19 Hypertensive States of Pregnancy

Current Obstetric & Gynecologic Diagnosis & Treatment

Hypertensive States of Pregnancy
19
Courtney Reynols! "D! #illiam C$ "abie! "D! & %a&a "$ Sibai!
"D
Preeclampsia

Classification

Pat&ogenesis

Pat&op&ysiology

Clinical 'inings

Differential Diagnosis

Complications

Prevention

Treatment

Prognosis
(clampsia

Pat&op&ysiology

Clinical 'inings

Treatment

Prognosis
C&ronic Hypertension

Clinical 'inings

Complications

Treatment

Prognosis
C&apter References
Hypertensive states in pregnancy inclue preeclampsia)
eclampsia! c&ronic &ypertension *eit&er essential or seconary
to renal isease! enocrine isease! or ot&er causes+! c&ronic
&ypertension ,it& superimpose preeclampsia! an gestational
&ypertension *Table 19-1+$ Preeclampsia is &ypertension
associate ,it& proteinuria an eema! occurring primarily in
nulliparas after t&e ./t& gestational ,ee0 an most fre1uently
near term$ Recent ata support t&e elimination of eema as a
iagnostic criterion$ (clampsia is t&e occurrence of sei2ures t&at
cannot be attribute to ot&er causes in a preeclamptic patient$
C&ronic &ypertension is efine as &ypertension t&at is present
before conception! before ./ ,ee0s3 gestation or t&at persists
for more t&an 4 ,ee0s postpartum$ Hypertension is efine as
bloo pressure e1ual to or greater t&an 15/69/ mm Hg or an
increase in mean arterial pressure of ./ mm Hg$ T&e use of an
increase in bloo pressure of 7/618 mm Hg over first)trimester
values is controversial$ Recent ata report no increase averse
events in ,omen ,it& t&ese c&anges$ Ho,ever! an increase in
bloo pressure by t&is amount ,arrants close observation$
Proteinuria is efine as t&e e9cretion of 7// mg or more in a
.5)&our specimen or 7/ mg6: in a ranom specimen$
Preeclampsia may occur in ,omen ,it& c&ronic &ypertension
*superimpose preeclampsia+; t&e prognosis is ,orse for t&e
mot&er an fetus t&an ,it& eit&er conition alone$ T&e criteria
for superimpose preeclampsia are ,orsening &ypertension *7/
mm Hg systolic or 18 mm Hg iastolic above t&e average of
values before ./ ,ee0s3 gestation+ toget&er ,it& eit&er
nonepenent eema or proteinuria$ Gestational &ypertension is
furt&er ivie into transient &ypertension of pregnancy if
preeclampsia is present at t&e time of elivery an t&e bloo
pressure is normal by 1. ,ee0s postpartum! an c&ronic
&ypertension if t&e elevation in bloo pressure persists beyon
1. ,ee0s postpartum$ T&is conition is often preictive of t&e
later evelopment of essential &ypertension$
Table 19-1$ Hypertensive states of pregnancy ot&er t&an
preeclampsia)eclampsia$
<t is fre1uently ifficult to etermine ,&et&er a patient &as
preeclampsia! c&ronic &ypertension! or c&ronic &ypertension
,it& superimpose preeclampsia$ T&is is partly because bloo
pressure normally ecreases uring t&e secon trimester! an
t&e ecrease may mas0 t&e presence of c&ronic &ypertension$
Renal biopsy stuies &ave s&o,n t&at only about =/> of
primigravias uner .8 years of age ,it& t&e tria of eema!
&ypertension! an proteinuria &ave glomeruloenot&eliosis! t&e
c&aracteristic lesion of preeclampsia$ T,enty)five percent &ave
unsuspecte renal isease$ <n multiparas ,it& c&ronic
&ypertension ,it& superimpose preeclampsia! about 7> &ave
glomeruloenot&eliosis an .1> &ave unerlying renal isease$
Renal biopsy is rarely performe in pregnancy because t&e
benefit usually oes not ?ustify t&e ris0$ T&e sensitivity an
specificity of bioc&emical mar0ers suc& as uric aci an
antit&rombin <<< are un0no,n$
PR((C:@"PS<@
Preeclampsia occurs in about 4> of t&e general population; t&e
incience varies ,it& geograp&ic location$ Preisposing factors
are nulliparity! blac0 race! maternal age belo, ./ or over 78
years! lo, socioeconomic status! multiple gestation!
&yatiiform mole! poly&yramnios! nonimmune fetal &yrops!
t,ins! obesity! iabetes! c&ronic &ypertension! an unerlying
renal isease$
Classification
T&ere are . categories of preeclampsia! mil an severe$ Severe
preeclampsia is efine as t&e follo,ingA *1+ bloo pressure
greater t&an 14/ mm Hg systolic or 11/ mm Hg iastolic on .
occasions 4 &ours apart; *.+ proteinuria e9ceeing . g in a .5)
&our perio or .-5B on ipstic0 testing; *7+ increase serum
creatinine *C 1$. mg6: unless 0no,n to be elevate previously+;
*5+ oliguria D8// m:6.5 &; *8+ cerebral or visual isturbances; *4+
epigastric pain; *=+ elevate liver en2ymes; *E+
t&rombocytopenia *platelet count F 1//!///6mm7+; *9+ retinal
&emorr&ages! e9uates! or papilleema; an *1/+ pulmonary
eema$
Pat&ogenesis
Preeclampsia &as been escribe as a isease of t&eories!
because t&e cause is un0no,n$ Some t&eories inclue *1+
enot&elial cell in?ury! *.+ re?ection p&enomenon *insufficient
prouction of bloc0ing antiboies+! *7+ compromise placental
perfusion! *5+ altere vascular reactivity! *8+ imbalance bet,een
prostacyclin an t&rombo9ane! *4+ ecrease glomerular
filtration rate ,it& retention of salt an ,ater! *=+ ecrease
intravascular volume! *E+ increase central nervous system
irritability! *9+ isseminate intravascular coagulation! *1/+
uterine muscle stretc& *isc&emia+! *11+ ietary factors! an *1.+
genetic factors$ T&e relatively ne, t&eory of enot&elial in?ury
e9plains many of t&e clinical finings in preeclampsia$ T&e
t&eory emp&asi2es t&at t&ere is more to preeclampsia t&an
&ypertension$ T&e vascular enot&elium prouces a number of
important substances incluing enot&elial)erive rela9ing
factor or nitric o9ie! enot&elin)1! prostacyclin! an tissue
plasminogen activator$ T&us! enot&elial cells moify t&e
contractile response of t&e unerlying smoot& muscle cells!
prevent intravascular coagulation! an maintain t&e integrity of
t&e intravascular compartment$ Several finings suggest
enot&elial in?ury in preeclampsia$ T&e c&aracteristic renal
lesion of preeclampsia Gglomeruloenot&eliosisH is manifeste
primarily by s,elling of t&e glomerular capillary enot&elial
cells$ T&e &ematologic c&anges of preeclampsia! ie!
