Mini-Review: Elizabeth Phipps, Devika Prasanna, Wunnie Brima, and Belinda Jim
Mini-Review: Elizabeth Phipps, Devika Prasanna, Wunnie Brima, and Belinda Jim
Mini-Review: Elizabeth Phipps, Devika Prasanna, Wunnie Brima, and Belinda Jim
1102 Copyright © 2016 by the American Society of Nephrology www.cjasn.org Vol 11 June, 2016
Clin J Am Soc Nephrol 11: 1102–1113, June, 2016 Preeclampsia: Updates in Pathogenesis, Definitions, and Guidelines, Phipps et al.
1103
Figure 1. | Pathogenesis of preeclampsia: two-stage model. AT1-AA, autoantibodies to angiotensin receptor 1; COMT, catechol-
O-methyl- transferase; HTN, hypertension; LFT, liver function test; PlGF1, placental growth factor 1; PRES, posterior reversible
encephalopathy syndrome; sEng, soluble endoglin; sFlt-1, soluble fms–like tyrosine kinase 1; sVEGFR1, soluble vascular endothelial
growth factor receptor 1; VEGF, vascular endothelial growth factor. Reprinted from reference 35, with permission.
Misfolded Proteins
Nitric Oxide Pathway Preeclamptic placentas have been shown to accumulate clusters
The nitric oxide (NO)/nitric oxide synthase (NOS) system of misfolded protein, which may contribute to the
is also deranged in preeclampsia. NO is a potent pathophysiology of the disease (62).
vasodilator that acts to induce relaxation in vascular smooth that urine samples in preeclampsia exhibited congophilia, a
muscle cells via a cyclic guanosine monophosphate well-recognized marker of protein instability and misfolding.
pathway (44). The urine congophilic material includes proteoforms of
Decreased levels of NO (45,46) and increased levels of ceruloplasmin, Ig free light chains, serpin peptidase inhibitor 1,
arginase (which degrades a precursor molecule in the albumin, IFN–inducible protein 6–16, and Alzheimer b-amyloid.
NOS pathway) have been reported in preeclampsia (47,48). The presence of b-amyloid aggregates in placentas of women
A deficiency in NO has been shown to correlate with with preeclampsia and fetal growth restriction further supports
metabolic derangements seen in preeclampsia, such as the notion that such protein aggregates might be directly
hypertension, proteinuria, and platelet dysfunction (45). pathogenic to the placenta.
Urine congophilia was found to be significantly elevated in
NO deficiency induces the uteroplacental changes high-risk women with severe preeclampsia and medically
characteristic of preeclampsia in pregnant mice, including indicated deliveries compared with in women who were
decreased uterine artery diameter, spiral artery length, and healthy pregnant controls and those with chronic or gestational
uteroplacental blood flow (49). These findings suggest that an hypertension (62). (High risk was defined as women with chronic
intact NOS system is essential for normal spiral artery hy- pertension, history of severe preeclampsia, twin preg-
remodeling and pregnancy. nancy, diabetes, diabetic nephropathy, nephrolithiasis,
membranous nephropathy, autoimmune disease, or sickle cell
disease with history of crises.)
Oxidative Stress
From early pregnancy on, the placenta assumes a state of Subtypes of Preeclampsia
oxidative stress arising from increased placental Ness and Roberts (63) in 1996: preeclampsia: placental and
mitochondrial activity and production of reactive oxygen maternal.
species (ROS), mainly superoxide anion (50,51). Others have categorized into early onset (,34 weeks of
In preeclampsia, a heightened level of oxidative stress is gestation) versus late onset (.34 weeks of gestation) (64).
encountered (51). In placental or early-onset pre- eclampsia, the etiology is
abnormal placentation under hypoxic conditions with higher
The source had been attributed to the placenta, where free levels of sFlt-1, lower PlGF, and higher sFlt-1-to-PlGF ratio
radical synthesis occurs, with maternal leukocytes and compared with in maternal preeclampsia (65,66).
the maternal endothelium likely contributors (53). Uterine Doppler studies have also been shown to have a higher
The superoxide–producing enzyme NADPH oxidase, for accuracy in identifying patients who will subsequently develop
example, has been shown to be present in placental early- rather than late-onset preeclampsia (67–69).
trophoblast. These findings support the abnormal high impedance to blood
Women with early onset of preeclampsia have been found flow in the uterine arteries that has been associated with failure of
to have higher superoxide production compared with those physiologic transformation of spiral arteries (70–72).
with late-onset disease (53). In maternal preeclampsia or late-onset preeclampsia, the
problem arises from the interaction between a presumably normal
placenta and maternal factors that are plagued with endothelial
Angiotensin Receptor 1 Autoantibodies dysfunction, making them susceptible to microvascular damage.
