Preeclampsia Syndrome
BS. Nguyễn Hồng Anh
Hypertensive disorders include preeclampsia, gestational hypertension, and chronic hypertension and complicate up to 10 percent of pregnancies. As a group, they are one member of the ealy trial—along with hemorrhage and infection—that contributes greatly to maternal morbidity (July, 2019).
Preeclampsia, either alone or superimpose on chronic hypertension, is the most angerous. In the United States from 2011 to 2015, 7 percent o pregnancy-relate maternal eaths were cause by preeclampsia or eclampsia (Petersen, 2019). Most hypertension-relate eaths are eeme preventable (Katsuragi, 2019). In response, Joint Commission (2019) accreite hospitals are now require to track their recognition an timely treatment o hypertension.
In 2018, a workshop to stuy preeclampsia was convene by the National Heart, Lung, an Bloo Institute. Tis buils on the prior work o the American College o Obstetricians an Gynecologists’ ask Force on Hypertension in Pregnancy (2013). Its purpose was to review topics regaring all aspects o preeclampsia an to recommen uture research areas. Many o these topics are iscusse throughout this chapter an Chapter 41.
TERMINOLOGY AND DIAGNOSIS
o coiy the classication o hypertensive isorers o pregnancy, the American College o Obstetricians an Gynecologists (2013, 2020) escribes our types o hypertensive isease:
1. Preeclampsia an eclampsia synrome
2. Chronic hypertension o any etiology
3. Preeclampsia superimpose on chronic hypertension
4. Gestational hypertension, in which enitive evience or the preeclampsia synrome oes not evelop an hypertension resolves by 12 weeks postpartum.
This classification aims to diferentiate preeclampsia syndrome, which is potentially more ominous, from other hypertensive disorders.
■ Diagnosis of Hypertensive Disorders
Hypertension is diagnosed empirically when systolic and diastolic blood pressures exceed 140 mm Hg and 90 mm Hg, respectively. Korotko phase V is use to ene iastolic pressure.
Previously or pregnant women, increases o 30 mm Hg systolic or 15 mm Hg iastolic above bloo pressure values taken at mipregnancy ha also been use as iagnostic criteria, even when absolute values were <140/90 mm Hg.
These incremental changes are no longer use to ene hypertension. However, bloo pressure surveillance in these gravias is reasonable because eclamptic seizures evelop in some whose bloo pressures have staye below 140/90 mm Hg (Alexaner, 2006).
In other cases, mean arterial pressures that suenly rise but that still lie in normal range—“elta hypertension”— may signiy preeclampsia (Maconal-Wallis, 2012; Zeeman, 2007). We use this term to escribe a relatively acute rise in bloo pressure in iniviual patients, albeit some still with pressures <140/90 mm Hg (Fig. 40-1). Some o these women will go on to have obvious preeclampsia, an some even evelop eclamptic seizures or hemolysis, elevate liver enzyme levels, an low platelet count (HELLP) synrome.
Historically, systolic an iastolic bloo pressure levels o 140/90 mm Hg have been arbitrarily use since the 1950s to ene “hypertension” in nonpregnant iniviuals. However, these levels were selecte by insurance companies to characterize a population o mile-age men. It seems more realistic to ene normal-range bloo pressures or specic populations— such as young, healthy, pregnant women (Lu, 2019; Rey, 2020). o provie such ata, >1000 women were recently stuie longituinally through pregnancy (Green, 2020). Data o this type may shape uture threshols.
■ Gestational Hypertension
Women with gestational hypertension have bloo pressures that reach 140/90 mm Hg or greater or the rst time ater mipregnancy but lack proteinuria. Almost hal o aecte women subsequently evelop preeclampsia (Jim, 2017). Even so, when bloo pressure rises appreciably, it is angerous to both mother an etus to ignore this elevation only because proteinuria has not yet evelope (Fishel Bartal, 2020). As
Chesley (1985) emphasize, 10 percent o eclamptic seizures evelop beore overt proteinuria can be etecte. Gestational hypertension is reclassie by some as transient hypertension i preeclampsia oes not evelop an bloo pressure returns to normal by 12 weeks postpartum.
■ Preeclampsia Syndrome
Preeclampsia is best described as a pregnancy-specic syndrome that can aect virtually every organ system. Although preeclampsia is more than simply gestational hypertension with proteinuria, the appearance o protein remains a primary iagnostic criterion. It is an objective marker an reects the system-wie enothelial leak that characterizes the preeclampsia synrome.
Last, preeclampsia can be ivie into early onset, <34 weeks; late onset, ≥34 weeks; preterm onset, <37 weeks; an term onset, ≥37 weeks (Burton, 2019; Poon, 2019). In some women with preeclampsia, neither overt proteinuria nor etal-growth restriction are eatures (Sibai, 2009).
Because o this, the ask Force (2013) suggests other iagnostic criteria, some o which are shown in Table 40-1. Multiorgan involvement may be reecte by thrombocytopenia, renal ys- unction, hepatocellular necrosis, central nervous system perturbations, or pulmonary eema.
Te markers liste in able 40-1 help also to classiy preeclampsia synrome severity. Although many use a ichotomous “mil” an “severe” classication, the ask Force (2013) iscourages the use o “mil preeclampsia.” It is problematic that there are criteria or the iagnosis o “severe” preeclampsia, but the binary eault classication is either implie or specically terme “mil,” “less severe,” or “nonsevere” (Alexaner, 2003; Linheimer, 2008). No consensus criteria ene “moerate” preeclampsia, which is an elusive thir category.
We use the criteria recommene by the American College o Obstetricians an Gynecologists (2020), some o which are liste in Table 40-2 an categorize isease as “severe” versus “nonsevere.”
Some symptoms are consiere ominous. Headaches or visual disturbances can precee eclampsia, which is a convulsion in a woman with preeclampsia that is not attributable to another cause. Te seizures are generalize an may appear beore, uring, or ater labor. Te proportion that evelops seizures later—ater 48 hours postpartum—approximates 10 percent (Sibai, 2005; Zwart, 2008). Another symptom, epigastric or right upper quadrant pain, requently accompanies hepatocellular necrosis, ischemia, an hepatic eema. Elevate serum hepatic transaminase levels can be one marker.
Last, thrombocytopenia also signies worsening preeclampsia. It represents platelet activation an aggregation an microangiopathic hemolysis. Other actors inicative o severe preeclampsia inclue renal or cariac involvement. When these signs an symptoms are prooun, they likely cannot be temporize, an elivery will more likely be require.
Importantly, ierentiating nonsevere an severe gestational hypertension or preeclampsia can be misleaing because what might be apparently mil isease may progress rapily to severe isease.
■ Preeclampsia Superimposed on Chronic
Hypertension
Any chronic hypertensive isorer preisposes a woman to evelop superimpose preeclampsia synrome. Chronic unerlying hypertension is iagnose in women with ocumente bloo pressures ≥140/90 mm Hg beore pregnancy or beore 20 weeks’ gestation, or both. Tus, in women who are not rst seen until ater mipregnancy, hypertensive isorers can be icult to classiy. For example, a woman with previously uniagnose chronic vascular isease who is seen beore 20 weeks requently has bloo pressures within normal range. During the thir trimester, however, as bloo pressures return to their originally hypertensive levels, it may be i- cult to etermine whether hypertension is chronic or inuce by pregnancy. Even a careul search or evience o preexisting en-organ amage may be utile, as many o these women have mil isease an no evience o ventricular hypertrophy, retinal vascular changes, or renal involvement.
In 20 to 50 percent o women with chronic hypertension, bloo pressure rises to obviously abnormal levels, typically ater 24 weeks’ gestation. I new-onset or worsening baseline hypertension is accompanie by new-onset proteinuria or other nings liste in able 40-1, superimpose preeclampsia is iagnose (American College o Obstetricians an Gynecologists, 2019a). Compare with “pure” preeclampsia, superimpose preeclampsia commonly evelops earlier in pregnancy. It tens to be more severe an more oten is accompanie by etalgrowth restriction. Te same criteria shown in able 40-2 also urther characterize the severity o superimpose preeclampsia.
INCIDENCE AND RISK FACTORS
Preeclampsia is ientie in 5 to 8 percent o all pregnancies (Jim, 2017; Poon, 2019). Young an nulliparous women are particularly vulnerable, whereas oler women are at greater risk or chronic hypertension with superimpose preeclampsia (Sheen, 2020). In one review o global stuies, the incience o preeclampsia in nulliparas range rom 3 to 10 percent (Sta, 2015). In multiparas, the incience ranges rom 2 to 5 percent (Jim, 2017; Poon, 2019).
Te incience o preeclampsia is also inuence by race, ethnicity, an genetic preisposition. In one stuy by the Maternal–Fetal Meicine Units (MFMU) Network, the incience o preeclampsia was 5 percent in white, 9 percent in Hispanic, an 11 percent in Arican American nulliparas (Myatt, 2012a,b). In aition, black women carry higher risk or associate severe averse outcomes (Gyam-Bannerman, 2020).
For several clinical actors, Bartsch an associates (2016) extracte ata rom more than 25 million pregnancies an calculate relative risks (Table 40-3). Major risks inclue oler age, nulliparity, obesity, iabetes, an chronic hypertension. Another is preeclampsia an especially HELLP synrome in a prior pregnancy (Malström, 2020). Unerlying metabolic syn- rome, hyperhomocysteinemia, or chronic kiney isease are others (Masouian, 2016; Wiles, 2020).