t&rombocytopenia an microangiopat&ic &emolytic anemia! are
similar to t&ose foun in t&rombotic t&rombocytopenic purpura
or &emolytic uremic synromeIisorers in ,&ic& enot&elial
ysfunction is t&oug&t to be important$ @ctivation of t&e clotting
cascae an increase sensitivity to pressors are compatible
,it& enot&elial cell ysfunction$ %ioc&emical evience inclues
an imbalance in t&e prostacyclinAt&rombo9ane ratio an &ig&
circulating concentrations of von #illebran factor! enot&elin!
an cellular fibronectin$ Serum from preeclamptic ,omen! ,&en
applie to &uman umbilical vein enot&elial cell cultures!
prouces no morp&ologic abnormalities in t&e cells but releases
procoagulants! vasoconstrictors! an mitogens$
<n summary! t&e current &ypot&esis for t&e pat&ogenesis of
preeclampsia is t&at an immunologic isturbance causes
abnormal placental implantation resulting in ecrease
placental perfusion$ T&e abnormal perfusion stimulates t&e
prouction of substances in t&e bloo t&at activate or in?ure
enot&elial cells$ T&e vascular enot&elium provies a single
target for t&ese bloo)borne proucts! ,&ic& e9plains t&e
multiple organ system involvement in preeclampsia$
Pat&op&ysiology
@$ C(JTR@: J(RKOLS SMST("
Tissues are capable of regulating t&eir o,n bloo flo,; t&is
process is 0no,n as autoregulation$ Cerebral perfusion is
maintaine by autoregulation at a constant level of about 88
m:6min61// g at a ,ie range of bloo pressures *'ig 19-1+$
Ho,ever! bloo pressure may rise to levels at ,&ic&
autoregulation cannot function$ #&en t&is occurs! t&e
enot&elial tig&t ?unctions open! causing plasma an re bloo
cells to lea0 into t&e e9travascular space$ T&is may result in
petec&ial &emorr&age or gross intracranial &emorr&age$ T&e
upper limit of autoregulation varies from one person to anot&er;
eg! c&ronic &ypertension may cause meial &ypertrop&y of t&e
cerebral vessels! resulting in a s&ift of t&e curve to t&e rig&t *'ig
19-1+$ T&is e9plains t&e parao9 of . patients ,it& e1ually
severe &ypertension ,&o &ave mar0ely ifferent clinical
presentations$ T&e young primigravia ,&ose bloo pressure is
normally 11/6=/ mm Hg may convulse ,it& a bloo pressure of
1E/61./ mm Hg! ,&ile a c&ronic &ypertensive may be
asymptomatic or &ave only a &eaac&e at t&e same pressure$
'igure 19-1$ Representation of t&e relations&ip bet,een cerebral
bloo flo, an mean arterial bloo pressure$ Cerebral bloo
flo, normally remains constant at mean arterial pressures of 4/-
15/ mm Hg$ <n c&ronically &ypertensive patients! meial
&ypertrop&y causes t&e lo,er an upper limits of autoregulation
to be s&ifte to &ig&er bloo pressure values$ *"oifie an
reprouce! ,it& permission! from Donalson NOA Jeurology of
Pregnancy$ Sauners! 19=E$+
T&e mec&anism of t&e cerebral amage in eclampsia is unclear$
T&e pat&ologic finings are similar to t&ose of &ypertensive
encep&alopat&y$ T&ese abnormalities inclue fibrinoi necrosis
an t&rombosis of arterioles! microinfarcts! an petec&ial
&emorr&ages$ <n bot& &ypertensive encep&alopat&y an
eclampsia! t&e lesions are ,iely istribute t&roug&out t&e
brain! but t&e brainstem is more severely affecte in t&e
former! ,&ile t&e corte9 is more severely affecte in t&e latter$
Ot&er ifferences in t&e t,o conitions are t&at eclampsia may
be seen in t&e absence of &ypertension an t&at retinal
&emorr&ages an infarcts are rare in eclampsia$ T,o t&eories
&ave been propose to e9plain t&e pat&ogenesis of &ypertensive
encep&alopat&y! vasospasm! an force ilation$ <n t&e first!
vasospasm causes local isc&emia! arteriolar necrosis! an
isruption of t&e bloo)brain barrier$ @ccoring to t&e secon!
as bloo pressure rises above t&e limit of autoregulation!
cerebral vasoilation occurs$ <nitially! some vessel segments
ilate! an some remain constricte$ Overistention of t&e
ilate segments results in necrosis of t&e meial muscle fibers
an amage to t&e vessel ,all$ <t is possible t&at bot&
mec&anisms are operant$
T&e presence of cerebral eema in preeclampsia)eclampsia is
controversial$ One set of researc&ers state t&at cerebral eema
,as not present in eclamptic patients ,&en autopsy ,as
performe ,it&in 1 &our of eat& an t&at suc& eema ,as a
late postmortem c&ange$ <n contrast! some ot&ers foun
generali2e cerebral eema in some autopsy specimens an
confirme increase intracranial pressure in eclamptics ,it&
prolonge coma *C 4 &ours+$ (arly stuies of cerebrospinal flui
opening pressure s&o,e elevate pressures; &o,ever! more
recent stuies &ave faile to confirm t&is$
Hea compute tomograp&ic *CT+ scans in ,omen ,it&
eclampsia &ave s&o,n abnormalities in about one)t&ir$ %y using
fourt&)generation e1uipment an ,it& a s&ort interval from
sei2ure to CT scan! abnormalities may be etecte in &alf t&e
patients$ T&e main finings are focal &ypoensities in t&e ,&ite
matter in t&e posterior &alf of t&e cerebral &emisp&eres ,it&
occasional lesions in t&e gray matter! temporal lobes! an
brainstem$ One researc&er suggeste t&at t&ese areas of
raiograp&ic &ypoensity represente petec&ial &emorr&ages
accompanie by local eema$ Subarac&noi or intraventricular
&emorr&ages may be seen in t&e most severe cases$
"agnetic resonance imaging *"R<+ is more sensitive at
emonstrating abnormalities t&an CT scan! but it is not as ,iely
available$ T.),eig&e "R< scans s&o, &ig& signal in t&e cortical
an subcortical ,&ite matter$ "ost of t&e abnormalities lie in
t&e occipital an parietal areas in ,aters&e areas ,&ere t&e
anterior! mile! an posterior circulations meet$ %asal ganglia
an brainstem abnormalities occur in more critically ill patients$
Cerebral angiograp&y &as been performe in a fe, patients ,it&
eclampsia! revealing iffuse arterial vasoconstriction$
(lectroencep&alograms *((Gs+ s&o, nonspecific abnormalities in
about =8> of patients after eclamptic sei2ures$ T&e pattern is
usually a iffuse slo,ing of activity *t&eta or elta ,aves+!
sometimes ,it& focal slo, activity an occasional paro9ysmal
