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Pathophysiology of Pre-eclampsia Hiten Mistry January 2020
Pathophysiology of Pre-eclampsia
Hiten Mistry
January 2020
Pre-eclampsia: the facts
• Pre-eclampsia affects 6 women in every 100 • 4 million women affected worldwide each year (76,000 deaths)
(Equivalent to 3 jumbo jets per week crashing!)
• Death rate in UK is relatively low due to excellent antenatal care pregnant women receive
• Accounts for >90% of obstetric morbidity/mortality in developing countries
Broughton Pipkin., NEJM 2001
Gestational hypertension (GH):
SBP 140 mmHg or DBP 90 mmHg on 2 occasions
6 hours apart
Pre-eclampsia:
GH + proteinuria
( 30 mg/mmol PCR or 2+ dipstick MSU/CSU)
Pre-eclampsia: definition
• Proteinuria is not mandatory for a diagnosis of pre-eclampsia. • Rather, this is diagnosed by the presence of de novo hypertension after 20 weeks’
gestation accompanied by proteinuria and/or evidence of maternal acute kidney injury, liver dysfunction, neurological features, haemolysis or thrombocytopenia, and/or fetal growth restriction.
The hypertensive disorders of pregnancy: ISSHP classification,
diagnosis & management recommendations for international practice
Brown et al Preg. Hyp. 2018;13:291-310
Pre-eclampsia: more than just hypertension and proteinuria
Hypertension >140/90mmHg
Proteinuria 300mg/24h: 30mg/mmol
Eclampsia
Fetal Growth Restriction
Thrombocytopenia
Splanchnic ischaemia
+
Hepatic Necrosis and Fatty liver
HELLP
Renal Impairment
Subgroups of Pre-eclampsia
• Early-onset pre-eclampsia: - delivery <34 weeks gestation - feature placental dysfunction - associated with fetal growth restriction • Late-onset pre-eclampsia: - delivery ≥34 weeks gestation - placentae usually normal - Maternal factors (such as metabolic syndrome and hypertension) have important roles - Most cases of eclampsia and maternal death occur in late disease • Superimposed pre-eclampsia: - PE superimposed with either chronic hypertension and/or chronic kidney disease. - About 25% of pregnant women with pre-existing hypertension develop superimposed pre-eclampsia
Gestational Hypertension
Normotensive Gestational HT Pre-eclampsia
N 223 117 71
Max SBP 120 150 158
Max DBP 75 100 118
Severe HT 0 22.2% 56.3%
Sev. Mat. Dis. 0 26.5 63.4
Birth gestation 40 39.2 36.9
Preterm<37w 3.6% 6.0% 35.2%
SGA (<10c) 11.7% 20.5% 25.4%
North et al BJOG 1999;106:767-773
• Very difficult to study scientifically because rare (1 in 2,000) and without warning
• Dangerous. In the UK 1 woman in 50 with eclampsia dies and 1 in 3 will have a major complication - 38% antenatally, 18% intrapartum, 44% postnatally
• 1 baby in 20 dies
• Most occur in 1st 48 hrs postnatally – can be up to 10 days post delivery
• A UKOSS study in 2005–2006 (Knight et al. 2007) identified a rate of eclampsia of
26.8 per 100,000 maternities, compared to a rate of 49 per 100,000 maternities in a survey from 1992 (Douglas and Redman 1994)
Eclampsia
HELLP: Haemolysis, elevated liver
enzymes, and low platelets
Haemolysis Diagnosis requires at least 2 of the following: • Abnormal peripheral smear (schistocytes, burr
cells) • Elevated serum bilirubin (≥ 1.2 mg/mL) • Low serum haptoglobin • Significant drop in haemoglobin levels, unrelated
to blood loss Elevated liver enzymes • Aspartate aminotransferase or alanine
aminotransferase at least twice the upper level of normal
• Lactate dehydrogenase at least twice the upper level of normal (this value is also elevated in severe haemolysis)
Low platelets • < 100,000 / mm3
• Hypertension
Most women with HELLP have hypertension, but up 15% may not
• Proteinuria
Most women with HELLP have proteinuria on dipstick (≥1+), but can be absent in up to 13%
HELLP
• Rare cases can lead to liver hematoma – life threatening
• Can occur antepartum, during labour, or in the postpartum period
• Symptoms include severe epigastric or retrosternal pain (on inspection), with or without shoulder/neck pain
• Eclampsia recognised by Ancient Greeks
“a headache accompanied by heaviness and convulsions during pregnancy is considered bad”
Aphorism XXXI 507 in the Coan Prognosis
• eklampsis: sudden flashing
• eklampein : to shine forth
History
A surgeon letting blood from a woman's arm, and a physician examining a urine-flask. Oil painting by a Flemish painter, 1700s Wellcome Library London
Historical ‘treatment’ for pre-eclampsia
• Less than 1 woman in every million who gives birth now dies from pre-eclampsia, but to detect it blood pressure and urine must be checked at every antenatal visit
• This represents a major success for research, audit and evidence-based guidelines leading to improvements in care.