O lesser actors, human immunoeciency virus (HIV) seropositivity, sleep-isorere breathing, an a male etus pose a slightly higher risk (Facco, 2017; Jaskolka, 2017; Sansone, 2016). Previously aecte amily members are another, an maternal an etal genetics are assuming greater preictive importance (Burton, 2019; Gray, 2018; Phipps, 2019). Last, preeclampsia requently complicates the “mirror synrome” (Chap. 18, p. 364) (ra, 2021). Although smoking uring pregnancy causes various averse pregnancy outcomes, ironically, it lowers the risk or hypertension uring pregnancy.
For eclampsia, seizure incience has ecline in areas where health care is more reaily available. In countries with aequate resources, the incience averages 1 case in 2000 to 3000 eliveries (Jaatinen, 2016; O’Connor, 2013; Schaap, 2019). At Parklan Hospital, the incience has ecline appreciably uring the past ecae an approximates 1 case in 2000 births (Fig. 40-2).
Tis requency may be relate to improve access to prenatal care an our active management approach (Chap. 41, p. 717).
ETIOPATHOGENESIS
Te mechanisms by which pregnancy incites or aggravates hypertension remain unsolve. Any satisactory theory concerning the origins o preeclampsia must account or the observation that gestational hypertensive isorers are more likely to evelop in women with the ollowing characteristics:
• Exposure to chorionic villi for the rst time
• Exposure to a superabundance of chorionic villi, as with twins or hyatiiorm mole
• Preexisting conditions associated with endothelial cell activation or inammation
• Genetic predisposition to hypertension developing during pregnancy.
A etus is not a requisite or preeclampsia to evelop. Although chorionic villi are essential, they nee not be intrauterine. For example, preeclampsia can evelop with an avance abominal pregnancy (Worley, 2008). Regarless o precipitating etiology, the cascae o promoting events leas to systemic vascular enothelial amage, vasospasm, plasma transuation, an ischemic an thrombotic sequelae.
■ Phenotypic Expression
Tis varies wiely or preeclampsia, an phenotype is aecte by the egree o remoeling o uterine spiral arterioles by enovascular trophoblasts. Tis process unerlies the “twostage isorer” theory o preeclampsia pathogenesis. Accor-
ing to Reman an coworkers (2015), stage I—the placental
synrome—is cause by aulty enovascular trophoblastic
remoeling that ownstream causes stage II—the maternal
synrome. Importantly, stage II can be moie by maternal conitions that also maniest enothelial cell activation
or inammation. Tese inclue chronic hypertension, renal
isease, obesity, immunological or connective tissue isorers,
an iabetes.
Such staging is articial, an preeclampsia synrome presents a spectrum o isease (Burton, 2019). Moreover, “iso-
orms” likely exist an are iscusse subsequently. Dierences
inclue maternal an etal characteristics, placental nings,
genetic actors, an early- versus late-onset isease (Gray, 2018;
Phipps, 2019; Poon, 2019).
■ Etiology
O suggeste mechanisms to explain the cause o preeclampsia,
primary ones inclue:
• Placental implantation with abnormal trophoblastic invasion
o uterine vessels
• Dysfunctional immunological tolerance between maternal,
paternal (placental), an etal tissues
Maternal maladaptation to cardiovascular or inammatory
changes o normal pregnancy
• Genetic factors that include predisposing genes and epigenetic inuences.
■ Stage I—Placental Syndrome
Normal placental implantation, as iscusse in Chapter 5 (p.
90), is characterize by extensive remoeling o the spiral arterioles within the eciua basalis (Fig. 40-3). In this “placental
be,” enovascular trophoblasts replace the vascular enothelial an muscular linings. Tis avantageously enlarges arteriole
iameter (Brosens, 2019). Veins are invae only supercially.
In some preeclampsia cases, but not all, trophoblastic invasion
may be incomplete. With this, eciual vessels, but not myometrial vessels, become line with enovascular trophoblasts.
Te eeper myometrial arterioles thus o not lose their enothelial lining an musculoelastic tissue. As a result, their mean
external iameter is only hal that o corresponing vessels in
normal placentas (Fisher, 2015). Tis mechanism is more prevalent in women with early-onset preeclampsia (Khozhaeva,
2016). Evience suggests a critical role or soluble antiangiogenic growth actors in this aulty enovascular remoeling
(McMahon, 2014).
From placental electron microscopy stuies, early preeclamptic changes inclue enothelial amage, insuation o plasma
constituents into vessel walls, myointimal cell prolieration, an
meial necrosis (De Wol, 1980). Hertig (1945) reerre to lipi
accumulation in myointimal cells an macrophages as atherosis. Tese nings are more common in placentas rom women
iagnose with preeclampsia beore 34 weeks’ gestation (Nelson, 2014). Acute placental vascular atherosis may also ientiy a
group o women at greater risk or atherosclerosis an cariovascular isease later in lie (Sta, 2015) (Chap. 41, p. 726). In pregnancy, abnormally narrow spiral arteriole lumens likely impair
placental bloo ow, reuce perusion, an create a hypoxic
environment (Burton, 2019).
At this point, these changes incite a systemic inammatory
response, which is stage II or the maternal synrome. Deective
placentation is posite to urther preispose aecte women
to gestational hypertension, preeclampsia synrome, preterm
elivery, etal growth-restriction, an placental abruption (Brosens, 2019; Labarrere, 2017; Nelson, 2014).
Immunological Factors
Maternal immune tolerance to paternally erive placental an
etal antigens is iscusse in Chapter 5 (p. 85). Loss o this tolerance is another cite theory or preeclampsia (Erlebacher, 2013).
Certainly, histological changes at the maternal–placental inter-
ace in those with preeclampsia suggest acute grat rejection.
olerance ysregulation might also explain the elevate risk
when the paternal antigenic loa is increase. One example is
complete molar pregnancies, which have iploi complement
o chromosomes solely rom the ather. Tose with later-stage
moles, have a high incience o early-onset preeclampsia.
Women with a trisomy 13 etus also have a 30- to 40-percent
incience o preeclampsia. Te gene or one preeclampsia-linke
actor, soluble ms-like tyrosine kinase 1, is on chromosome 13
(Bolah, 2006). Tese women have elevate serum levels o
antiangiogenic actors, which can aect the placenta (p. 694).
Last, women previously expose to paternal antigens, such as
a prior pregnancy with the same partner, may be “immunize”
against preeclampsia. Conversely, multiparas impregnate by a
new partner have a greater risk o preeclampsia (Mostello, 2002).
Burton an colleagues (2019) reviewe the possible role
o immune malaaptation in preeclampsia pathophysiology.
In women estine to have preeclampsia, extravillous trophoblasts early in pregnancy express reuce amounts o immunosuppressive nonclassic human leukocyte antigen G (HLA-G).
Black women more commonly have the 1597∆C gene allele,
which is associate with incomplete HLA-G expression an
may preispose to preeclampsia (Loisel, 2013). Tis immune
malaaptation may contribute to the eective placental vascularization seen with preeclampsia.
As iscusse in Chapter 4 (p. 61), -helper (T) lymphocytes uring normal pregnancy are prouce so that type 2
activity is increase in relation to type 1. Tis is the so-calle
type 2 bias (Phipps, 2019; Reman, 2015). T2 cells promote
humoral immunity, whereas T1 cells stimulate inammatory
cytokine secretion (Ma, 2019). Beginning in the early secon
trimester in women who evelop preeclampsia, T1 action is
increase.
Genetic Factors
Preeclampsia appears to be a multiactorial, polygenic isorer.
In one stuy o almost 1.2 million Sweish births, a genetic
association was oun or gestational hypertension an or preeclampsia (Nilsson, 2004). War an aylor (2015) cite an
incient risk or preeclampsia o 20 to 40 percent or aughters
o preeclamptic mothers; 11 to 37 percent or sisters o preeclamptic women; an 22 to 47 percent or twins. Ethnoracial
actors are important an evience by the high incience o
preeclampsia in Arican American women. Latina women have
a lower incience because o interactions o American Inian
an white race genes (Shahabi, 2013).
Te hereitary preisposition or preeclampsia likely stems
rom interactions o literally hunres o inherite genes—both
maternal an paternal—that control many enzymatic an metabolic unctions throughout every organ system (Burton, 2019;
riche, 2014). Plasma-erive actors may inuce some o these
genes in preeclampsia (Leseva, 2020; Mackenzie, 2012). Tus, the
clinical maniestation in any given woman with the preeclampsia synrome will reect a spectrum. In this regar, phenotypic
expression will ier among similar genotypes epening on
interactions with environmental components (Yang, 2013).
Hunres o genes have been stuie or their possible association with preeclampsia (Buurma, 2013; Sakowicz, 2016;
War, 2015). However, because o the complex phenotypic
expression o preeclampsia, it is oubtul that any one cani-
ate gene will be oun responsible. Last, a preeclampsia pre-
isposition has also been linke to genes o the etus (Burton,
2019; Gray, 2018; Leseva, 2020).