spi0e activity$ T&ese abnormalities may be seen in ot&er
conitions! suc& as &ypo9ia! renal isease! polycyt&emia!
&ypocalcemia! an ,ater into9ication$ T&e
electroencep&alograp&ic pattern is unaffecte by magnesium
sulfate$ <t graually returns to normal 4-E ,ee0s postpartum$
Lncomplicate eclampsia causes no permanent neurologic
eficit$
%$ (M(S
%ot& serous retinal etac&ment an cortical blinness may
occur$
C$ PL:"OJ@RM SMST("
Pulmonary eema may occur ,it& severe preeclampsia or
eclampsia$ <t may be cariogenic or noncariogenic an usually
occurs postpartum$ <n some cases it may be relate to e9cessive
flui aministration or to elaye mobili2ation of e9travascular
flui$ <t may also be relate to ecrease plasma colloi oncotic
pressure from proteinuria! use of crystallois to replace bloo
loss! an ecrease &epatic synt&esis of albumin$ Pulmonary
eema is particularly common in patients ,it& unerlying
c&ronic &ypertension an &ypertensive &eart isease! ,&ic& may
be manifeste by systolic ysfunction! iastolic ysfunction! or
bot&$ @spiration of gastric contents is one of t&e most reae
complications of eclamptic sei2ures$ T&is may result in eat&
because of asp&y9ia from particulate matter plugging ma?or
air,ays or in c&emical pneumonitis from aspirate gastric aci$
@spiration may cause various types of pneumonia! ranging from
patc&y pneumonitis to full)blo,n ault respiratory istress
synrome$
D$ C@RD<OK@SCL:@R SMST("
Plasma volume is reuce in patients ,it& preeclampsia$ Jormal
p&ysiologic volume e9pansion oes not occur! possibly because
of generali2e vasoconstriction! capillary lea0! or some ot&er
factor$ %ecause t&e cause of t&e reuce volume is un0no,n!
management is controversial$ One t&eory is t&at t&e ecrease
volume is a primary event causing a c&ronic s&oc0li0e state$
Hypertension is t&oug&t to be t&e result of release of a pressor
substance from t&e &ypoperfuse uterus or of compensatory
secretion of catec&olamines$ Proponents of t&is t&eory avocate
avoiance of iuretics an use of volume e9paners$ @not&er
t&eory is t&at ecrease volume is seconary to
vasoconstriction$ Proponents of t&is t&eory avocate t&e use of
vasoilators an ,arn t&at volume e9paners may aggravate
&ypertension or cause pulmonary eema$
Stuies using t&e S,an)Gan2 cat&eter &ave emonstrate a
spectrum of &emoynamic finings in preeclampsia ranging from
a lo,)output! &ig&)resistance state to a &ig&)output! lo,)
resistance state$ One stuy foun a lo, ,ege pressure! lo,
cariac output! an &ig& systemic vascular resistance in
untreate nulliparous preeclamptic ,omen! ,&ile patients ,&o
receive various t&erapies an ,ere usually referre! a ,ie
range of &emoynamics ,as foun$ T&e conclusion ,as t&at t&e
untreate preeclamptic patient ,as significantly volume)
eplete an t&at t&e ,ie spectrum of &emoynamic finings
in t&e treate group resulte from prior t&erapy an t&e
presence of ot&er variables suc& as labor! multiparity! an
pree9isting &ypertension$
<n anot&er stuy of a &eterogeneous population of pretreate
an nonpretreate patients! a generally consistent profile
emerge$ Preeclampsia ,as in general a &ig& cariac output
state associate ,it& an inappropriately &ig& perip&eral
resistance$ @lt&oug& t&e systemic vascular resistance ,as ,it&in
t&e normal range for pregnancy! it ,as still inappropriately &ig&
for t&e elevate cariac output$ T&e failure of t&e circulation to
ilate in t&e setting of increasing cariac output appeare to be
a c&aracteristic feature of preeclampsia$ T&e normal ,ege an
central venous pressures foun in t&eir stuy suggeste
venoconstriction ,it& central relocation of intravascular volume
if t&e generally accepte reports of ecrease plasma volume in
preeclampsia are correct$ T&ey postulate splanc&nic
venoconstriction as t&e mec&anism of t&is volume s&ift$
Jormal pregnant ,omen are resistant to t&e vasoconstrictor
effects of angiotensin <<$ Pregnant ,omen re1uire about .O
times t&e amount of angiotensin << re1uire by nonpregnant
,omen to raise t&e iastolic bloo pressure ./ mm Hg$ Patients
,&o ,ill evelop superimpose preeclampsia lose t&eir
refractoriness to angiotensin << many ,ee0s before &ypertension
evelops$ T&ese patients may be ientifie as early as 1E-.5
,ee0s3 gestation by infusion of angiotensin <<$
Jormal pregnant ,omen lose t&eir refractoriness to angiotensin
<< after treatment ,it& prostaglanin synt&etase in&ibitors suc&
as aspirin or inomet&acin; t&is suggests t&at prostaglanin is
involve in meiating vascular reactivity to angiotensin << in
pregnancy$ Refractoriness to angiotensin << can be restore in
patients ,it& preeclampsia by t&e aministration of
t&eop&ylline! a p&osp&oiesterase in&ibitor t&at increases
intracellular levels of c@"P$ T&erefore! prostaglanins
synt&esi2e in t&e arteriole may moulate vascular reactivity to
angiotensin << by altering t&e intracellular level of c@"P in
vascular smoot& muscle$
($ :<K(R
T&e spectrum of liver isease in preeclampsia is broa! ranging
from subclinical involvement ,it& t&e only manifestation being
fibrin eposition along t&e &epatic sinusois to rupture of t&e
liver$ #it&in t&ese e9tremes lie t&e H(::P synrome *&emolysis!
elevate liver en2ymes! an lo, platelets+ an &epatic
infarction$
'$ P<DJ(MS
T&e c&aracteristic lesion of preeclampsia!
glomeruloenot&eliosis! is a s,elling of t&e glomerular capillary
enot&elium t&at causes ecrease glomerular perfusion an
glomerular filtration rate$ 'ibrin split proucts &ave been foun
on t&e basement membrane by some observers! ,&o &ave
suggeste t&at intravascular coagulation may be seconary to
t&romboplastin release from t&e placenta$ Ho,ever! t&e fibrin
split proucts are foun infre1uently an only in small amounts$
Ot&er investigators &ave etecte <g"! <gG! an complement in
t&e glomeruli of some patients an &ave suggeste an
immunologic mec&anism$ Serial renal biopsies &ave s&o,n t&at
t&e lesion is totally reversible over about 4 ,ee0s$
G$ %:OOD
"ost patients ,it& preeclampsia)eclampsia &ave normal clotting
