

Question 14

What is the NICE diagnostic criteria for PE?

Answer 14

• NICE changed their criteria in 2019 to be in keeping with the International Society for the Study of Hypertension in Pregnancy. ISSHP recognised this in 2001 and gave their criteria for diagnosing PE based on all of there parameters. NICE acted in 2019 (hence why centres sometimes provide the evidence, go through the right governance channels, implement criteria sooner and publish the results).
  NICE have now incorporated the International Hypertension Society criteria.
  1) High blood pressure (threshold = >140/90 mmHg) is the main feature and then other factors are added on to reach a diagnosis. Normotensive <20 weeks (BUT can have superimposed PE on
  background of Chronic HTN).
  2) Proteinuria is one of the factors, which can be measured using a dipstick. A sample can then be sent off to produce a quantitative result (less subjective). Otherwise, can measure the protein in samples or carry out a “spot” test.
  Proteinuria is no longer a prerequisite. >300 mg/24 hrs OR Protein:Creatinine ratio (PCR) >30 mg/mmol
  OR +2 urine dipstick
  3) Other parameters can be used. The liver, the kidney (Creatinine >90 μmol/litre), the brain, the spleen and the baby itself can be used (uteroplacental = Fetal growth restriction, abnormal umbilical artery Doppler
  waveform analysis, or stillbirth).
• There are cut-offs for different blood tests to produce a diagnosis of PE.
• Neurological tends to be symptom-based, e.g. eclampsia (seizure), altered mental state, stroke, with high blood pressure to produce a PE diagnosis.
• If there is growth restriction in the baby or looking at blood flow (dopplers) with high blood pressure, it can be classified as PE.

Question 15

What are the signs and symptoms of PE?

Answer 15

• May be asymptomatic. Identified due to high blood pressure and abnormal bloods. The common symptoms have been outlined on the slide.
  1) Headaches
  2) Flashing lights
  3) Proteinuria
  4) Brisk jerks
  5) Epigastric (top of the abdomen) pain.
  6) Nausea/vomiting and confusion is usually caused by cerebral irritation.
• Need to ensure that high blood pressure is being measured correctly. For example, a tight cuff on a big arm will give false readings. Also, need to ensure that the right Korotkoff sounds are being measured (there are five and the fifth sound should be absent).
• The abdomen may be palpated to identify epigastric pain. The reflexes may also be elicited, such as the knee-jerk reflex or clonus in the Achilles tendon.

Question 16

How can sFlt-1:PlGF ratio an indicator of PE?

Answer 16

• The placenta releases growth factors. There is vascular endothelial growth factor (VEGF) and placental growth factor (PlGF; a type of VEGF). They are involved in the promotion, proliferation and the survival of vascular and endothelial cells. They have a receptor. Their normal receptor is membrane-bound Flt. This is attached to the endothelium and when the PlGF and VEGF attach to the membrane-bound receptor, it will promote all of these things. It will have a healthy endothelium and cause vasodilation, allowing a low resistant blood flow and optimum oxygen delivery. However, when the placenta becomes hypoxic, the placenta starts upregulating soluble Flt. Soluble Flt is the same as membrane-bound Flt, but it is in the blood stream (rather than being attached to the endothelial cells). This mops up the PlGF and VEGF (so it doesn’t attach to the membrane-bound Flt). Therefore, the endothelium does not become optimum and it becomes sick. Those blood vessels become very constricted. This is why vascular constriction and endothelial dysfunction occur in blood cells and results in problems with different organs. High sFlt and a low PlGF produces a high ratio (because the denominator is low). Therefore, this can be used to correlate to severity of disease.
• In reality, different cut-offs can be looked at to either aid the diagnosis or predict PE. Depending on gestation, the sFlt/PlGF ratio (which is carried out with other blood tests) can be used to rule out or indicate PE. The cut-offs are different as the patient approaches term. When in between the two cut-off values, the patient should be monitored more closely as it could be that they are going to develop it soon. This allows patients to be triaged (normal sFlt/PlGF ratio = can send patient home to come back if there is a problem, high ratio = admit the patient to monitor them, blood pressure management (ensure they are safe) and get them as close to term as possible).