■ Stage II—Maternal Syndrome
Endothelial Cell Activation
Inammatory changes are believe to be a continuation o the
placental synrome. In response to ischemia or other inciting causes, placental actors are release an initiate a series
o events (Burton, 2019; Davige, 2015). Tus, antiangiogenic an metabolic actors an other inammatory leukocyte
meiators are thought to provoke the systemic endotheliopathy,
which is use synonymously here with endothelial cell activation or dysunction. Injury to systemic enothelial cells is seen
as a centerpiece o preeclampsia pathogenesis (Burton, 2019;
Phipps, 2019).
Cellular ysunction may result rom an extreme activate
state o leukocytes in the maternal circulation (Gervasi, 2001).
Briey, cytokines such as tumor necrosis actor α (NF-α) an
the interleukins may contribute to the systemic oxiative stress
associate with preeclampsia. Tis is characterize by generation o highly toxic oxygen raicals. Tese injure systemic vascular enothelial cells, lower nitric oxie prouction by these
cells, an interere with prostaglanin balance. Other sequelae
inclue prouction o the lipi-laen macrophage oam cells
seen in placental atherosis; activation o systemic microvascular coagulation, which is manieste by thrombocytopenia; an
greater systemic capillary permeability, which is reecte by
eema an proteinuria.
Intact enothelium has anticoagulant properties. Also, systemic enothelial cells, by releasing nitric oxie, blunt the response
o vascular smooth muscle to agonists. Injure or activate
enothelial cells may prouce less nitric oxie an may secrete
substances that promote coagulation an vasopressor sensitivity.
Further evience o enothelial activation inclues changes in
glomerular capillary enothelial morphology, greater capillary
permeability, an elevate bloo concentrations o substances
associate with enothelial activations. Likely, multiple actors
in the plasma o preeclamptic women combine to exert these
vasoactive eects (Myers, 2007; Walsh, 2009).
Vasospasm and Hypertension
Vasospasm has long been associate with preeclampsia. Systemic enothelial activation causes vasospasm, which elevates
resistance to prouce hypertension. Concurrently, systemic
enothelial cell injury promotes interstitial leakage, an platelets an brinogen are eposite in the subenothelial space.
Enothelial junctional proteins are also isrupte, an the subenothelial region o resistance arteries unergoes ultrastructural change (Suzuki, 2003; Wang, 2002). Te much larger
venous circuit is similarly involve.
With iminishe bloo ow because o malistribution
rom vasospasm an interstitial leakage, ischemia o the surrouning tissues can cause necrosis, hemorrhage, an other
en-organ isturbances. One important clinical correlate to
these changes is the markely attenuate bloo volume seen in
women with severe preeclampsia (Zeeman, 2009).
Increased Pressor Responses
As iscusse in Chapter 4 (p. 53), pregnant women normally evelop reractoriness to inuse vasopressors (AbulKarim, 1961). Women with early preeclampsia, however,
have enhance vascular reactivity to inuse norepinephrine
an angiotensin II (Raab, 1956; alleo, 1968). Moreover,
increase sensitivity to angiotensin II clearly precees the
onset o gestational hypertension (Gant, 1974). Paraoxically,
women who evelop preterm preeclampsia have lower circulating levels o angiotensin II (Chase, 2017).
Numerous prostaglandins are thought to be central to preeclampsia synrome pathophysiology. Specically, the blunte
pressor response seen in normal pregnancy is at least partially
ue to iminishe vascular responsiveness meiate by enothelial prostaglanin synthesis. For example, compare with
normal pregnancy, enothelial prostacyclin (PGI2) prouction
is lower in preeclampsia. Tis action appears to be meiate by
phospholipase A2 (Davige, 2015). At the same time, thromboxane A2 secretion by platelets is increase, an the prostacyclin: thromboxane A2 ratio eclines. Te net result avors
greater sensitivity to inuse angiotensin II an vasoconstriction (Spitz, 1988). Tese changes appear as early as 22 weeks
in gravias who later evelop preeclampsia (Chavarria, 2003).
Nitric oxide is a potent vasoilator an is synthesize rom
1-arginine by enothelial cells. Inhibition o nitric oxie synthesis raises mean arterial pressure, lowers heart rate, an reverses
the pregnancy-inuce reractoriness to vasopressors. Nitric
oxie likely is the compoun that maintains the normal lowpressure vasoilate state characteristic o normal etoplacental
perusion (Myatt, 1992). Nitric oxie meiates the eects o
placental growth actor (PlGF) an vascular enothelial growth
actor (VEGF) in vitro (Zhang, 2017). Te eects o nitric
oxie prouction in preeclampsia are unclear. It appears that
the synrome is associate with ecrease enothelial nitric
oxie synthase expression an thus lower nitric oxie activity
(Davige, 2015).
Endothelins are 21-amino-aci pepties an potent vasoconstrictors. Enothelin l (E-1) is the primary isoorm prouce
by human enothelium (Karumanchi, 2016a). Plasma E-1
levels are elevate in normotensive pregnant women. Women
with preeclampsia have even higher levels, an these pepties
may meiate renal injury (Phipps, 2019). Woman with preeclampsia evelop unctional autoantiboies to the enothelin
an angiotensin II receptors (Buttrup, 2018). Interestingly,
treatment o preeclamptic women with magnesium sulate
lowers E-1 concentrations (Sagsoz, 2003). In animal stuies,
silenal reuces E-1 concentrations (Gillis, 2016).
Angiogenic and Antiangiogenic Factors
Placental vasculogenesis is evient by 21 ays ater conception. Te list o pro- an antiangiogenic substances involve
in placental vascular evelopment is extensive, an the VEGF
an angiopoietin amilies are the most stuie. Angiogenic
imbalance escribes excessive amounts o antiangiogenic actors, which are thought to be stimulate by worsening hypoxia
at the uteroplacental interace. rophoblast o women estine
to evelop preeclampsia overprouce at least two antiangiogenic pepties that enter the
maternal circulation (Karumanchi, 2016b).
First, soluble ms-like tyrosine
kinase 1 (sF1t-1) is a soluble
variant o the membrane-boun
receptor or VEGF. As epicte
in Figure 40-4, elevate maternal sFlt-1 levels inactivate an re-
uce circulating PlGF an VEGF
concentrations, leaing to enot helial ysunction (Phipps, 2019).
As shown in ata rom Myatt
an coworkers (2013), sFlt-1 levels
begin to rise in maternal serum
months beore preeclampsia is
evient (Fig. 40-5). Tese high
levels in the secon trimester are associate with a much higher
risk or preeclampsia evelopment (Haggerty, 2012; March,
2015). Tis elevation rom normal levels appears even sooner
with early-onset isease (Vatten, 2012). Tese actors are also
operative in pregnancies complicate by etal-growth restriction (Herraiz, 2012).
A secon antiangiogenic peptie, soluble endoglin (sEng),
inhibits various transorming growth actor beta (GF-β) iso-
orms rom bining to enothelial receptors (see Fig. 40-4).
Enoglin is one o these receptors. Decrease bining to enoglin iminishes enothelial nitric oxie-epenent vasoilation. Serum levels o sEng also begin to rise months beore
clinical preeclampsia evelops (Haggerty, 2012).
Simultaneously elevate levels o sFlt-1 an sEng are associate with more severe orms o preeclampsia (Phipps, 2019).
In one systematic review, thir-trimester increases in sFlt-1
levels an lower PlGF concentrations were oun to correlate with preeclampsia evelopment ater 25 weeks’ gestation
(Wimer, 2007). From another stuy, oubling o sFlt-1 an
sEng expression increase the preeclampsia risk by 39 an 74
percent, respectively (Haggerty, 2012). Te cause o placental
overprouction o antiangiogenic proteins remains an enigma.
Concentrations o the soluble orms are not higher in etal circulation or amnionic ui o preeclamptic women, an their
levels in maternal bloo issipate ater elivery (Sta, 2007).
Clinical use o antiangiogenic protein levels to preict an
iagnosis preeclampsia is being evaluate (p. 703). Moreover,
one preliminary report escribe therapeutic apheresis to
reuce sFlt-1 levels (Tahani, 2016).
PATHOPHYSIOLOGY
■ Cardiovascular System
Disturbances in the cariovascular system are common with
preeclampsia synrome. Tese are relate to: (1) greater cariac
aterloa impose by hypertension; (2) cariac preloa, which
is reuce by a pathologically iminishe volume expansion
uring pregnancy an which is increase by aministration o
intravenous crystalloi or oncotic solutions; an (3) enothelial
activation leaing to leakage o intravascular ui into the extracellular space.
Hemodynamic Changes and Cardiac Function
Te cariovascular aberrations o pregnancy-relate hypertensive isorers vary. Moiying actors inclue preeclampsia
severity, egree o hypertension, presence o unerlying chronic
isease, an the point in the clinical spectrum in which these are
stuie. In some women, these cariovascular changes may precee hypertension (Easterling, 1990; Khalil, 2012; Melchiorre,
2013). Nevertheless, with the clinical onset o preeclampsia,
cariac output eclines, ue at least in part to greater peripheral
resistance (Ferrazzi, 2018).
Myocardial Function
Serial echocariographic stuies ocument iastolic ysunction in up to 45 percent o women with preeclampsia (Guirguis,
2015; Vaught, 2018). With this ysunction, ventricles o not
properly relax an cannot ll appropriately. In some aecte
women, unctional ierences persist up to 4 years ater elivery
(Evans, 2011; Orabona, 2017). Diastolic ysunction stems
rom ventricular remoeling, which is a malaaptive response to
the increase aterloa o preeclampsia an aims to maintain normal contractility. High levels o antiangiogenic proteins may be
contributory (Shahul, 2016). In otherwise healthy gravias, these
changes are usually inconsequential. But in those with unerlying ventricular ysunction—or example, concentric ventricular
hypertrophy rom chronic hypertension—urther iastolic ys-
unction may cause cariogenic pulmonary eema (Warhana,
2018). Tis is iscusse urther in Chapters 50 (p. 883) an 52
(p. 916).