stuies$ <n some! a spectrum of abnormalities may be foun!
ranging from isolate t&rombocytopenia to microangiopat&ic
&emolytic anemia to isseminate intravascular coagulation
*D<C+$ T&rombocytopenia is t&e most common abnormality; a
count of less t&an 18/!///6Q: is foun in 18-./> of patients$
'ibrinogen levels are actually elevate in preeclamptic ,omen
as compare ,it& normotensive patients$ :o, fibrinogen levels
in preeclampsia)eclampsia are usually associate ,it& abruptio
placentae or fetal emise$ (levate fibrin split proucts are
seen in ./> of patients *usually in t&e range of 1/-5/ Q:6m:+$
"icroangiopat&ic &emolytic anemia ,it&out ot&er signs of D<C
may be seen in about 8> of patients! an evience of D<C is also
present in about 8>$ <n t&e past! D<C ,as t&oug&t to be t&e
cause of preeclampsia; no, it is regare as a se1uela of t&e
isease$
T&e H(::P synrome escribes patients ,it& &emolytic anemia!
elevate liver en2ymes! an lo, platelet count$ Criteria for t&e
iagnosis at t&e aut&ors3 institution are sc&istocytes on t&e
perip&eral bloo smear! lactic e&yrogenase C 4// L6:! total
bilirubin C 1$. mg6:! aspartate aminotransferase C =/ L6:! an
platelet count F 1//!///6mm7$ T&is synrome is present in
about 1/> of patients ,it& severe preeclampsia)eclampsia$ <t is
fre1uently seen in Caucasian patients ,it& elay in iagnosis or
elivery an in patients ,it& abruptio placentae$ T&e synrome
may occur remote from term *eg! at 71 ,ee0s+ an ,it& no
elevation of bloo pressure$ T&e synrome is fre1uently
misiagnose as &epatitis! gallblaer isease! iiopat&ic
t&rombocytopenic purpura! or t&rombotic t&rombocytopenic
purpura$ "ost &ematologic abnormalities return to normal ,it&in
.-7 ays after elivery! but t&rombocytopenia may persist for a
,ee0$
H$ (JDOCR<J( SMST("
T&e role of t&e renin)angiotensin)alosterone system in t&e
regulation of bloo pressure uring normal an &ypertensive
pregnancy &as not been clearly efine$ <n normal pregnancy!
estrogen3s effect on t&e liver mar0ely increases prouction of
renin substrate$ T&is increases plasma renin activity! plasma
renin concentration! an angiotensin << levels$ Plasma
alosterone levels rise even &ig&er t&an can be accounte for by
t&e prevailing plasma renin activity$ Despite t&e &ig& plasma
concentration of alosterone! t&ere is no bloo pressure
increase or &ypo0alemia in normal pregnancy; inee! bloo
pressure falls in t&e mitrimester$ T&is may be ue to
counterregulatory factors suc& as t&e natriuretic effect of
progesterone or activation of vasoepressor systems suc& as
0inins or prostaglanins$
<nterpreting renin! angiotensin! an alosterone levels in stuies
of preeclampsia is ifficult because of ifferences in t&e
efinition of preeclampsia *parity! egree of proteinuria! early)
or late)onset isease+! ifferences in ta0ing of bloo samples
*values may be affecte by be rest! soium inta0e! labor! etc+!
an ifferences in assay tec&ni1ues$ <n t&e ma?ority of stuies!
renin! angiotensin! an alosterone are all suppresse in
preeclampsia! but t&ey are still above nonpregnant levels$ T&e
available evience suggests t&at t&e renin)angiotensin system is
only seconarily involve in preeclampsia$
@trial natriuretic peptie *@JP+ is a volume regulatory &ormone
synt&esi2e by cariac myocytes! ,&ic& &as potent natriuretic!
iuretic! an vasorela9ant properties$ @JP secretion is
stimulate by increase atrial pressure an alterations in soium
balance$ (levate concentrations of @JP accompany pat&ologic
states c&aracteri2e by flui overloa suc& as cirr&osis!
congestive &eart failure! an c&ronic renal failure$ Ho,ever!
@JP is elevate in preeclampsia! a isorer supposely
c&aracteri2e by &ypovolemia$ <t is even elevate in t&e secon
trimester before t&e onset of clinical evience of preeclampsia$
T&e mec&anism for t&e elevation is un0no,n$ <t may be t&at
enot&elin or anot&er vasoactive peptie is stimulating release
of @JP$ <t may also be t&at t&e ,iely accepte concept of
central &ypovolemia in preeclampsia is incorrect$
<$ C@T(CHO:@"<J(S
Lrinary an bloo catec&olamine levels are t&e same in
normotensive pregnant ,omen! ,omen ,it& preeclampsia! an
nonpregnant controls$ Ho,ever! it cannot be rule out t&at
sympat&etic activity is of pat&ogenetic importance for initiation
or maintenance of &ypertension in patients ,it& preeclampsia$
Catec&olamine levels increase uring labor! presumably o,ing to
stress$ T&e vascular refractoriness to catec&olamines is lac0ing
in preeclampsia! as is t&e refractoriness to ot&er enogenous
vasopressors suc& as antiiuretic &ormone an angiotensin <<$
N$ PROST@CMC:<J
Prostacyclin is a prostaglanin iscovere in 19=4$ <t increases
intracellular c@"P in smoot& muscle cells an platelets resulting
in vasoilator an platelet antiaggregatory effects$ <ts &alf)life is
about 7 minutes! brea0ing o,n in plasma to 4)0eto)PG'1a!
,&ic& is stable an can be measure as an inication of
prostacyclin levels$ T&ese plasma levels are lo,! inicating t&at
prostacyclin acts p&ysiologically at t&e local level rat&er t&an as
a circulating &ormone$
Prostacyclin is mae primarily in t&e enot&elial cell from
arac&ionic aci! cataly2e by t&e en2yme cycloo9ygenase$
Cycloo9ygenase can be in&ibite by aspirin)li0e rugs$
"ec&anical or c&emical perturbation of t&e enot&elial cell
membrane stimulates formation an release of prostacyclin$ 'or
e9ample! pulsatile pressure or c&emicals suc& as bray0inin or
t&rombin stimulate prostacyclin generation in t&e vessel ,all$
T&rombo9ane @. generate by platelets from arac&ionic aci
via cycloo9ygenase inuces vasoconstriction an platelet
aggregation$ T&us! prostacyclin an t&rombo9ane &ave opposing
roles in regulating platelet)vessel ,all interaction$
@spirin irreversibly in&ibits cycloo9ygenase$ Cycloo9ygenase
must be prouce continuously by enot&elial cells! because
t&ey recover t&eir ability to synt&esi2e prostacyclin ,it&in a fe,
&ours after a ose of aspirin$ On t&e ot&er &an! platelets o not