To aid diagnosis:

1) 10+0 - 33+6 weeks
- Rule-out = ratio <33
- Rule-in = ratio >85
2) 34+0 - delivery
- Rule-out = ratio <33
- Rule-in = ratio >110

Prediction:

1) 24+0 - 36+6 weeks
- Rule-out (in next 1 week) = ratio <38
- Rule-in (within next 4 weeks) = ratio >/= 38

Question 17

What is the cost benefit of determining the sFlt/PlGF ratio?

Answer 17

• In reality, this prevents patients from having to be admitted and, hence, saves costs of admission. Doing this with less than 35 weeks pregnant women can save £2500 pounds. QALYs = quality adjusted life years. This indicates what the disease burden is. A score of 1 = perfect health, a score of 0 = death. When doing the sFlt/PlGF ratio, it is being improved very minutely but not worsening it, which is very important. It is important to be careful with resources and it is not at detriment to the patient. Hence, this ratio is used, also it helps triage management of these patients.

Question 18

How does the sFlt/PlGF ratio allow patients to be triaged?

Answer 18

• This ratio helps triage where patients are going to be managed. If they have mild blood pressure and a normal ratio, they would be sent home. If they have a high blood pressure and a high ratio, they will be admitted.
• Blood pressure
  1) Mild = 140 – 149/90 – 99
  2) Moderate =150 – 159/100 – 109
  3) Severe = 160+/110+
• Ratio = 38
  1) Patient can be discharged (mild HDP) or admitted for 24 hours (moderate HDP).
  2) Review in 1 week in hypertension clinic
• Ratio >38-84
  1) Patient can be discharged or admitted for 24 hours.
  2) Review in 1 week in hypertension clinic
• Ratio >/= 85 (severe HDP)
  1) Admit to ward
  2) Senior obstetric review

Question 19

How is blood pressure managed?

Answer 19

• When talking about management, it is important to firstly reduce the blood pressure to a level that will not cause detriment to the mum, i.e. stroke, liver dysfunction etc., but it also should not be reduced too much that it reduces perfusion to the placenta (causing baby to become unwell and hypoxic). Hence, the target blood pressure.
• BP Target = 130 – 140/80 – 90

1) First Line = Labetalol (CI Asthma, Ischemic Heart Disease), Max 2g/day (500mg qds)
2) Second Line = Nifedipine (CI Aortic Stenosis), Max 80mg/day (20-30mg tds)
3) Consider = MethylDopa (CI Depression), Max 3g/day (1000mg tds)

• There are different medications that can be given = Labetalol, Nifedipine and MethylDopa. They are all safe in pregnancy, but they do have contraindications. For example, Nifedipine cannot be given to a woman with aortic stenosis because if her resistance is dropped too much, perfusion of her body will be reduced due to the stenotic heart.

Question 20

How is blood pressure managed depending on underlying cause?

Answer 20

• Sometimes, however, these medications are given without much thought to what needs to the underlying cause. Blood pressure management is not trying to treat PE, but instead trying to reduce the adverse outcome because of high blood pressure. Blood pressure is a product of cardiac output and vascular resistance. It is the balance between the two.

BP = CO X TVR
CO = HR X SV

• SV relatively constant in 2nd-3rd trimester so HR will be driver for changes in CO
• Increasing evidence for targeted use of anti-HTN meds:
  1) If BP high and pulse rate <90 = High resistance, Low Output therefore a vasodilator more appropriate (Nifedipine)
  2) If BP high and pulse rate >90 = Low resistance, High Output therefore rate control more appropriate (Labetalol)
  3) Caution with FGR – Scan needed if changing medications
• Have to think about whether the patient is having a problem with high cardiac output or high resistance. If it was high cardiac output, Labetalol would be used because it reduces the rate and contractility of the heart. If there is high vascular resistance, Nifedipine would be given because it is a vasodilator.
• Stroke volume cannot be checked by the bedside as it requires an echo. The surrogate marker for cardiac output is heart rate. This is not too bad, because stroke volume in the second and third trimester is relatively constant, whereas heart rate is the one that drives charges in cardiac output. From that perspective, a cut-off of 90 can be used for the heart rate. If the heart rate is above 90 and they have high blood pressure, then it is usually a high cardiac output (heart is beating fast and heart rate is a surrogate marker for cardiac output). Therefore, a rate control would be used to reduce the blood pressure. If the heart rate is low, the vascular resistance must be high (it is a balance between the two that produces blood pressure). In this instance, Nifedipine would be used.
• This is currently being studied by Mulder in the Netherlands and results will be reported soon. Likely to confirm expectations, because this is the way that blood pressure is managed in the non-pregnant population.