Ventricular Function
Despite the relatively high requency o iastolic ysunction
with preeclampsia, clinical cariac unction in most aecte
women is appropriate (Hibbar, 2015). In some preeclamptic women, high-sensitivity cariac troponin levels are slightly
elevate (Morton, 2018). With severe preeclampsia, aminoterminal pro–brain natriuretic peptie (N–pro-BNP) levels
are increase (Zachary, 2017).
Women with preeclampsia synrome usually have slightly
hyperynamic ventricular unction (Fig. 40-6). Both these an
normotensive pregnant women have a cariac output that is
appropriate or let-sie lling pressures. Tis pressure can be
altere by intravenous ui volumes. Tus, aggressive hyration results in overtly hyperdynamic ventricular unction. Tis is
accompanie by elevate pulmonary capillary wege pressures,
an pulmonary eema may evelop espite normal ventricular
unction. Tis is partly because o an alveolar enothelial-epithelial leak, an it is compoune by ecrease oncotic pressure
rom a low serum albumin concentration. In sum, aggressive
ui aministration to otherwise normal women with severe
preeclampsia substantially elevates normal let-sie lling
pressures an raises a physiologically normal cariac output to
hyperynamic levels.
■ Blood Volume
In those with eclampsia, hemoconcentration is a hallmark eature
(Pritchar, 1984). Data rom Zeeman an associates (2009)
show that normally expecte pregnancy bloo volume expansion is severely curtaile (Fig. 40-7). Women o average size have
a nonpregnant bloo volume o 3000 mL, an uring the last
several weeks o a normal pregnancy, this averages 4500 mL
(Chap. 4, p. 59). With eclampsia, however, much or all o the
anticipate 1500 mL excess is lost. Such hemoconcentration
results rom generalize vasospasm that ollows enothelial activation an then rom leakage o plasma into the interstitial
space. In women with preeclampsia—epening on its severity—hemoconcentration is usually not as marke.
Tese changes have substantial clinical consequences. Women
with severe hemoconcentration are unuly sensitive to bloo loss
at elivery that otherwise may be consiere normal. Vasospasm
an enothelial leakage o plasma persist or a variable time ater
elivery as the enothelium is restore to normal. As this takes
place, vasoconstriction reverses, an as the bloo volume reexpans, the hematocrit usually alls rom ilution. Importantly, a
substantive cause o this all in hematocrit requently is the blood loss
incurred at delivery.
■ Hematological Changes
Thrombocytopenia
Te platelet count is routinely measure in women with any
orm o gestational hypertension. Te requency an intensity
o thrombocytopenia vary an are epenent on the severity an uration o preeclampsia (Hellmann, 2007; Hupuczi,
2007). Overt thrombocytopenia—ene by a platelet count
<100,000/µL—reects severe isease (see able 40-2). In general, the lower the platelet count, the higher the likelihoo o
maternal an etal morbiity an mortality. In most cases, elivery is avisable because thrombocytopenia usually worsens.
Ater elivery, the platelet count may continue to ecline or
the rst ay or so. It then usually rises progressively to reach
a normal level within 3 to 5 ays. As iscusse later, in some
instances with HELLP synrome, the platelet count continues to all ater elivery. I this nair is elaye until 48 to 72
hours, preeclampsia synrome may be incorrectly attribute to
one o the thrombotic microangiopathies (Chap. 59, p. 1060).
Another platelet alteration is platelet activation an increase
α-egranulation. Tis leas to release o β-thromboglobulin
an actor 4 an to enhance platelet clearance (Kenny, 2015).
Platelet volume concomitantly increases as young platelets
are release (Bellos, 2018). Paraoxically, in most stuies, in
vitro platelet aggregation is reuce compare with the normal
increase that is characteristic o pregnancy. Tis likely is ue to
platelet “exhaustion” ollowing in-vivo activation. Although the
cause is unknown, immunological processes or simply platelet
eposition at sites o enothelial amage may be implicate.
Levels o platelet-boun an circulating platelet-binable
immunoglobulins are elevate, which suggests platelet surace
alterations. Abnormally low platelet levels o not evelop in
the etuses o women with preeclampsia espite severe maternal thrombocytopenia (Kenny, 2015; Pritchar, 1987). Tus,
thrombocytopenia in a hypertensive woman is not a etal inication or cesarean elivery.
Hemolysis
Severe preeclampsia is requently accompanie by hemolysis,
which maniests as elevate serum lactate ehyrogenase levels
an reuce haptoglobin levels (Burwick, 2018). Other evi-
ence comes rom schizocytosis, spherocytosis, an reticulocytosis in peripheral bloo (Cunningham, 1985; Pritchar, 1954,
1976). Re cell istribution with (RDW) reects variability
in the size o circulating re bloo cells, an RDW is higher
in preeclamptic women (Aam, 2019). Tese erangements
result in part rom microangiopathic hemolysis cause by enothelial isruption with platelet aherence an brin eposition.
Cunningham an coworkers (1995) postulate that erythrocyte morphological changes were partially cause by serum
lipi alterations. Relate, substantively ecrease long-chain
atty aci content is oun in erythrocytes o women with preeclampsia (Mackay, 2012).
Ater early reports o hemolysis an thrombocytopenia with
severe preeclampsia, escriptions were ae o abnormally
elevate serum liver transaminase levels that inicate hepatocellular necrosis (Chesley, 1978). Weinstein (1982) reerre to
this combination o events as the HELLP syndrome (p. 699).
Coagulation Changes
Subtle changes consistent with intravascular coagulation commonly are oun with preeclampsia an eclampsia (Cunningham,
2015; von Daelszen, 2018). Some inclue elevate actor VIII
consumption, increase levels o brinopepties A an B an o
d-imers, an reuce concentrations o the regulatory proteins—
antithrombin III an proteins C an S. Coagulation aberrations
generally are mil an selom clinically signicant (Kenny,
2015; Pritchar, 1984). Unless placental abruption is comorbi,
plasma brinogen levels o not ier remarkably rom levels
oun in normal pregnancy (Cunningham, 2015). As preeclampsia worsens, so o abnormal nings with thromboelastography,
which is escribe in Chapter 44 (p. 774) (Pisani-Conway,
2013). Despite these changes, routine laboratory assessments o
coagulation, such as prothrombin time (P), activate partial
thromboplastin time (aP), an plasma brinogen level, are
not require in the management o pregnancy-associate hypertensive isorers.
■ Endocrine and Hormonal Alterations
Plasma levels o renin, angiotensin II, aldosterone, deoxycorticosterone, an atrial natriuretic peptide (ANP) are substantively
augmente uring normal pregnancy. ANP is release uring atrial wall stretching rom bloo volume expansion, an it
respons to cariac contractility (Chap. 4, p. 65). Serum ANP
levels rise in pregnancy, an its secretion is urther enhance
in preeclampsia (Gu, 2018). Levels o its precursor—proatrial
natriuretic peptide—also are elevate in preeclampsia. Vasopressin
levels are similar in nonpregnant, in normally pregnant, an
in preeclamptic women, although its metabolic clearance is
elevate in the latter two (Dürr, 1999).
■ Fluid and Electrolyte Alterations
In women with severe preeclampsia, the volume o extracellular
fuid, which maniests as eema, is usually much greater than
that in normal pregnant women. Te mechanism responsible
or pathological ui retention is enothelial injury an subsequent extravasation o intravascular ui. Aecte women also
have reuce plasma oncotic pressure. Tis urther isplaces
intravascular ui into the surrouning interstitium. In women
with preeclampsia, electrolyte concentrations o not ier
appreciably rom those o normal pregnant women.
Following an eclamptic convulsion, the serum pH an
bicarbonate concentration are lowere ue to lactic aciosis an
compensatory respiratory loss o carbon ioxie. Te intensity
o aciosis relates to the amount o lactic aci prouce—
metabolic aciosis—an the rate at which carbon ioxie is
exhale—respiratory aciosis.
■ Kidney
During normal pregnancy, renal bloo ow an glomerular
ltration rate (GFR) rise appreciably (Chap. 4, p. 68). With
preeclampsia, several reversible physiological changes ensue.
O clinical importance, renal perusion an GFR are slightly
reuce. Most o the ecrement in GFR is rom increase renal
aerent arteriolar resistance that may be elevate up to veol
(Conra, 2015; Cornelis, 2011).
Morphological changes are characterize by glomerular endotheliosis, which blocks ltration (Phipps, 2019). Diminishe
ltration causes serum creatinine levels to rise to values seen
in nonpregnant iniviuals, that is, 1 mg/mL, an sometimes
higher. Acute kiney injury is iscusse subsequently.
Plasma uric aci concentration is typically elevate in preeclampsia. Te elevation excees that attributable to the reuce
GFR an likely is also ue to enhance tubular reabsorption
(Chesley, 1945). At the same time, preeclampsia is associate
with iminishe urinary excretion o calcium, perhaps because
o greater tubular reabsorption (auel, 1987).