&ave a nucleus an t&erefore cannot ma0e fres& cycloo9ygenase$
T&rombo9ane synt&esis recovers only as ne, platelets enter t&e
circulation$ Platelet life span is about 1 ,ee0$ T&us! aily
treatment ,it& lo,)ose aspirin results in c&ronic in&ibition of
t&rombo9ane metabolites an ecrease e9cretion of
prostacyclin metabolites in preeclamptic patients$ :o,)ose
aspirin t&erapy is aime at restoring t&e presume t&rombo9ane)
prostacyclin imbalance in preeclampsia$
P$ J<TR<C OR<D(
Jitric o9ie *JO+ is an enogenous vasoilator an in&ibitor of
platelet aggregation an acts synergistically ,it& prostacyclin$ <t
is prouce by enot&elial cells from :)arginine$ Synt&esis can
be in&ibite by arginine analogs suc& as JG)monomet&yl):)
arginine an JG)nitro):)arginine$ <ntravenous in?ection of one of
t&ese in&ibitors into rats! rabbits! or guinea pigs causes an
immeiate rise in bloo pressure t&at is reverse by :)arginine$
T&is inicates t&at continual basal release of JO from
enot&elial cells 0eeps t&e vasculature in a ilate state$ JO
acts only in t&e immeiate vicinity of t&e cell t&at releases it$
@ny t&at escapes into t&e bloostream ecays c&emically to
form nitrite or is immeiately inactivate by &emoglobin$
JO plays an important role in several pat&ologic processes$ <t is
one of t&e meiators of &ypotension in septic s&oc0$ @
eficiency of JO contributes to t&e cause of &ypertension an
at&erosclerosis$ Currently it is t&oug&t t&at t&e JO system may
be more important t&an t&e prostaglanins in t&e pat&ogenesis
of preeclampsia$ C&ronic bloc0ae of t&e enogenous JO system
prouces a moel of &ypertension an renal amage in pregnant
an nonpregnant rats$ Some stuies &ave s&o,n t&at t&ere is
ecrease e9cretion of JO in t&e urine of pregnant preeclamptic
,omen! but ,&et&er JO plays an important pat&op&ysiologic
role in t&e evelopment of preeclampsia remains un0no,n$
:$ (JDOTH(:<J)1
<n aition to t&e rela9ing factors prostacyclin an JO! t&e
vascular enot&elium releases vasoconstrictor substances$ T&e
vasoconstrictor enot&elin ,as iscovere in 19EE$ T&ere are 7
ifferent isopeptiesA enot&elin 1! .! an 7$ (not&elin)1 is t&e
only enot&elin manufacture by enot&elial cells$ (not&elins
are also synt&esi2e by 0iney cells an nervous tissue$ T&ere
are ,iesprea enot&elin)bining sites incluing t&ose in t&e
brain! lung! 0iney! arenal! spleen! intestine! an placenta$ <t
is t&oug&t t&at enot&elins act as enogenous agonists of
i&yropyriine)sensitive calcium c&annels$ T&e most stri0ing
property of enot&elin)1 is its long)lasting vasoconstrictor
action$ <t is 1/ times more potent t&an angiotensin <<$ (not&elin
may play a role in constriction of placental vessels after elivery
an may regulate closure of t&e uctus arteriosus in t&e
ne,born$ T&e mitogenic effects of enot&elin)1 may cause
vascular ,all &ypertrop&y in at&erosclerosis an &ypertension$
(not&elin)1 may play a role in renal vasoconstriction in acute
renal failure$ @ 7)fol elevation of plasma enot&elin 1 an . &as
been foun in ,omen ,it& preeclampsia compare ,it&
gestation)matc&e controls$
One &ypot&esis is t&at prostacyclin is an antiplatelet an
vasoilator mec&anism &el in reserve to reinforce t&e JO
system ,&en enot&elial amage occurs$ :ac0 of JO may be a
causative factor in &ypertension$ (not&elin)1 is release by
enot&elial cells to constrict t&e unerlying smoot& muscle in an
emergency suc& as laceration$ (9cess enot&elin)1 may also be
involve in t&e genesis of &ypertension$
"$ P:@C(JT@
<n normal pregnancy! t&e proliferating trop&oblast invaes t&e
eciua an t&e a?acent myometrium in . formsA interstitial
an enovascular$ T&e role of t&e interstitial form is not clear
but it may serve to anc&or t&e placenta$ T&e enovascular
trop&oblastic cells invae t&e maternal spiral arteries! ,&ere
t&ey replace t&e enot&elium an estroy t&e meial elastic an
muscular tissue of t&e arterial ,all$ T&e arterial ,all is replace
by fibrinoi material$ T&is process is complete by t&e en of t&e
first trimester! at ,&ic& time it e9tens to t&e
eciuomyometrial ?unction$ T&ere appears to be a resting
p&ase in t&e process until 15 to 14 ,ee0s3 gestation! ,&en a
secon ,ave of trop&oblastic invasion e9tens o,n t&e lumen
of t&e spiral arteries to t&eir origin from t&e raial arteries eep
in t&e myometrium$ T&e same process is t&en repeate! ie!
replacement of t&e enot&elium! estruction of t&e meial
musculoelastic tissue! an fibrinoi c&ange in t&e vessel ,all$
T&e en result is t&at t&e t&in),alle! muscular spiral arteries
are converte to sacli0e! flacci uteroplacental vessels! ,&ic&
passively ilate to accommoate t&e greatly augmente bloo
flo, re1uire in pregnancy *'ig 19-.+$
'igure 19-.$ T&e placental be in normal an preeclamptic
pregnancy$ <n preeclampsia! t&e p&ysiologic c&anges in t&e
uteroplacental arteries o not e9ten beyon t&e
eciuomyometrial ?unction! leaving a constricting segment
bet,een t&e raial artery an t&e eciual portions$
*Reprouce! ,it& permission! from %rosens <@A "orp&ological
c&anges in t&e uteroplacental be in pregnancy &ypertension$
Clin Obstet Gynaecol 19==;5A8=7$+
Preeclampsia evelops follo,ing a partial failure in t&e process
of placentation$ 'irst! not all t&e spiral arteries of t&e placental
be are invae by trop&oblast$ Secon! in t&ose arteries t&at
are invae! t&e first p&ase of trop&oblastic invasion occurs
normally! but t&e secon p&ase oes not occur! an t&e
myometrial portions of t&e spiral arteries retain t&eir reactive
musculoelastic ,alls$
<n aition! acute at&erosis *a lesion similar to at&erosclerosis+
evelops in t&e myometrial segments of t&e spiral arteries of
patients ,it& preeclampsia$ T&e lesion is c&aracteri2e by
fibrinoi necrosis of t&e arterial ,all! t&e presence of lipi an
lipop&ages in t&e amage ,all! an a mononuclear cell
infiltrate aroun t&e amage vessel$ @cute at&erosis may
progress to vessel obliteration ,it& corresponing areas of
placental infarction$