• This is a positive reflection on the standard and provision of care for women with hypertensive disorders of pregnancy
Good care makes a difference
Causes of maternal death from hypertensive disorders of
pregnancy (1997– 2014)
1997–2002 2003–8 2009–14
Intracranial
Haemorrhage 16 18 7*
Eclampsia/cerebral oedema
0 6 3
Pulmonary oedema 3 0 0
Hepatic rupture 2 1 0
Hepatic
Necrosis/HELLP 9 5 4*
AFLP 7 7 1
Total 37 37 14*
MBRRACE-UK - Saving Lives, Improving Mothers’ Care 2016
Pre-eclampsia – Future Health
• Systematic Review of 3,488,160 women
Bellamy BMJ 2007
Spiral artery Relative Risk Weighted
mean f/u
Hypertension 3.70 (2.70 to 5.05) 14.1 yrs
Ischaemic heart disease
2.16 (1.86 to 2.52) 11.7 yrs
Stroke 1.81 (1.41 to 2.27) 10.4 yrs
Oxidative stress associated with cardiovascular risk
R2 = 0.061
r =0.248
Correlation P = 0.003
Kurlak et al., Frontiers in Physiology. 2014
Neonatal complications
Hypertension and
Cardiovascular disease
(Bellamy et al., BMJ 2007)
Chronic Kidney Disease
(Al Salmi et al., AJKD 2008)
Pre-eclampsia
(Dempsey et al., AJOG 2003)
Developmental problems
(Mulder et al.,Int. Neuropsychol. Soc.
2011)
Increasing Incidence of pre-eclampsia in USA 1998-2006
Kuklina et al., Obstet Gynecol. 2009 Ananth et al., BMJ. 2013
The Placenta
Placentation
1. Decidualisation
- endometrial cells decidual cells
2. Blastocyst implantation
- maternal-fetal molecular “cross-talk”
3. Trophoblast proliferation
- state of relative hypoxia
4. Trophoblast invasion of spiral arteries
- normal oxygenation resumes
Multepe et al., JCI., 2010
Restricted spiral artery remodelling in pre-eclampsia
Brosens et al., Obs Gyn Annu 1972
Pre-eclampsia – the root of the problem
J. et al. J. Perinat. Med. 2006
Oxidative stress, Inflammation & Pre-eclampsia
Borzychowski et al., Sem. Mat Neo Med. 2007
Stage 1 (Early Pregnancy)
Stage 2 (Late Pregnancy)
Poor Placentation
Oxidatively stressed placenta
Fetal Effects (e.g. FGR)
Release of placental factors (e.g. debris, sFlt-1)
Maternal systemic inflammatory response
Endothelial dysfunction
Clinical signs of pre-eclampsia
Local Effects
Systemic Effects
Oxidative Stress & Pre-eclampsia
Maternal [TBARS]
Non-Pregnant Normal Pregnant Pre-eclampsia0.0
0.5
1.0
1.5
Group
[TB
AR
S]
nm
ol/m
l
Umbilical [TBARS]
Normal Pregnant Pre-eclampsia0.0
0.5
1.0
1.5
Group
[TB
AR
S]
nm
ol/L
** ** *
** P < 0.005; * P < 0.05
Mistry et al., Hypertension. 2008
Xanthine Oxidase & NAD(P)H
Williams et al., Placenta. 2010
Adaptations in normal pregnancy & pre-eclampsia
Salas et al., Hypertension 2006
VEGF/PlGF and sFlt-1 in pre-eclampsia
Davison et al., JASN 2004
Muna Noori et al., Circulation 2010
Normotensive pregnancy Gestational Hyptertension Term Pre-eclampsia Preterm Pre-eclampsia
PlGF and sFlt-1 in pre-eclampsia
Summary of the pathophysiology of pre-eclampsia
Chaiworapongsa et al., Nat. Rev. Neph. 2014
• Collaborative Low-dose Aspirin Study in Pregnancy (CLASP) found to be beneficial (Lancet 1994)
• Aspirin for high risk women → 17% reduction in pre-eclampsia
• Low rates of adverse outcome