Proteinuria
Detection o proteinuria helps to establish the iagnosis o
preeclampsia (see able 40-1). Abnormal protein excretion
is empirically ene by 24-hour urinary excretion exceeing
300 mg; a spot urine protein: creatinine ratio ≥0.3; or persistent protein values o 30 mg/L (1+ ipstick) in ranom urine
samples. Although worsening or nephrotic-range proteinuria
was in the past consiere by most to be a sign o severe isease, this oes not appear to be the case (American College o
Obstetricians an Gynecologists, 2013; Bartal, 2020).
Problematically, the optimal metho o establishing abnormal levels o either urine protein or albumin remains to be
ene. For a 24-hour quantitative specimen, the consensus threshol value is ≥300 mg/24 h (American College o
Obstetricians an Gynecologists, 2013; Bartal, 2020). Using
a urinary protein excretion threshol o 165 mg in a 12-hour
sample shows equivalent ecacy (Stout, 2015).
Determination o urinary protein: creatinine ratio may supplant the cumbersome 24-hour quantication (Morris, 2012).
In one systematic review, ranom urine protein:creatinine
ratios <130 to 150 mg/g, that is, 0.13 to 0.15, inicate a
low likelihoo o proteinuria exceeing 300 mg/ (Papanna,
2008). Ratios <0.08 or >1.19 have negative an positive pre-
ictive values o 86 an 96 percent, respectively (Stout, 2013).
However, mirange ratios, or example, 300 mg/g or 0.3, have
poor sensitivity an specicity. Any mirange ratio shoul be
repeate, an i persistent, a 24-hour urine collection or measurement o protein excretion shoul be consiere.
With urine ipstick assessment, results epen on urine
concentration an are notorious or alse-positive an -negative results. A concentrate urine specimen may show a ipstick
value o 1+ to 2+ in women who actually excrete <300 mg/.
Importantly, proteinuria may evelop late, an some women
may alreay be elivere or have ha an eclamptic convulsion
beore it appears. At presentation, 10 to 15 percent o women
with HELLP synrome o not have proteinuria (Sibai, 2004).
In another report, 17 percent o women with eclampsia i not
have proteinuria by the time o seizures (Zwart, 2008).
Anatomical Changes
Sheehan an Lynch (1973) requently oun microscopic
changes that were ientie at autopsy in the kineys o
eclamptic women. Glomeruli are enlarge by approximately 20
percent, they are “blooless,” an capillary loops variably are
ilate an contracte. Enothelial cells are swollen—terme
glomerular capillary endotheliosis (Spargo, 1959). Such swelling
may be severe enough to block or partially block the capillary
lumens (Fig. 40-8). Last, homogeneous subenothelial eposits
o proteins an brin-like material are seen (Hecht, 2017).
Enothelial swelling may result rom angiogenic protein
“withrawal.” Tis is cause by the complexing o ree angiogenic proteins with a compatible circulating antiangiogenic
protein receptor (see Fig. 40-4). Te angiogenic proteins are
crucial or poocyte health, an their inactivation leas to
poocyte ysunction an enothelial swelling (Conra, 2015;
Phipps, 2019). Eclampsia is characterize by greater excretion
o these epithelial poocytes (White, 2014).
Acute Kidney Injury
In one stuy, preeclampsia synrome cause acute kiney injury
(AKI) in 5 percent o patients an in 14 percent o those with
HELLP synrome (Novotny, 2020). With severe preeclampsia,
Roriguez an colleagues (2021) reporte AKI in 15 percent
o women in a stuy rom Parklan Hospital. In most, AKI
was stage 1. In another stuy o 72 women with preeclampsia an renal ailure, hal ha HELLP synrome, an a thir
ha placental abruption (Drakeley, 2002). In a review o 183
women with HELLP synrome, 5 percent ha AKI (Haa,
2000). O those with renal injury, hal ha placental abruption, an most ha postpartum hemorrhage. Abnormal renal
values usually begin to normalize 10 ays or later ater elivery
(Cornelis, 2011; Spaan, 2012). Although mil egrees o AKI
are encountere, clinically apparent acute tubular necrosis is
almost invariably inuce by comorbi hemorrhage an subsequent hypovolemia an hypotension (Chap. 43, p. 753).
o evaluate AKI etiology clinically, urine electrolytes may
be obtaine. Results with preeclampsia reect an intrarenal
cause. In most with preeclampsia, the urine soium concentration is elevate. Instea, changes that inicate a prerenal mechanism inclue increase urine osmolality, elevate urine: plasma
creatinine ratio, an low ractional excretion o soium.
In response to oliguria, soiumcontaining crystalloi temporarily improves urine output. However, rapi
inusions may cause clinically appar ent pulmonary eema (p. 695).
Intensive intravenous ui therapy
is not inicate as “treatment” or
women with preeclampsia an oliguria, unless urine output is iminishe
rom hemorrhage or ui loss rom
vomiting or ever. In nonpregnant iniviuals, intravenous saline inusions
have emonstrate a negative impact
on renal unction. However, at Parklan Hospital, transition rom Ringer
lactate to normal saline i not signi-
cantly impair renal unction in women
with preeclampsia (Yule, 2020).
■ Liver
Hepatic changes are common in
women with severe preeclampsia
synrome. Several gross an microscopic anatomical erangements lea to elevate serum hepatic transaminase levels. Tis
transaminitis inicates hepatocellular injury an is a marker or
severe preeclampsia. Values are selom more than 500 U/L,
but levels exceeing 2000 U/L have been reporte (Chap.
58, p. 1031). In general, serum concentrations inversely ollow
platelet levels, an they both usually return to normal levels
within 3 ays ater elivery.
Anatomical Changes
Regions o periportal hemorrhage in the liver periphery typiy the hepatic lesions o eclampsia (Hecht, 2017; Sheehan,
1973). Extensive involvement such as shown in Figure 40-9 is
unusual. Sheehan an Lynch (1973) escribe that some egree
o hepatic inarction accompanie hemorrhage in almost hal o
women who ie with eclampsia. Tese nings correspone
with reports uring the 1960s that escribe elevate serum
hepatic transaminase levels. Pritchar an associates (1954)
escribe hemolysis an thrombocytopenia with eclampsia.
Tis constellation o hemolysis, hepatocellular necrosis, an
thrombocytopenia was later terme HELLP synrome. Similarities with hepatic sinusoial obstruction are reviewe by von
Salmuth an coworkers (2020).
Liver involvement with preeclampsia may clinically isplay
several maniestations. First, pain is consiere a sign o severe
isease. It typically maniests as moerate to severe right upper
quarant or miepigastric pain an tenerness. Tese women
usually have elevate serum aspartate transaminase (AS) or
alanine transaminase (AL) levels. In some cases, however,
the amount o hepatic tissue involve with inarction may be
surprisingly extensive yet still clinically insignicant. o stuy
this, we perorme magnetic resonance (MR) imaging in 16
women with HELLP synrome (Nelson, 2018). All but two
ha evience o acute liver injury, an the volume o involvement correlate with serum AS levels. Frank inarction is
unusual, an in our experiences, it may be worsene or precipitate by hypotension rom obstetrical hemorrhage. It occasionally causes hepatic ailure—also calle shock liver (Morgan,
2019; Yoshihara, 2016).
Hepatic Hematoma
In another presentation, periportal hemorrhage an inarction
may exten to evelop a hepatic hematoma. Tis in turn can
exten to orm a subcapsular hematoma that may rupture.
Compute tomography (C) scanning or MR imaging greatly
ais iagnosis (Fig. 40-10). Unrupture hematomas are probably more common than clinically suspecte an are more likely
to be oun with HELLP synrome (Nelson, 2018). Although
FIGURE 40-10 Abdominal CT imaging performed postpartum in
a woman with severe HELLP syndrome and right-upper quadrant
pain. A large subcapsular hematoma (asterisk) is seen confluent
with intrahepatic infarction and hematoma (arrowhead). Numerous
flame-shaped hemorrhages are seen at the hematoma interface
(arrows).
once consiere a surgical conition, current management o
a hepatic hematoma is usually observation unless bleeing is
ongoing. In some cases, however, prompt surgical intervention
or angiographic embolization may be liesaving (Chanrasekaran, 2020). In one review o 180 cases o hepatic hematoma or
rupture, 94 percent o aecte gravias ha HELLP synrome,
an in 90 percent o the total, the capsule ha rupture (VigilDe Gracia, 2012). Te maternal mortality rate was 22 percent,
an the perinatal mortality rate was 31 percent. Another review
o 73 cases oun similar outcomes (Gupta, 2021). In rare
cases, liver transplantation is necessary (Escobar Viarte, 2019).
Acute atty liver o pregnancy is sometimes conuse with
preeclampsia (Byrne, 2020; Nelson, 2013). It too has an onset
in late pregnancy, an oten hypertension, elevate serum
transaminase an creatinine levels, an thrombocytopenia
are comorbi. In istinction, the hallmark o acute atty liver
is marke liver ysunction. Liver unction overall is usually
normal in HELLP synrome. able 58-1 (p. 1031) highlights
these clinical ierences.
No convincing ata link pancreatic involvement with preeclampsia synrome. In 407 women with severe preeclampsia, the incience was 1 percent (Sang, 2019). Tat sai, the
occasional case o concurrent hemorrhagic pancreatitis is likely
unrelate (Lynch, 2015). In our experiences rom Parklan
Hospital, lipase an amylase levels are selom elevate in
women with preeclampsia (Nelson, 2018).