T&us! in preeclampsia t&ere is an area of vascular resistance in
t&e spiral artery because of failure of t&e secon ,ave of
trop&oblastic invasion$ <n aition! acute at&erosis furt&er
compromises t&e vascular lumen$ Conse1uently! t&e fetus is
sub?ecte to poor intervillous bloo flo, from t&e time of early
gestation; t&is may result in intrauterine gro,t& retaration or
stillbirt&$ @nti&ypertensive t&erapy may be etrimental because
perip&eral vasoilatation may furt&er reuce t&e alreay
compromise placental bloo flo,$
Clinical 'inings
@$ SM"PTO"S @JD S<GJS
1$ HypertensionIHypertension is t&e most important criterion
for t&e iagnosis of preeclampsia! an it may occur suenly$
"any young primigravias &ave bloo pressure reaings of 1//-
11/64/-=/ mm Hg uring t&e secon trimester$ @n increase of 18
mm Hg in t&e iastolic or 7/ mm Hg in t&e systolic pressure
s&oul be consiere ominous$ T&us! in t&ese patients! bloo
pressures of 1./6E/ mm Hg may be relative &ypertension$ T&e
bloo pressure is often 1uite labile$ <t usually falls uring sleep
in patients ,it& mil preeclampsia an c&ronic &ypertension!
but in patients ,it& severe preeclampsia! bloo pressure may
increase uring sleep! eg! t&e most severe &ypertension may
occur at .A// @"$
.$ ProteinuriaIProteinuria is t&e last sign to evelop$ (clampsia
may occur ,it&out proteinuria$ One set of researc&ers foun no
proteinuria in .9> of one series of eclamptic patients$ "ost
patients ,it& proteinuria ,ill &ave glomeruloenot&eliosis on
0iney biopsy$ Proteinuria in preeclampsia is an inicator of
fetal ?eopary$ T&e incience of SG@ infants an perinatal
mortality is mar0ely increase in patients ,it& proteinuric
preeclampsia$
7$ (emaIPreviously a ,eig&t gain of more t&an . lb6,0 or a
suen ,eig&t gain over 1 to . ays ,as consiere ,orrisome$
Ho,ever! eema is a common occurrence in ,omen ,it& normal
pregnancy! an preeclampsia may occur in ,omen ,it& no
eema$ T&e use of eema as a efining criterion for
preeclampsia is controversial! an most recent reports omit it
from t&e efinition$
5$ Differing clinical picture in preeclamptic crisesIPreeclampsia)
eclampsia is a multisystem isease ,it& varying clinical
presentations$ One patient may present ,it& eclamptic sei2ures!
anot&er ,it& liver ysfunction an intrauterine gro,t&
retaration! anot&er ,it& pulmonary eema! still anot&er ,it&
abruptio placentae an renal failure! an anot&er ,it& ascites
an anasarca$
%$ :@%OR@TORM '<JD<JGS
T&e &emoglobin an &ematocrit may be elevate ue to
&emoconcentration! or in more severe cases! t&ere may be
anemia seconary to &emolysis$ T&rombocytopenia is often
present$ 'ibrin split proucts an ecrease coagulation factors
may be etecte$ Lric aci is usually elevate above 4 mg6:$
Serum creatinine is most often normal */$4-/$E mg6:+ but may
be elevate in severe preeclampsia$ @lt&oug& &epatic
abnormalities occur in about 1/> of patients! t&e bilirubin is
usually belo, 8 mg6: an t&e aspartate aminotransferase *@ST+
belo, 8// <L$ @l0aline p&osp&atase may increase .) to 7)fol$
:actate e&yrogenase may be 1uite &ig& *because of &emolysis
or liver in?ury+$ %loo glucose an electrolytes are normal$
Lrinalysis reveals proteinuria an occasional &yaline casts$
Differential Diagnosis
See Table 19-1$
Complications
Preeclampsia may be associate ,it& early elivery an fetal
complications ue to prematurity$ 'etal ris0s inclue acute an
c&ronic uteroplacental insufficiency$ <n t&e most severe cases!
t&is may result in intrapartum fetal istress or stillbirt&$ C&ronic
uteroplacental insufficiency increases t&e ris0 of intrauterine
gro,t& retaration an oligo&yramnios$
Prevention
"ore t&an 1// clinical! biop&ysical! an bioc&emical tests &ave
been reporte to preict preeclampsia$ Lnfortunately! most
suffer from poor sensitivity! an none are suitable for routine
use as a screening test in clinical practice$ @s a result! most
stuies of prevention &ave use patients ,it& various ris0 factors
for preeclampsia$
@$ C@:C<L" SLPP:("(JT@T<OJ
Several aut&ors &ave reporte reuce urinary e9cretion of
calcium uring preeclampsia an for several ,ee0s prior to t&e
onset of clinically apparent isease$ <n aition! abnormal
intracellular calcium metabolism in platelets an re bloo cells
&as been emonstrate in ,omen ,it& preeclampsia as
compare ,it& normotensive pregnant ,omen$ Ho,ever! t&ere
are no ata suggesting t&at calcium supplementation prevents
preeclampsia in ,omen ,it& lo,)ris0 pregnancies$
T&e Jational <nstitutes of Healt& stuie 58E9 &ealt&y
nulliparous ,omen by ranomly assigning t&em to receive . g
elemental calcium or placebo aily at 17 to .1 ,ee0s3 gestation$
<n t&is stuy t&ere ,as no ecrease in t&e incience or severity
of preeclampsia in t&e group receiving calcium$ Ho,ever!
ranomi2e trials on ,omen consiere to be at &ig& ris0 for
eveloping preeclampsia &ave suggeste a reuction in t&e
incience of t&e isease among ,omen receiving supplemental
calcium$
%$ @SP<R<J
T&ere is evience to suggest t&at t&rombo9ane @. prouction is
mar0ely increase! ,&ile prostacyclin prouction is reuce in
,omen ,it& ,ell)establis&e preeclampsia an prior to t&e
onset of preeclampsia$ <n aition! placental infarcts an
t&rombosis of t&e spiral arteries &ave been emonstrate in
pregnancies complicate by preeclampsia! particularly in t&ose
,it& severe fetal gro,t& retaration or fetal emise$ @s a result
of t&ese finings! several aut&ors &ave use various
antit&rombotic agents in an attempt to prevent preeclampsia$
Toay t&e prevailing opinion is t&at aspirin prop&yla9is oes not
benefit most ,omen in t&e prevention of preeclampsia$ (ig&t
large stuies &ave been one ,orl,ie to investigate t&is
treatment$ @ll emonstrate minimal to no reuction in t&e
incience of preeclampsia$ So t&e place of aspirin in
preeclampsia prevention is uncertain$ <t may be t&at t&e
benefits are confine to &ig&)ris0 ,omen$ @ furt&er matter of
concern is t&e &ig&er incience of abruptio placentae foun in
t&e aspirin)treate patients in one stuy$