• No association with placental abruption or fetal intracerebral bleeding
• Maximum benefit if commenced before 16/40 • Aspirin restores prostacyclin levels in endothelium to produces vasodilatory and
antiplatelet effect again
• Found to be more beneficial in prevention of pre-term but not term pre-eclampsia
Aspirin
Magnesium sulphate (MgSO4)
• Large multi-centre RCT (n >10,000; Magpie Study)
• Placebo vs MgSO4 for prevention of eclampsia
• In MgSO4 group 40 developed eclampsia vs 96 on placebo
• Risk reduction 58%
• Fewer maternal deaths in MgSO4 group (11 vs 20 in the placebo group)
• No increased morbidity or mortality at 2 years follow up
Altman D et al., Lancet 2002
• Women with a history of new-onset hypertension in pregnancy have an increased risk of future hypertension and cardiovascular disease
• Women who deliver preterm (before 34 weeks of gestation) are at even higher risk
• Follow-up after pregnancy is vital to ensure that ongoing disease is appropriately investigated and managed
• Simple lifestyle changes may help reduce these risks.
• Do we counsel women adequately about the long-term risk of disease after hypertensive pregnancy?
• Are we missing opportunities for disease prevention?
New-onset hypertension in pregnancy: a review of the long-term maternal effects (2012) Green, Loughna, Broughton Pipkin
Long-term follow-up
Hypertensive diseases of pregnancy – research worth investing in
I was sent this by an American friend, who was involved in the case. Pre-eclampsia still kills, in the US as well as Sub-Saharan Africa.
“The week of March 15th, 2004, Corina Pineda, 19 and pregnant for the first time, began having cramps. She was hospitalized for 3 days and
then sent home. The following Monday she had her weekly doctor's appointment. She wasn't feeling well. After taking her BP, the staff realized
how ill Cori was and life-flighted her to Miami Jackson Memorial Hospital. Her mother caught an immediate plane to Miami.
Waking from an emergency C-section, Cori found her mother there. They were able to talk a bit and pray. Cori seemed stable so her mother
decided to leave for a minute to check on the baby girl in the NICU who was only 2.5 lbs. When she returned to ICU a short-time later
she found the doctors working on Cori who was turning yellow from liver failure. The medical team spent the next four hours trying to save Cori.
Her mother was there when Cori, her beautiful daughter who should have been celebrating her baby's birth, died in her arms.
I have personally spoken with four families in the past four months who have lost a wife/daughter/sister/mother to this terrible disease and
one family where the woman may be permanently disabled due to her stroke. Please remember these mothers.
Countless more have lost their babies...even more now sit vigil in NICU praying daily that their baby will just get through another day.
All of these women were mothers. Some left babies and partners behind. All left a wake of loss, confusion and devastation.
All of these families have said to me "Why didn't we know?” I have no good answer for them.”