HELLP Syndrome
Tis acronym stans or hemolysis, elevate liver enzyme levels, an low platelet count. No strict enition o the syn-
rome is universally accepte, an thus its reporte incience
varies.
In women with preeclampsia, those with HELLP synrome
typically have worse outcomes than those without it (Martin,
2012, 2013). In the previously note stuy o 183 women with
HELLP synrome, 40 percent ha averse outcomes, an two
mothers ie (Haa, 2000). Complications inclue eclampsia
in 6 percent, placental abruption—10 percent, AKI—5 percent,
an pulmonary eema—10 percent. Stroke, hepatic hematoma,
coagulopathy, acute respiratory istress synrome, an sepsis were
other complications. In one review o 693 women with HELLP
synrome, 10 percent ha concurrent eclampsia (Keiser, 2011).
Obstetrical outcomes also may suer. In one stuy comparing
women with HELLP against those with preeclampsia, rates o
eclampsia were greater with HELLP—15 versus 4 percent; preterm birth—93 versus 78 percent; an perinatal mortality—9 versus 4 percent, respectively (Sep, 2009). Because o these marke
clinical ierences, some postulate that HELLP synrome has a
istinct pathogenesis (Reimer, 2013; Vaught, 2016).
■ Central Nervous System
Heaaches an visual symptoms are common with severe preeclampsia, an associate convulsions ene eclampsia. Te
earliest anatomical escriptions o brain involvement came
rom autopsy specimens, but C an MR imaging an Doppler stuies have ae important insights.
Neuroanatomical Lesions
From early anatomical escriptions, brain pathology accounte or only approximately a thir o
atal cases, such as the one shown in Figure 40-11.
In act, most eaths were rom pulmonary eema,
an brain lesions were coinciental. Tus, although
gross intracerebral hemorrhage was seen in up to 60
percent o eclamptic women, it was atal in only hal
o these (Richars, 1988). With ata rom Sheehan
an Lynch (1973) shown in Figure 40-12, cortical an subcortical petechial hemorrhages are other
principal lesions oun at autopsy in women with
eclampsia. Te classic microscopic vascular lesions
consist o brinoi necrosis o the arterial wall an
perivascular microinarcts an hemorrhages. Other
lesions inclue nonhemorrhagic areas o “sotening” throughout the brain, hemorrhages in the
white matter, an subcortical eema (Hecht, 2017;
Willar, 2018). Hemorrhage in the basal ganglia
or pons, oten with rupture into the ventricles, may
evelop.
Cerebrovascular Pathophysiology
Clinical, pathological, an neuroimaging nings have le
to two general theories to explain cerebral abnormalities with
eclampsia. Enothelial cell ysunction likely plays a key role
in both. Te rst theory suggests that in response to acute an
severe hypertension, cerebrovascular overregulation leas to
vasospasm an eventual tissue inarction (rommer, 1988).
Little objective evience supports this mechanism.
Te secon theory is that suen elevations in systemic
bloo pressure excee the normal cerebrovascular autoregulatory
capacity (Schwartz, 2000). Regions o orce vasoilation an
vasoconstriction evelop, especially in arterial bounary zones.
At the capillary level, isruption o en-capillary pressure causes
increase hyrostatic pressure, hyperperusion, an extravasation
o plasma an re cells through enothelial tight-junction openings. Tis leas to vasogenic edema.
Most likely, the true mechanism combines these two. Tus,
a preeclampsia-associate interenothelial cell leak evelops at
bloo pressure levels much lower than those that usually cause
vasogenic eema, an this is couple with a loss o upper-limit
autoregulation (Fugate, 2015; Zeeman, 2009). As shown in
Figure 40-13, these abnormalities maniest as the posterior
reversible encephalopathy syndrome (PRES). Lesions principally
involve the occipital an parietal cortices, but other areas
are oten involve, although less extensively (Elow, 2013;
Zeeman, 2004a).
Cerebral Blood Flow
Autoregulation is the mechanism by which cerebral bloo
ow remains relatively constant espite alterations in cerebral
perusion pressure. In nonpregnant iniviuals, this mechanism protects the brain rom hyperperusion when mean arterial pressures increase up to 160 mm Hg. Tese pressures are ar
greater than those seen in most women with eclampsia. Tus,
to explain eclamptic seizures, it was theorize that autoregulation must be altere by pregnancy. Some investigators have
shown impaire autoregulation in women with preeclampsia
(Bergman, 2021b; Janzarik, 2014). When stuie 2 to 3 years
postpartum, women who ha preeclampsia ha returne to
normal autoregulation (Janzarik, 2018).
Zeeman an associates (2003) showe that cerebral bloo
ow uring the rst two trimesters o normal pregnancy is similar to nonpregnant values. But uring the last trimester, ow
signicantly rops by 20 percent. Tey oun greater cerebral
bloo ow in this trimester in women with severe preeclampsia compare with ow in normotensive pregnant women (Lee,
2019; Zeeman, 2004b). aken together, these nings suggest
that eclampsia occurs when cerebral hyperperusion orces capillary ui interstitially because o enothelial amage. Tis leak
leas to perivascular eema. Some ata suggest that the bloo-
brain barrier is not impaire, but in-vitro stuies may inicate
increase permeability (Bergman, 2021a; Burwick, 2018).
Neurological Manifestations
Several neurological maniestations typiy the preeclampsia synrome. Each signies severe involvement an requires
immeiate attention.
First, headache and scotomata are thought to arise rom
cerebrovascular hyperperusion that has a preilection or the
occipital lobes. In women preceing an eclamptic convulsion,
up to 75 percent have heaaches, an 20 to 30 percent have
visual changes (Sibai, 2005; Zwart, 2008). Te heaaches vary
in severity an persistence. In our experiences, they are unique
in that they o not usually respon to traitional analgesia but
requently improve ater magnesium sulate inusion.
Convulsions are iagnostic or eclampsia. Tese are cause by
abnormal excessive or synchronous neural activity in the brain.
Evience suggests that extene seizures can cause signicant
brain injury an later brain ysunction.
Blindness an generalized cerebral edema are iscusse in subsequent sections. Last, women with eclampsia have been shown
to have some cognitive ecline when stuie 5 to 10 years ollowing the involve pregnancy (Bergman, 2021c). Tis is iscusse urther in Chapter 41 (p. 727).
Neuroimaging Studies
With C imaging, localize hypoense lesions are requently
seen with eclampsia at the gray- an white-matter junction an
primarily in the parietooccipital lobes. Frontal an inerior
temporal lobes, the basal ganglia, an thalamus are other sites
(Brown, 1988). Tese hypoense areas correspon to petechial
hemorrhages an local eema. Eema o the occipital lobes or
iuse cerebral eema may cause blinness, lethargy, an con-
usion (Cunningham, 2000). Wiesprea eema can appear
as marke compression or even obliteration o the cerebral
ventricles. Such women may evelop signs o impening liethreatening transtentorial herniation.
Several MR imaging acquisitions are use to stuy women
with eclampsia (Singh, 2021). Common nings are hyperintense 2 lesions in the subcortical an cortical regions o
the parietal an occipital lobes, which reect PRES (see Fig.
40-13). Te basal ganglia, brainstem, an cerebellum are other
involve sites (Brewer, 2013; Zeeman, 2004a). PRES lesions are
almost universal in women with eclampsia, an their incience
in women with severe preeclampsia approximates 20 percent
(Hosapatna Basavarajappa, 2020; Mayama, 2016). Although
usually reversible, a ourth o these hyperintense lesions with
eclampsia have restricte iusion that signiy cerebral inarctions. Tese have persistent MR imaging nings (Loureiro,
2003; Zeeman, 2004a).
Visual Changes and Blindness
Retinal artery an venular calibers are ecrease in women with
preeclampsia (Soma-Pillay, 2018). Tese changes, along with
visual cortex involvement, can cause scotomata, blurre vision,
or iplopia, which is common with severe preeclampsia an
eclampsia. Tese symptoms usually improve with magnesium
sulate therapy, or lowere bloo pressure, or both.
Blindness is rare with preeclampsia alone, but it complicates
up to 15 percent o women with eclampsia (Cunningham,
1995). It can evelop a week or more ollowing elivery. Blin-
ness is usually reversible an may arise rom three potential
areas. Tese are the occipital lobe’s visual cortex, the lateral
geniculate nuclei, an the retina.
Occipital blinness is also calle amaurosis. With MR imaging,
aecte women usually have evience o extensive occipital lobe
vasogenic eema. O 15 women care or at Parklan Hospital,
occipital blinness laste rom 4 hours to 8 ays, but it resolve
completely in all cases (Cunningham, 1995). Rarely, extensive
cerebral inarctions may result in total or partial visual eects.
In the retina, ischemia, inarction, or serous etachment
may occur (Hanor, 2014). Retinal inarction, terme Purtscher
retinopathy, is rare (Fig. 40-14). Serous retinal detachment is
usually unilateral an selom causes total visual loss. Asymptomatic serous retinal etachment is relatively common with
preeclampsia (Gupta, 2019). In most cases o eclampsia-associate blinness, visual acuity subsequently improves (Manura,
2021). I blinness is cause by retinal artery occlusion, vision
may be permanently impaire (Roos, 2012).