T&ere is currently no proven ,ay to prevent preeclampsia! but
goo prenatal care an regular visits to t&e p&ysician ,ill allo,
for early iagnosis before t&e conition becomes severe$
Pregnant ,omen at &ig& ris0 for preeclampsia *t&ose ,it& a
&istory of &ypertension before conception or in a previous
pregnancy! especially before 75 ,ee0s! or multiparity; ,omen
,it& iabetes! collagen vascular isease! or renal isease; an
,omen ,it& multifetal pregnancy+ s&oul unergo baseline
testing early in t&e pregnancy$ Suc& tests ma0e it easier later in
t&e pregnancy to etermine if preeclampsia is eveloping$ T&ese
inclue &ematocrit an &emoglobin! platelet count! serum
creatine an uric aci! an .5)&our urine collection for protein
an creatinine clearance if 1B protein is present on ipstic0$
#omen ,it& a pree9isting &istory of &ypertension are at
increase ris0 of intrauterine gro,t& retaration an s&oul
&ave early ultrasouns if ating is in 1uestion! follo,e by
follo,)up scans to monitor gro,t&$ T&e p&ysician must &ave full
0no,lege of t&e patient profile an must maintain a &ig& ine9
of suspicion t&roug&out t&e pregnancy$ (clampsia cannot al,ays
be prevente$ Patients may eteriorate suenly an ,it&out
,arning$
Treatment
@$ "<:D PR((C:@"PS<@
1$ Treatment of mot&erIT&e treatment of preeclampsia is be
rest an elivery$ T&e patient is usually &ospitali2e upon
iagnosis! since t&is iminis&es t&e possibility of convulsions an
en&ances t&e c&ance of fetal survival$ Hospitali2ation to prevent
premature elivery in preeclampsia is far less e9pensive t&an
t&e cost of caring for a premature infant$
#omen ,it& mil preeclampsia ,&o can be relie on to follo,
t&e p&ysician3s instructions may be treate as outpatients$ @
typical &ome regimen consists of be rest! aily urine ipstic0
measurements of proteinuria! an bloo pressure monitoring$
Patients are seen at least t,ice ,ee0ly for antepartum fetal
&eart rate testing an perioic .5)&our urine protein
measurements$ Patients must be ,arne of anger signals suc&
as severe &eaac&e! epigastric pain! or visual isturbances$ T&e
occurrence of t&ese signals! increasing bloo pressure! or
proteinuria manates communication ,it& t&e p&ysician an
probable &ospitali2ation$
Hospitali2e patients are allo,e to be up an aroun as t&ey
feel comfortable$ T&e bloo pressure is measure every 5 &ours!
an patients are ,eig&e aily$ Lrine ipstic0 testing for protein
is performe aily$ T,enty)four)&our urine stuies for creatinine
clearance an total protein are obtaine t,ice ,ee0ly$ :iver
function! uric aci! electrolytes! an serum albumin are
etermine on amission an ,ee0ly$ Coagulation stuies suc&
as prot&rombin clotting time! partial t&romboplastin time!
fibrinogen! an platelet count s&oul be one in patients ,it&
severe preeclampsia$ @ssessments of gestational age an
estimate fetal ,eig&t are performe by ultrasonic e9amination
on amission an t&ereafter as inicate *usually every .
,ee0s+$
@nti&ypertensive meications are usually ,it&&el unless t&e
iastolic bloo pressure e9cees 1// mm Hg an t&e gestational
age is 7/ ,ee0s or less$ *:ong)term anti&ypertensive t&erapy is
iscusse later uner C&ronic Hypertension$+ Seatives ,ere
use in t&e past but &ave become isfavore because t&ey
interfere ,it& fetal &eart rate testing an because one of t&emI
p&enobarbitalIimpaire vitamin P-epenent clotting factors in
t&e fetus$ T&e usual inications for elivery of patients ,it&
preeclampsia are summari2e in Table 19-.$
Table 19-.$ <nications for elivery in patients ,it&
preeclampsia$
.$ @ssessment of fetal statusI'etal status is evaluate by t,ice)
,ee0ly nonstress tests an ultrasoun assessment of amniotic
flui volume$ Jonreactive nonstress tests re1uire furt&er
evaluation ,it& eit&er a biop&ysical profile or an o9ytocin
c&allenge test$ @mniocentesis to etermine t&e
lecit&inAsp&ingomyelin *:AS+ ratio is not fre1uently use in
preeclampsia! since early elivery is usually for maternal
inications! but it may be useful as t&e fetus approac&es
maturity$ Corticosterois s&oul be use to accelerate fetal lung
maturity in patients ,it& preeclampsia ,&en t&ere is an
immature :AS ratio if it is t&oug&t t&at elivery may occur in t&e
ne9t .-= ays$ #it& rapily ,orsening preeclampsia! fetal
monitoring s&oul be continuous because of t&e ris0 of abruptio
placentae an uteroplacental insufficiency$
%$ S(K(R( PR((C:@"PS<@
T&e goals of management of severe preeclampsia are *1+
prevention of convulsions! *.+ control of maternal bloo
pressure! an *7+ initiation of elivery$ Delivery is t&e efinitive
moe of t&erapy if severe preeclampsia evelops at or beyon
74 ,ee0s3 gestation or if t&ere is evience of fetal lung maturity
or fetal ?eopary$ <f elivery of a preterm infant *F 74 ,ee0s3
gestation+ is anticipate! maternal transfer to a tertiary care
center is avise to ensure proper neonatal intensive care$
"anagement of patients ,it& severe preeclampsia occurring
earlier in pregnancy is controversial$ Some institutions use
anti&ypertensive rugs to control maternal bloo pressure until
fetal lung maturity is reac&e$ Corticosterois s&oul be use to
accelerate lung maturity$
@ll ,omen at 5/ ,ee0s ,it& mil preeclampsia s&oul be
elivere$ @t 7E ,ee0s! ,omen ,it& mil preeclampsia an a
favorable cervi9 s&oul be inuce$ @nyone at 7.-75 ,ee0s ,it&
severe preeclampsia s&oul be consiere for elivery! an t&e
fetus may benefit from corticosterois$ <n patients .7-7. ,ee0s
,it& severe preeclampsia! elivery may be elaye in an effort
to reuce perinatal morbiity an mortality$ T&is s&oul be one
only at a tertiary care center$ T&e mot&er s&oul be place on
magnesium sulfate for a minimum of t&e first .5 &ours ,&ile t&e
iagnosis is mae$ %loo pressure s&oul be controlle ,it& t&e
meications to be iscusse$ T&e patient s&oul be given
corticosterois to promote fetal lung maturity$ T&e mot&er may
be closely observe ,it& fre1uent laboratory evaluations$
<nications for elivery inclue evelopment of symptoms!