Turning to immune mechanisms, link between These commonly used classifications seem to have prognostic
autoantibodies to angiotensin receptor 1 (AT1-AAs) and value, because placental or early-onset preeclampsia carries a
preeclampsia. significantly higher risk of maternal and fetal complications
These autoantibodies seem to be pathogenic in a (64,73,74). They also harbor a greater prevalence of placental
variety of proposed pathways. lesions, especially between 28 and 32 weeks of gestation (75).
AT1-AAs isolated from sera of preeclampsia women Hence, placental or early-onset preeclampsia is associated with
cause upregulation of ROS and the NADPH oxidase fetal growth restriction and adverse maternal and neonatal
components as well as NK-kB. outcomes (76,77).
Blockade with an angiotensin receptor 1 (AT1) receptor Maternal or late-onset pre- eclampsia seems to be a
blocker, such as losartan, was able to attenuate these decompensated response to the oxidase stress in the placenta by a
changes. dysfunctional maternal endothelium. Endothelial dysfunction,
AT1-AA–induced hypertension may be via endothelin which is one aspect of a systemic maternal inflammatory response,
(56). may result in generalized vasoconstriction and reduced blood
the only available class of medication that seems to to multiple organs, including the heart, kidney, and brain (78).
ameliorate AT1-AA–induced preeclampsia is the However, because the level of pathology does not seem to be at
angiotensin receptor blocker, which happens to be the placenta, it is generally associated with a lower rate of fetal
teratogenic. involvement and more favorable perinatal outcomes (77,79).
the presence of AT1-AA seems to induce sFlt-1 release
via activation of the calcineurin/nuclear factor of activated t
cells pathway (58). Furthermore, AT1-AA stimulates sFlt-1
and sEng by inducing TNF-a and overcoming its negative
regulator, HO (59).
hypertension, preeclampsia (de novo or superimposed on chronic
hypertension), and white coat hypertension (92). The main
Maternal Outcomes categories from each society have been summarized in Table 1.
Multiple clinical studies of women with preeclampsia
show an increased risk of developing cardiovascular
diseases later in life (80). Hypertension, ischemic heart BP Targets
disease, and stroke the Control of Hyper- tension in Pregnancy Study:
Early-onset preeclampsia conferred a higher risk of target of diastolic BP of 85 mmHg had nonsignificant maternal and
end organ damage in terms of cardiovascular, respiratory, fetal outcomes compared with a less tight control level of 100 mmHg.
central nervous, renal, and he- patic systems compared The less tight control group, however, had a higher incidence of severe
with late onset (87). hypertension, thrombocytopenia, elevated liver enzymes with
symptoms, and a trend toward a higher incidence of hemolysis,
Guidelines elevated liver enzymes, and low platelets syndrome.
The well-classification system was adopted by the Thus, it seems that tighter control of BP is not only safe for the fetus
National High Blood Pressure Education Program but potentially beneficial to the mother.
(NHBPEP) Working Group in 1990. The updated version It seems that the development of preeclampsia/ eclampsia is
in 2000 has become a standard that the American College independent of the BP level, which limits our ability to prevent and
of Obstetrics and Gynecology (ACOG) follows (88). treat this condition.
one of the most important advances or amendments is Preconception Counseling, Prevention, Treatment,
the ACOG definition of preeclampsia: it no longer requires and Postpartum Care in Preeclampsia
the presence of proteinuria as long as there is evidence of The care of the woman at risk for preeclampsia starts
other end organ damage (Table 1). with preconception counseling followed by prevention, treatment,
and appropriate postpartum follow-up.
Comparison of Guidelines from International
Societies
In the United States: the classification scheme as per the
ACOG in 2013 comprising four categories remains
unchanged (89). In 2014, the Society of Obstetricians and
Gynecologists of Canada released revised recommendations
on hypertension in pregnancy on the basis of literature
reviews and criteria from the Canadian Task Force on
Preventative Health Care (90). The National Institute for
The ACOG recommends that women who had preeclampsia in a
Health and Care Excellence in the United Kingdom in 2010
prior pregnancy seek preconception counseling and assessment. In
introduced evidence-based guidelines on the diagnosis
addition, they recommend that for women who have a history of
and management of hypertension during pregnancy, birth,
chronic hypertension, the use of angiotensin–converting enzyme
and the postnatal period (www.
inhibitors and angiotensin receptor blockers is contraindicated for
nice.org.uk/guidance/cg1 07). The Society of Obstetric
those desiring pregnancy (we do not recommend against the use
Medicine of Australia and New Zealand has expanded its
of angiotensin–converting enzyme inhibitors and angiotensin
definition of chronic hypertension (91). Finally, the
receptor blockers in women with comorbidities, such as diabetes,
International Society for the Study of Hypertension in
proteinuria, or CKD, because of the weak evidence of congenital
Pregnancy submitted a revised statement in 2014 that
malforma- tions in the first trimester (95,96). We do recommend that
includes the categories of chronic hypertension, gestational
these agents be discontinued after pregnancy has been confirmed.)