Cerebral Edema
Maniestations that suggest wiesprea cerebral eema are
worrisome. During 13 years at Parklan Hospital, 10 o 175
women with eclampsia were iagnose with symptomatic cerebral eema (Cunningham, 2000). Symptoms range rom lethargy, conusion, an blurre vision to obtunation an coma.
In most cases, symptoms waxe an wane. O these 10, three
became comatose an ha imaging nings o transtentorial
herniation. One woman ie.
Mental status changes generally correlate with the egree
o involvement seen with C an MR imaging stuies. Tese
women are very susceptible to sudden and severe blood pressure
elevations, which can acutely worsen the already widespread vasogenic edema. Tus, careul bloo pressure control is essential.
■ Uteroplacental Perfusion
Compromise uteroplacental perusion is almost certainly a major
contributor to the increase perinatal morbiity an mortality
rates associate with preeclampsia synrome (Harmon, 2015).
Contributing eects in enovascular trophoblastic invasion were
iscusse earlier (p. 692). Tus, measurement o uterine, intervillous, an placental bloo ow woul likely be inormative.
Attempts to assess these in humans have been hampere. Barriers
inclue the placenta’s inaccessibility, the complexity o its venous
efuent, an the nee or invasive techniques or raioisotopes.
As a surrogate, sonographic measurement o uterine artery
bloo ow velocity can estimate resistance to uteroplacental bloo ow. Vascular resistance is estimate by comparing
arterial systolic an iastolic velocity waveorms (Chap. 14, p.
262). By the completion o placentation, impeance to uterine
artery bloo ow is markely ecrease, but with abnormal placentation, abnormally high resistance persists (Everett, 2012;
Napolitano, 2012). In earlier stuies, peak systolic:iastolic
velocity ratios rom uterine an umbilical arteries in preeclamptic pregnancies were measure. In some cases, but not all, resistance was higher (Ferrazzi, 2018; ruinger, 1990).
Another Doppler waveorm, terme uterine artery “notching,” has been linke with increase risks or preeclampsia
or etal-growth restriction (Groom, 2009). However, in one
MFMU Network stuy, notching ha a low preictive value
except or early-onset, severe isease (Myatt, 2012a).
Resistance in uterine spiral arteries also has been measure.
In one stuy, mean resistance values were greater in all women
with preeclampsia compare with those in normotensive controls (Matijevic, 1999). Another stuy use MR imaging an
other techniques to assess placental perusion ex vivo in the
myometrial arteries remove rom women with preeclampsia
or etal-growth restriction (Ong, 2003). In both conitions,
myometrial arteries exhibite similar vascular responses.
Despite these nings, evience or compromise uteroplacental circulation is oun in only a ew women who later
evelop preeclampsia. Inee, when preeclampsia evelops
uring the thir trimester, only a thir o women with severe
isease have abnormal uterine artery velocimetry (Li, 2005). In
a stuy o 50 women with HELLP synrome, only a thir ha
abnormal uterine artery waveorms (Bush, 2001). In general,
the extent o abnormal waveorms correlates with severity o
etal involvement (Ghiini, 2008; Groom, 2009).
Tese sonographic nings have value or preiction o etalgrowth restriction but not preeclampsia (American College o
Obstetricians an Gynecologists, 2019b; Demers, 2019). Several other ow velocity waveorms have been investigate or
preeclampsia preiction. However, none is suitable or clinical
use (De Kat, 2019; ownsen, 2018).
Fetal-growth Restriction
Discusse in etail in Chapter 47, this potential consequence o
preeclampsia can serve as one severity inicator (see able 40-2).
Namely, poor growth is usually conne to etuses o women
estine to evelop severe preeclampsia (Mateus, 2019). Perry
an colleagues (2020) reporte that pregnancies complicate by
etal-growth restriction more likely ha maternal hemoynamic
inices similar to preeclampsia. Measures showe higher mean
arterial pressure, greater systemic vascular resistance, lower car-
iac output, an elevate uterine artery pulsatility inex. Fetuses
born to preeclamptic mothers have cariac remoeling similar
to growth-restricte etuses (Youse, 2020).
PREDICTION
Some biological markers implicate in the genesis o the preeclampsia synrome have been measure to help preict its
evelopment. Although most have been evaluate in the rst hal
o pregnancy, some have been teste as preictors o severity in
the thir trimester. Still others have been use to orecast recurrent preeclampsia. Overall, these eorts have resulte in testing
strategies with poor sensitivity an poor positive preictive values
or preeclampsia (Cone-Aguelo, 2015; De Kat, 2019). Currently, no screening tests or preeclampsia are predictably reliable,
valid, and economical.
Because combinations o tests an risk actors might be superior to single preictors, some have evelope multivariable
screening algorithms (Boutin, 2021; Brunelli, 2020; Copel, 2020;
Serra, 2020; Snell, 2020). One rst-trimester screening protocol
using serum sFlt-1 levels has been propose (Pihl, 2020). Other
examples are mipregnancy algorithms (Black, 2020; Peguero,
2021; Stepan, 2020). None has been aequately verie su-
ciently or wiesprea clinical use (Capriglione, 2020).
■ Vascular Resistance Testing
and Placental Perfusion
Most tests in this category are cumbersome, time consuming,
an inaccurate. o evaluate bloo pressure changes, three tests
assess the bloo pressure rise in response to a stimulus. In one,
women at 28 to 32 weeks’ gestation rest in the let lateral ecubitus position an then roll to lie supine. With this roll-over
test, rising bloo pressure in response to the maneuver signi-
es a positive test. Te isometric exercise test employs the same
principle by squeezing a hanball. Te angiotensin II inusion
test provies incrementally higher oses intravenously, an the
hypertensive response is quantie. Sensitivities o all three
tests range rom 55 to 70 percent, an specicities approximate 85 percent (Cone-Aguelo, 2015).
Uterine artery Doppler velocimetry is posite to reect aulty
trophoblastic invasion o the spiral arteries. Te poor preictive
value o this or preeclampsia was escribe in the Uteroplacental Perusion section (p. 702).
■ FetalPlacental Unit Endocrine Function
Several serum analytes have been propose to help preict preeclampsia. Newer ones are continually ae. In general, none
o these tests is clinically benecial or hypertension preiction.
■ Renal Function Tests
Hyperuricemia results rom reuce uric aci clearance cause
by iminishe glomerular ltration, increase tubular reabsorption, an ecrease secretion. In one stuy, the sensitivity
o serum uric aci levels to etect preeclampsia range rom 0
to 55 percent, an specicity was 77 to 95 percent (Cnossen,
2006). Tese are selom use to iagnose preeclampsia (Chescheir, 2019).
Isolate gestational proteinuria is a risk actor or preeclampsia (Jayaballa, 2015; Morgan, 2016). But, as a preictive test or
preeclampsia, microalbuminuria has sensitivities ranging rom
7 to 90 percent an specicities spanning 29 to 97 percent
(Cone-Aguelo, 2015).
■ Endothelial Dysfunction and Oxidative Stress
Enothelial activation an inammation are major participants
in preeclampsia pathophysiology. Levels o some implicate
compouns are elevate in the bloo o aecte women an
have been assesse as preictors.
Fibronectins are high-molecular-weight glycoproteins release
rom enothelial cells an extracellular matrix ollowing enothelial injury. In one systematic review, however, neither cellular
nor total bronectin levels were clinically useul to preict preeclampsia (Leeang, 2007).
Trombocytopenia an platelet dysunction are integral eatures o preeclampsia. Platelet activation causes their augmente
estruction an lower bloo concentrations. Platelet volume
is increase because o platelet immaturity, an platelet volume has been escribe to be an early preictor o preeclampsia (Bellos, 2019; Mayer-Pickel, 2021). Although markers o
coagulation activation escribe earlier (p. 696) are elevate,
they substantively overlap with levels in normotensive pregnant
women (von Daelszen, 2018).
O oxidative stress markers, higher levels o lipi peroxies
couple with ecrease antioxiant activity can be seen with
preeclampsia. Other markers are iron, transerrin, and erritin; resistin; hyperhomocysteinemia; blood lipids; an antioxi-
ants such as ascorbic acid an vitamin E (Christiansen, 2015;
Cone-Aguelo, 2015; Mackay, 2012; Mignini, 2005). However, none has sucient preictive value.
■ Angiogenic and Antiangiogenic
Factor Imbalance
An imbalance in angiogenic an antiangiogenic actors is convincingly linke to preeclampsia pathogenesis (p. 694). Serum
levels o VEGF an PlGF begin to rop beore clinical preeclampsia evelops. At the same time, levels o some antiangiogenic actors, such as sFlt-1 an sEng, begin to rise. Factor levels
an ratios ier signicantly between women with preeclampsia
an those who are normotensive. Tese show especially goo
preictive perormance with early-onset preeclampsia (Burton,
2019; Cereira, 2019; Phipps, 2019; Stepan, 2020).
Tese tests also can serve as iagnostic ajuncts (Duhig,
2019; Zeisler, 2016). First, they may ai ierentiating
between preeclampsia an mimics that inclue chronic hypertension, chronic kiney isease, systemic lupus erythematosus,
an immunological thrombocytopenia. Tese tests can also
help ierentiate mil an severe isease. Tese plus other
multiple markers will likely have a uture role in rst-trimester
preeclampsia screening (Sovio, 2019).