Question 21

Does blood pressure always have to be checked in the clinic?

Answer 21

• There are special machines that are calibrated for pregnancy that patients can use to monitor BP at home. Patients are taught how to use it, observed using it and then sent home where they have an app on their phone to input readings. If the measurements are above the range, the app will instruct them on what to do, e.g. recheck, go to hospital immediately, take medication. This is both safe and cost effective = reducing the amount of times they have to present to the hospital and also the amount of times they have to be admitted. In doing so, it is important to remember that blood pressure readings are often higher in the clinical setting because patients are more stressed. There is a reduction in the number of PE diagnoses, because patients do not reach the threshold for hypertension when they are in a more relaxed setting. Reduces the number of PE diagnoses and these patients do not have to be induced because they do not have PE.
• Safe and cost effective
• Reduction in induction of labour, antenatal admissions and PE diagnosis
• No compromise of maternal and pregnancy outcomes
• This review found that in doing so, there was no compromise in the maternal or pregnancy outcome. It was safe, cost-effective and better for the patients.

Question 22

What is the inclusion and exclusion criteria for home BP monitoring?

Answer 22

1) Inclusion criteria
- Mild/Moderate HDP (inc cHTN)
- Able to consent/use app
- No indication for admission
- At risk of PE (e.g. High UtA 2nd trimester)

2) Exclusion criteria
- Declines
- Unable to consent/use app
- Delivery planned <7 days
- If PE diagnosed (unless having regular in- person assessments)

Question 23

Why don’t we deliver straight away due to PE?

Answer 23

1) Complications of prematurity
2) Possibility of failed induction needing Caesarean section
3) Attempts to prolong pregnancy are justified for pre-term PE
4) Severe uncontrolled PE needs delivery after stabilization

• The main issue is prematurity. Babies that are delivered extremely early can have many problems, such as failure to thrive, chronic lung disease, problems with their bowels (e.g. necrotising enterocolitis), neurodevelopment (e.g. cerebral palsy). These are lifelong problems that will be with the baby forever. It is important to deliver for the right reason and to aim not to deliver too prematurely. When thinking about early delivery, this can include inducing them which may not always be successful, so they may end up requiring a caesarean section.
• Therefore, the attempt to prolong pregnancy for preterm PE is justified. However, uncontrollable PE requires delivery as soon as possible, because the mother will become very ill.

Question 24

How is severe PE defined?

Answer 24

• Severe PE is traditionally defined as a blood pressure of 160/110 with proteinuria and signs of imminent eclampsia, e.g. brisk reflexes due to neuronal irritability, blurred vision as the cerebral arteries are going into vasospasm, epigastric pain which is swelling of the liver capsule which causes pain (tension).
• This is the criteria for severe PE as part of the MAGPIE trial in 2002, which looked at how it can reduce eclampsia by administering magnesium sulphate.
  1) Diastolic BP ≥ 110 mm X 2
  2) Systolic BP ≥ 160 mm X 2 and
  3) ≥ ++ proteinuria
  4) Signs or symptoms of imminent eclampsia = Hyper-reflexia (neuronal irritability), Frontal headache, Blurred vision (cerebral vasospasm), Epigastric tenderness (tension on liver capsule)

Question 25

What is used to prevent seizures?

Answer 25

• Magnesium sulphate to women with preeclampsia reduces the risk of an eclamptic seizure.
• Women allocated magnesium sulphate had a 58% lower risk of an eclamptic seizure
  (58% reduction 95% CI 40–71%).
• Maternal mortality lower in treatment group (11/5055 vs 20/5055)
• Reduced risk of placental abruption
  (RR 0.67, 95% CI = 0.45 – 0.89)
• Magnesium sulphate is the only medication that can reduce an eclamptic seizure in PE. Women in the magnesium sulphate group had a 58% reduction in seizures. In that group, the mortality rate was much lower too. Also reduced the risk of placental abruption as blood pressure was controlled more effectively. Although magnesium sulphate is not used as an antihypertensive, it does cause vasodilation which can then help. Most of these women that have severe PE will have a very high vascular resistance (they are at this end stage where vasculature resistance is very high).
  Must consider magnesium sulphate for women with symptoms of severe PE.