1
Table 1. Comparison of definitions among different societies 1
0
RCOG (www.nice.org. 6
Category ACOG (89) SOGC (90) SOMANZ (91) ISSHP (92) Cl
uk/guidance/cg107)
in
ic
Chronic HTN/ sBP$140 mmHg and/or sBP$140 mmHg and/or HTN that is present at sBP$140 mmHg and/or High BP predating the al
essential HTN dBP$90 mmHg known dBP$90 mmHg that the booking visit or dBP$90 mmHg pregnancy Jo
to predate conception or develops either before 20 wk or if the confirmed before ur
detected before 20 wk prepregnancy or at ,2010 woman is already pregnancy or before 20 n
of gestation, with no taking al
wk of gestation completed wk of
of
underlying cause Preexisting HTN with antihypertensive gestation without a th
comorbid conditions medication when known cause e
Preexisting HTN with referred to maternity A
superimposed services m
preeclampsia er
ic
Gestational New-onset elevations of BP HTN that develops for the New HTN presenting New onset of HTN after When de novo HTN is present a
HTN after 20 wk of gestation, first time at $2010 wk of after 20 wk without 20 wk of gestation after 20 wk of gestation in n
often near term, in the gestation significant proteinuria without any maternal the absence of proteinuria S
absence of accompanying Gestational HTN with or fetal features of and maternal organ/ o
proteinuria comorbid conditions preeclampsia followed uteroplacental dysfunction ci
Gestational HTN with et
by return of BP to
evidence of preeclampsia normal within 3 mo
postpartum
Preeclampsia/ HTN as defined above, Gestational HTN with one or Preeclampsia is new HTN Multisystem disorder When de novo HTN is present
eclampsia associated with more of the following presenting after 20 wk unique to human after 20 wk of gestation in
proteinuria (24-h excretion with significant pregnancy characterized the presence of proteinuria
$300 mg), diagnosed after proteinuria by HTNand involvement and maternal organ/
20 wk of uneventful New proteinuria Eclampsia is a convulsive of one or more other uteroplacental dysfunction
gestation up to 2 wk condition associated organ systems and/or
postpartum with preeclampsia the fetus
In the absence of proteinuria, One or more Hemolysis, elevated liver
new-onset HTN with new enzymes, and low
onset of any of the platelet count
following adverse syndrome
Platelet count ,100,000/ml, conditionsa Severe preeclampsia:
serum creatinine .1.1 preeclampsia with
mg/dl, or doubling of severe HTN and/or
concentration in absence of One or more severe symptoms and/or
other renal disease complicationsb biochemical and/or
Transaminitis to twice hematologic
normal concentration impairment
Pulmonary edema
Cerebral/visual symptoms
Cl
Table 1. (Continued) in
J
RCOG (www.nice.org. A
Category ACOG (89) SOGC (90) SOMANZ (91) ISSHP (92)
uk/guidance/cg107) m
S
Preeclampsia/ HTN diagnosed before or in HTN along with the None specified Woman with chronic One or more of the above o
c
eclampsia early gestation and development of one or more HTN developing one or features of preeclampsia (i.e., N
superimposed development of associated of the following at $20 wk more of the systemic proteinuria and maternal e
on chronic proteinuria Resistant HTN features of preeclampsia organ/uteroplacental p
HTN New or worsening after 20 wk of gestation dysfunction) occur in hr
proteinuria addition to HTN ol
One or more adverse 1
1:
conditionsa 1
One or more severe 1
complicationsb 0
Other HTN White coat HTN: elevated White coat HTN: BP that is None specified White coat HTN: raised White coat HTN: normal BP 2
effects BP primarily in the elevated in the office but BP inthepresence ofa using 24-h ABPM in the first –
consistently normal outside 1
presence of health care clinical attendant but half of pregnancy
providers of the office (,135/85 normal BP otherwise as
mmHg) by ABPM or HBPM assessed by ABPM or
Transient hypertensive effect: HBPM
elevated BP may be caused Secondary HTN: raised
by environmental stimuli BP in the presence of an Pr
(e.g., the pain of labor) e
inciting factor such as
e
Masked hypertensive effect: CKD (e.g., GN, reflux cl
BP that is consistently nephropathy, and adult a
normal in the office polycystic kidney disease) m
(sBP,140 mmHg or Renal artery stenosis p
dBP,90 mmHg) but Systemic disease with renal si
elevated outside of the a:
involvement (e.g., U
office ($135/85 mmHg) diabetes mellitus or p
by ABPM or repeated SLE) d
HBPM Endocrine disorders (e.g., at
pheochromocytoma, e