■ Other Markers
Cell-ree DNA (cDNA) o placental origin can be etecte in
maternal plasma (Chap. 16, p. 327). It is hypothesize that
cDNA is release in preeclampsia by accelerate apoptosis o
cytotrophoblasts. However, one MFMU Network stuy oun
no correlation between total cDNA levels an preeclampsia
preiction (Silver, 2017).
Other investigate markers inclue glycosylate hemoglobin A1c, serum cystatin-c, an rst-trimester estimate placental volume (Bellos, 2019; Cavero-Reono, 2018; Kim, 2021).
Proteomic, metabolomic, an transcriptomic technologies can
be employe to stuy serum an urinary proteins an cellular
metabolites. Preliminary stuies inicate their potential preictive value (Bahao-Singh, 2013; Ma, 2014).
PREVENTION
Various strategies use to prevent or moiy preeclampsia
severity have been evaluate. Some are liste in Table 40-4.
With the possible exception o aspirin, none is convincingly
an reproucibly eective.
■ Dietary and Lifestyle Modifications
A low-salt iet was one o the earliest researche preventions
but is not supporte by ata (De Snoo, 1937). O stuies, one
ranomize trial showe that a soium-restricte iet was ine-
ective in preventing preeclampsia (Knuist, 1998).
Regular exercise uring pregnancy is linke to a lower risk o
eveloping preeclampsia (Barakat, 2016; Morris, 2017). In one
systematic review, a similar tren towar risk reuction with
exercise was note (Kasawara, 2012). Only a ew stuies have
been ranomize.
Somewhat relate, one retrospective cohort stuy o 677
nonhypertensive women were hospitalize or be rest because
o threatene preterm elivery (Abenhaim, 2008). When outcomes o these women were compare with those o the general
obstetrical population, be rest was associate with a signi-
cantly reuce risk o eveloping preeclampsia (relative risk
0.27). From two small ranomize trials, prophylactic be rest
or 4 to 6 hours aily at home was successul in signicantly
lowering the preeclampsia incience in women with normal
bloo pressures (Meher, 2006). Currently, the Society or
Maternal-Fetal Meicine (2020) oes not recommen reuce
activity or women with hypertensive isorers or or prevention o preeclampsia.
Calcium supplementation has been stuie, but in one trial
o more than 4500 low-risk nulliparas, supplementation aile
to ecrease the risk or preeclampsia or pregnancy-associate
hypertension (Levine, 1997). Similar nings were reporte
rom another trial (Homeyer, 2019). In aggregate, most trials
show that unless women are calcium ecient, supplementation oers no benets (Palacios, 2019; Sanchez-Ramos, 2017).
Subclinical hypothyroidism is associate with increase preeclampsia risk. Tis insuciency has been postulate to stem
rom ioine eciency, but a recent metaanalysis oun no association between ioine suciency an preeclampsia (Businge,
2021). Folic acid was evaluate in a ranomize trial (Wen,
2018). Nearly 2500 high-risk women were given a 4-mg olic
aci ose aily or placebo. Te incience o preeclampsia in
both groups approximate 14 percent.
Cardioprotective atty acids oun in some sh likely prevent
inammation-meiate atherogenesis. Tus, it was posite that
they might also prevent preeclampsia. However, ranomize
trials conucte thus ar show no such benets rom sh oil
supplementation (Zhou, 2012). In one longituinal cohort
stuy, a seaoo iet, compare with a western one, provie a
protective eect against preeclampsia (Ikem, 2019).
■ Antihypertensive Drugs
Because o the prior purporte benets o soium restriction
or preeclampsia prevention, iuretic therapy became popular
with the avent o chlorothiazie in 1957 (Flowers, 1962). In
one metaanalysis o nine ranomize trials with more than
7000 pregnancies, women given iuretics ha a lower incience
o eema an hypertension but not o preeclampsia (Churchill,
2007). Because women with chronic hypertension are at high
risk or preeclampsia, several ranomize trials have evaluate
various antihypertensive rugs to reuce the incience o superimpose preeclampsia (Chap. 41, p. 713). A critical analysis o
these trials by Sta an coworkers (2015) aile to emonstrate
benets or this goal.
■ Antioxidants
Data imply that an imbalance between oxiant an antioxiant
activity plays a role in preeclampsia pathogenesis. Tus, naturally occurring antioxiants—vitamins C, D, an E—might
reuce such oxiation. Several ranomize stuies have assesse
antioxiant vitamin supplementation or women at high risk
or preeclampsia (Burton, 2019; Villar, 2009). Te Combine
Antioxiant an Preeclampsia Preiction Stuies (CAPPS) by
the MFMU Network inclue almost 10,000 low-risk nulliparas (Roberts, 2010). None o these stuies showe reuce
preeclampsia rates in women supplemente with vitamins C
an E compare with those given placebo.
Statins were propose to prevent preeclampsia because they
stimulate heme oxygenase-1 expression, which inhibits sF1t-1
release. Early animal ata suggest that statins may prevent
hypertensive isorers o pregnancy (Lewis, 2017). Te MFMU
Network plans a ranomize trial to test pravastatin or prevention, an a pilot stuy is complete (Costantine, 2016).
Metormin inhibits hypoxic inducible actor 1α by lowering mitochonrial electron transport chain activity. It reuces
sFlt-1 an sEng activity an thus has potential to prevent
preeclampsia (Brownoot, 2016). In a preliminary stuy, pre-
iabetic women were given metormin or placebo throughout
pregnancy, an metormin-treate women ha a lower inci-
ence o severe preeclampsia (Racine, 2021). However, other
clinical stuies are lacking.
■ Antithrombotic Agents
Preeclampsia is characterize by vasospasm, enothelial cell
ysunction, inammation, an activation o platelets an the
coagulation–hemostasis system. Other sequelae inclue placental inarction an spiral artery thrombosis (Nelson, 2014).
Tus, antithrombotic agents have been evaluate to prevent
preeclampsia. Low-molecular-weight heparin has been stuie
in ranomize trials. In a subsequent metaanalysis using iniviual ata rom 963 women, the risk or recurrent preeclampsia, abruption, or etal-growth restriction was similar in women
receiving heparin or placebo (Roger, 2016).
Low-dose Aspirin
In low oses o 50 to 150 mg aily, aspirin eectively inhibits
platelet thromboxane A2 biosynthesis. It has minimal eects
on vascular prostacyclin prouction. Still, several clinical trials
have shown limite benets in preeclampsia prevention. In a
ranomize trial rom the MFMU Network, risks or averse
outcomes were not signicantly reuce with aspirin therapy
(Caritis, 1998). Tis stuy was ollowe by numerous similar
stuies an metaanalyses.
In another ranomize trial o more than 1600 women at
high risk or preterm preeclampsia, oral low-ose aspirin was
given aily rom 11 to 14 weeks’ gestation until 36 weeks to prevent recurrence (Rolnik, 2017). Te rate o preterm preeclampsia recurrence was 1.6 percent in the aspirin group compare
with 4.3 percent in the placebo arm. In a metaanalysis, Roberge
an colleagues (2017) oun that aspirin prophylaxis initiate
beore 16 weeks’ gestation was associate with a signicant risk
reuction—approximately 60 percent—o preeclampsia an
etal-growth restriction. At the same time, however, Meher
an associates (2017) perorme an iniviual participant ata
metaanalysis an reporte a much lower—approximately 10
percent—risk reuction. Eects were signicant whether therapy was initiate beore or ater 16 weeks’ gestation.
In a subsequent metaanalysis, Roberge an coworkers (2018)
oun that aspirin prophylaxis given starting ≤16 weeks’ gestation reuce the risk o preterm, but not term, preeclampsia.
urner an colleagues (2020) reporte that aspirin improve
some perinatal outcomes inepenent o eects on preeclampsia risk. But to the contrary, the review by Chaemsaithong an
coworkers (2020) oun no benets even when low-ose aspirin was given beore 11 weeks’ gestation.
Base on these ata, the U.S. Preventive Services ask Force
(2021) recommens low-ose aspirin prophylaxis or women
at high risk or preeclampsia. Te American College o Obstetricians an Gynecologists (2018, 2020) now recommens
low-ose aspirin be given between 12 an 28 weeks’ gestation
to help prevent preeclampsia in high-risk women. Caniates
inclue those with ≥1 o the ollowing: prior preeclampsia,
chronic hypertension, overt iabetes, renal isease, autoimmune isorers, an multietal gestation. Supplementation
may be considered or those with more than one o these qualities: nulliparous, age oler than 35 years, obese, amily history o preeclampsia, vulnerable socioemographics, an prior
low-birthweight or growth-restricte neonate. Tese results
have also raise the question as to whether all pregnant women
shoul be given aspirin (Ayala, 2019).
Low-dose aspirin coupled with heparin mitigates thrombotic sequelae in women with lupus anticoagulant (Chap.
62, p. 1116). Because o a similarly high prevalence o placental thrombotic lesions oun with severe preeclampsia,
trials have assesse the possible merits o such treatments
or women with prior preeclampsia. In two ranomize trials, women with a history o early-onset preeclampsia were
given aspirin alone or a regimen o enoxaparin plus aspirin
(Groom, 2017; Haa, 2016). Outcomes were similar.
Low-molecular-weight heparin, with or without aspirin, may
ecrease the risk or preeclampsia in high-risk women (e
Vries, 2012; Wang, 2020).
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