Question 26

For controlled PE, what study looked at whether the pregnancy should be prolonged after 36+6 weeks?

If term is reached, which is traditionally 37+ weeks, should we continue with the pregnancy or deliver?

Answer 26

The HYPITAT study looked at the induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks’ gestation (HYPITAT): a multicentre, open-label randomised controlled trial.
- It is the HYPITAT study that currently guides management.

Question 27

What was the methodology used in the HYPITAT study?

Answer 27

• Women with mild PE or gestational HTN were recruited at 36 weeks (n = 756)
• Randomized between delivery and conservative management
• Severe PE were excluded (BP above 170/110, proteinuria of 5.0 gm/day or more, presence of symptoms). Women with severe PE were excluded; needed to be delivered and this risk couldn’t be taken (they would most likely get eclampsia).

Question 28

What were the results from the HYPITAT study?

Answer 28

• Composite adverse maternal outcome (mainly severe HTN) was less common in IOL (31%) than conservative arm (44%)
• MgSO4 use was doubled (6% vs 12%) with conservative treatment
• Fetal outcome was no different
• CS rate was lower (14%) with IOL than conservative arm (19%, p = 0.085)
• Composite adverse outcomes are usually used because adverse outcomes are thankfully rare.
• When combining them, such as abruption with severe hypertension and eclampsia, a composite outcome can be produced using the important factors that women want to know about. It was found that inducing at 37 weeks can reduce adverse outcome from 44% to 31%. In the group that had induction, rather than expectant management, less magnesium sulphate had to be used. This is intuitive, because they have less severe high blood pressure. Therefore, the symptoms for severe PE will not occur. There was no difference in foetal outcome, so inducing at 37 weeks is not at detriment to the baby. Interestingly, there was a lower caesarean section rate with induction compared to expectant management. This is likely because delivery is occurring with a relatively good placenta, compared to 39 weeks when placental function will deteriorate. The p-value does not quite reach 0.05, so it can be argued how reliable this is.

Question 29

What was the conclusion from the HYPITAT study?

Answer 29

• Authors concluded that induction of labour is recommended for women with mild PE or mild gestational hypertension at a gestational age beyond 37+0 weeks

Question 30

What study looked at whether delivery should be considered for PE between 34-37 weeks?

Answer 30

• Pheonix study = planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial.
• There is always a little bit of a grey area. When thinking about prematurity, the risks are much worse with lower gestations. Between 34 to 37 weeks, prematurity is not too much of an issue if delivery is required. The authors of the next trial were looking at whether it is better to deliver late preterm (34-37 weeks), rather than waiting until 37 weeks.

Question 31

What was the methodology used in the PHOENIX study?

Answer 31

• Singleton or DCDA pregnancies with mild/moderate PE were recruited at 34 - 36 weeks (n = 901)
• Randomized between delivery (n=450) and conservative management (n=451)
• Those with a planned delivery within 48 hours of randomization were not recruited
• In 2019, a paper was published on the PHOENIX study at KCL. They recruited singleton or DCDA pregnancies (DCDA twins have separate placentas, so it can be argued that the women have two singletons and this is why they were included in the study). These women had mild to moderate PE and they were randomised between delivery and conservative management. Those that were planned to have delivery within the next 48 hours were excluded because they could not really be randomised (conservative management has to be more than two days).

Question 32

What were the results from the PHOENIX study?

Answer 32

• Composite adverse maternal outcome (mainly progression to severe PE) was less common in IOL (65%) than conservative arm (75%) p=<0.05
• Composite adverse neonatal outcome (mainly due to admission for prematurity) was more common in IOL (42%) than conservative arm (34%) p=<0.05
• No difference in CS rate (55%) with IOL than conservative arm (61%, p = 0.085)
• The results of this study were good for the mother. There was less progression to severe PE in the induction of labour group vs the conservative arm. On the other hand, there was more adverse outcome in the baby in the induction of labour group compared to the conservative arm. However, looking at the outcomes for baby, the reason they were admitted to special care was because of “prematurity” rather than an actual problem. Any preterm baby is usually sent to NICU for support to establish their postnatal life.
• When looking at the caesarean section rate, there was no difference between the two.

Question 33

What was the conclusion from the PHOENIX study?