Cushing syndrome, s
and primary in
P
hyperaldosteronism) at
Coarctation of the aorta h
o
ACOG, American College of Obstetrics and Gynecology; SOGC, Society of Obstetricians and Gynecologists of Canada; RCOG, Royal College of Obstetricians and Gynecologists; g
SOMANZ, Society of Obstetric Medicine of Australia and New Zealand; ISSHP, International Society for the Study of Hypertension in Pregnancy; HTN, hypertension; sBP, systolic BP; e
dBP, diastolic BP; ABPM:, ambulatory BP monitoring; HBPM, home BP monitoring. n
a e
Adverse condition: involvement of organ systems, such as central nervous (headache, visual symptoms, seizure, etc.), cardiorespiratory (chest pain, hypoxia, poorly controlled HTN, etc.), si
hematologic (low platelet count, elevated international normalized ratio [INR] or partial thromboplastin time [PTT], etc.), renal (elevated creatinine, elevated uric acid, new s,
indication for dialysis, etc.), hepatic (right upper quadrant pain, transaminitis, low plasma albumin, etc.), or fetoplacental system (abnormal fetal heart rate, D
b e
oligohydramnios, stillbirth, etc.). Severe complications: complications of central nervous (e.g., eclampsia, posterior reversible encephalopathy syndrome [PRES], cortical blindness, Glasgow
fi
coma scale ,13, stroke, transient ischemic attack [TIA], or reversible ischemic neurological deficit [RIND]), cardiorespiratory (e.g., uncontrolled severe HTN over 12 hours, despite use of ni
three antihypertensive agents, oxygen saturation ,90%, pulmonary edema, positive inotropic support, or myocardial ischemia or infarction), hematologic (platelet count ,503109/L or ti
transfusion of any blood product), renal (AKI or new indication for dialysis), hepatic (INR.2 in the absence of disseminated intravascular coagulopathy [DIC] or warfarin), or fetoplacental o
system (abruption with evidence of maternal or fetal compromise, reverse ductus venosus A wave, or stillbirth). n
s,
a
n
1108 Clinical Journal of the American Society of Nephrology
Table 2. BP targets
Quality of
Intervention Evidence Benefit(s) Data Comments
Calcium 13 RCTs, 15,730 RR, 0.45 (95% CI, High High-dose calcium
supplementation women analyzed 0.31 to 0.65) (97) (.1 g/d) reduced the
by a Cochrane risk of preeclampsia
review (97) in subgroups with
low calcium intake of
,1 g/d and women
at high risk of
preeclampsia
Vitamin C and E Multicenter RCT RR, 1.20 (95% CI, High Patients were given
supplementation involving 1877 0.82 to 1.75) (98) 1000 mg vitamin C
women (98) and 400 IU vitamin E;
RR, 0.97 (95% CI,
Multicenter RCT associated with low–
0.80 to 1.17) (54) birth weight
involving 2410
women (54) babies (54)
Aspirin Meta-analysis of 34 Reduction in
Before 16 wk of High (99); fair preeclampsia,
RCTs involving gestation: RR, to good (100)
11,348 women (99) especially if used
0.47 (95% CI, 0.34 before 16 wk of
Meta-analysis of 13 to 0.65); after 16
RCTs involving gestation in high-risk
wk of gestation: women
12,184 women RR, 0.81 (95% CI,
(100) The USPSTF Study
0.63 to 1.03) (99) suggests that low-
ARR52%–5% (100) dose aspirin in high-
risk women has
important benefits
when used as early as
the second trimester
Significant reduction in
UFH and LMWH Meta-analysis of 10 RR, 0.43 (95% CI, secondary outcome of
RCTs involving Fair to good
0.28 to 0.65) (101) preeclampsia in high-
1139 women (101) risk patients;
significant reduction in
risk of perinatal
mortality, preterm
birth before 34 and 37
wk of gestation, and
infant birth weight
,10th percentile; it
was not possible to
evaluate the effect of
UFH compared with
RCTs ranging from LMWH
Magnesium sulfate 1687 to 2138 0.009% versus 0% High Significant reduction in
of phenytoin the incidence of initial
women (102,103) versus and recurrent seizures
magnesium to in women with
prevent gestational HTN
eclampsia compared with use of
(P50.004) (102); anticonvulsants, like
52% lower risk of phenytoin and
recurrent diazepam
convulsion than
diazepam (95%
CI, 64% to 37%
reduction); 67%
lower risk of
recurrent
convulsions than
phenytoin (95%,
CI 79% to 47%
reduction) (103)
RCT, randomized, controlled trial; RR, relative risk; 95% CI, 95% confidence interval; ARR, absolute risk reduction; USPSTF, US
Preventive Services Task Force; UFH, unfractionated heparin; LMWH, low molecular weight heparin; HTN, hypertension.
1110 Clinical Journal of the American Society of Nephrology
Adverse Events in
Drug Dose Pregnancy Comments