Answer 33

• Authors concluded that between 34-36+6 weeks, induction of labour should be considered for women with mild/moderate PE to reduce maternal complications vs expectant to 37+0 weeks, but with higher chance of NNU admission (due to prematurity)
• It was not a recommendation because there was an apparent increase in neonatal adverse outcome.
• It is important to be aware that baby may have to be admitted to special care due to prematurity.

Question 34

Why is post-natal management important and what does it entail?

Answer 34

1) Carefully assess women with signs or symptoms of pre-eclampsia
2) Assess need to continue anti-hypertensives
3) Arrange appropriate follow-up
4) An assessment of BP and proteinuria by the general practitioner at the 6 weeks postnatal check is recommended.
5) If hypertension or proteinuria persists then further investigation is required.
6) Women whose pregnancies have been complicated by severe pre- eclampsia or eclampsia should be offered a formal postnatal review to discuss the events of the pregnancy.
7) Pre-conceptional counselling should be offered where the events that occurred, any risk factors and any preventative therapies can be discussed.

• If the mother developed PE during pregnancy, the mother’s blood pressure is likely to spike again and result in eclampsia after the baby is born (post-natal care is very important). This is because the body undergoes massive change after birth; the cardiovascular function tries to return to its pre-pregnancy state within a couple of days. In pregnancy, it is normal to have low vascular resistance so there is more volume in the blood for the baby and also for delivery (to compensate for blood loss). That low resistance also aids the adaptation for pregnancy to allow suitable gas exchange. If a woman has PE and already has high vascular resistance, when the body tries to reach even higher vascular resistance, it makes sense that the blood pressure can spike (the danger period is usually day 3 to 5 after delivery). This post-natal period is when 50% of eclampsias occur.
• Therefore, patients with PE should be monitored for at least five days, especially if they have severe PE. If they are in hospital being monitored, it is easier to act quickly to try to reduce blood pressure and stop eclampsia.
• Hopefully, when the body begins to return to normal, blood pressure will reduce and they may not need any anti-hypertensives (may be able to stop them). However, that period between leaving the hospital and going to see the GP at six weeks is a danger period. Most women are on home blood pressure monitoring prior to delivery, so they continue this for the 6 weeks after delivery. If there are any concerns, they can come into the hospital to see obstetrics or visit the GP for management. If high blood pressure and proteinuria persist further than the six weeks, they may have a new diagnosis of chronic hypertension. This happens in about 30% of women. They would need to have a discussion about how to reduce risk, i.e. lifestyle changes (exercise, diet, losing weight = traditional methods of primary prevention), treatment of the blood pressure and monitoring for end-organ damage (should have blood tests ever year to check the liver and kidney, check blood pressure to ensure it is being managed effectively).
• Must do a formal post-natal review in any patients that have had severe PE or eclampsia. They need a care plan in place to ensure they do not have consequences of PE and also to help with planning for future pregnancies.
• Having pre-conceptual counselling can also help to reduce risks, i.e. lose weight, healthy diet, exercise, blood pressure control. If they are on blood pressure medications that may cause problems with early pregnancy, particularly ACE inhibitors, then they may get switched to a different type of medication, such as labetalol or methyldopa, that does not cause embryopathy. It is important to speak to women before they leave to ensure they have a care plan in place.

PE can kill. It is important not to allow it to reach this point; need to manage it effectively by prevention and aspirin. When they do have a diagnosis, it is important to gain control of their blood pressure, monitor end organ damage and deliver appropriately.
The severity and progression of the disease are variable. This is why it is important to monitor them closely.

Question 35

Summary!

Answer 35

• Pre-eclampsia can kill
• The severity and progression of the disease are variable
• Both mother and fetus are at risk
• Is a multi-organ disease
• Severe pre-eclampsia needs multi-disciplinary input
• The only effective treatment is delivery
• PE can kill. It is important not to allow it to reach this point; need to manage it effectively by prevention and aspirin. When they do have a diagnosis, it is important to gain control of their blood pressure, monitor end organ damage and deliver appropriately.
• The severity and progression of the disease are variable. This is why it is important to monitor them closely.
• Multidisciplinary input is required for severe PE, which includes anaesthetists, intensivists, medics, obstetricians, neonatal team etc. Everyone needs to be involved to try and produce the best outcome.
• The only effective “treatment” is delivery, but there is long term sequelae so whether PE is cured by delivering the baby is debatable. There is lifelong risk and the risk factors need to be managed to reduce adverse outcome.