laboratory evience of organ amage! an fetal eterioration
*Table 19-.+$ <f t&e gestational age is less t&an .7 ,ee0s! t&e
patient s&oul be offere inuction of labor to terminate t&e
pregnancy$
Kaginal elivery is preferable to cesarean section an labor
inuction s&oul be aggressive$ @ clear enpoint for elivery
s&oul be etermine! usually ,it&in .5 &ours$ <f elivery is not
ac&ieve ,it&in t&e set time frame! cesarean is ,arrante$
Prognosis
See belo,! uner (clampsia$
(C:@"PS<@
(clampsia occurs in /$.-/$8> of all eliveries! ,it& occurrence
being influence by t&e same factors as in preeclampsia$ <n rare
instances! eclampsia evelops before ./ ,ee0s3 gestation$ @bout
=8> of eclamptic sei2ures occur before elivery$ @bout 8/> of
postpartum eclamptic sei2ures occur in t&e first 5E &ours after
elivery! but t&ey may occur as late as 4 ,ee0s postpartum$
Pat&op&ysiology
T&e pat&ogenesis of eclamptic sei2ures is poorly unerstoo$
Sei2ures &ave been attribute to platelet t&rombi! &ypo9ia ue
to locali2e vasoconstriction! an foci of &emorr&age in t&e
corte9$ T&ere is also a mista0en tenency to e1uate eclampsia
,it& &ypertensive encep&alopat&y$ T&ere is a poor correlation
bet,een occurrence of sei2ures an severity of &ypertension$
Sei2ures may occur ,it& insignificant bloo pressure elevations
t&at are only slig&tly &ig&er t&an reaings recore .5 &ours
previously$ T&e &allmar0s of &ypertensive encep&alopat&y
*retinal &emorr&ages! e9uates! an papilleema+ are very
infre1uent in eclampsia! ,&ere funuscopic c&anges are
minimal$
Clinical 'inings
T&ere is usually no aura preceing t&e sei2ure! an t&e patient
may &ave one! t,o! or many sei2ures$ Lnconsciousness lasts for
a variable perio of time$ T&e patient &yperventilates after t&e
tonic)clonic sei2ure to compensate for t&e respiratory an lactic
aciosis t&at evelops uring t&e apneic p&ase$ 'ever is rare but
is a poor prognostic sign$ Sei2ure)inuce complications may
inclue tongue biting! bro0en bones! &ea trauma! or aspiration$
Pulmonary eema an retinal etac&ment &ave also been note
follo,ing sei2ures$
Treatment
@$ PR(J@T@: TR(@T"(JT
1$ Control of sei2uresI<n many centers outsie t&e Lnite
States! anticonvulsants are not use prop&ylactically$ 'or
e9ample! in t&e Lnite Pingom it is t&oug&t t&at t&e maternal
ris0 of eclampsia! alt&oug& variable! can be preicte$
@nticonvulsant rugs suc& as ia2epam! p&enytoin! an
c&lormet&ia2ole are use sparingly$ <n t&e Lnite States!
obstetricians believe t&e ris0 of eclampsia to be unpreictable
an not correlate ,it& symptoms of preeclampsia! bloo
pressure reaings! eep tenon refle9es! or t&e egree of
proteinuria$ "ost aut&orities recommen giving anticonvulsants
to all patients in labor ,&o &ave &ypertension ,it& or ,it&out
proteinuria or eema$ Since many ,omen ,ill be treate ,&o
are at lo, ris0 for sei2ures! t&e rug must be safe for mot&er
an fetus$ 'ifty years of e9perience ,it& magnesium sulfate &as
s&o,n it to be effective an safe$ T&e mec&anism of t&e
anticonvulsant action of magnesium sulfate is un0no,n$ <ts use
&as been critici2e on t&e grouns t&at it oes not cross t&e
bloo)brain barrier an oes not &ave a central nervous system
in&ibitory effect$ #&ile early stuies faile to s&o, a significant
increase in cerebrospinal flui *CS'+ magnesium concentrations
uring t&erapy! more recent stuies &ave s&o,n about a ./>
increase in CS' magnesium levels! an t&ese levels parallel t&ose
in t&e serum$ "agnesium sulfate ecreases t&e amount of
acetylc&oline release at t&e neuromuscular ?unction! resulting
in perip&eral neuromuscular bloc0ae at &ig& magnesium
concentrations; &o,ever! t&is oes not account for its
anticonvulsant effect$ @ recent stuy emonstrate t&at
magnesium sulfate &a a central anticonvulsant effect on
electrically)stimulate &ippocampal sei2ures in rats$ T&e
researc&ers speculate t&at since magnesium ion bloc0s calcium
entry into neurons t&roug& t&e J)met&yl)D)aspartate *J"D@+
receptor-operate calcium c&annel! magnesium sulfate mig&t be
acting t&roug& t&is mec&anism$ On t&e ot&er &an! anot&er
stuy foun t&at magnesium sulfate ,as ineffective in altering
sei2ure isc&arge in pentylenetetra2ole)inuce status
epilepticus in rats$ T&ese researc&ers argue t&at because
magnesium bloc0s calcium entry t&roug& t&e J"D@ receptor-
operate calcium c&annel in a voltage)epenent manner! it
,oul be ineffective in neurons t&at are continuously
epolari2ing as in status epilepticus$ 'inally! Doppler stuies of
brain bloo flo, in preeclamptic ,omen suggest t&at magnesium
sulfate vasoilates t&e smaller)iameter intracranial vessels
istal to t&e mile cerebral artery an may e9ert its main
effect in t&e prop&yla9is an treatment of eclampsia by
reversing vasospastic cerebral isc&emia$
Ot&er actions are transient mil &ypotension uring intravenous
loaing! transient mil ecrease in uterine activity uring active
labor! tocolytic effect in premature labor! an potentiation of
epolari2ing an nonepolari2ing muscle rela9ants$ "agnesium
sulfate &as unpreictable effects on fetal &eart rate variability
*increase! ecrease! or unc&ange+$
"aternal ose)relate effects at various serum levels areA 1/
mg6:! loss of eep tenon refle9es; 18 mg6:! respiratory
paralysis; an .8 mg6:! cariac arrest$ T&e t&erapeutic level is
bet,een 5$E an E$5 mg6:$ T&is range is empiric! base on
levels obtaine ,it& an intramuscular ose usually foun to be
effective$ "agnesium sulfate is usually given intravenously as a
loaing ose of 4 g over ./ minutes follo,e by a constant
infusion of . g6&$ <f plasma levels are lo,er t&an 8 mg6:! t&e
maintenance ose is increase to 7 g6&$
Patients may &ave sei2ures ,&ile receiving magnesium sulfate$ <f
a sei2ure occurs ,it&in ./ minutes after t&e loaing ose! t&e
convulsion is usually s&ort! an no treatment is inicate$ <f t&e
sei2ure occurs more t&an ./ minutes after t&e loaing ose! an
aitional .-5 g of magnesium sulfate may be given$ Lsually a
magnesium level ra,n acutely reveals subt&erapeutic levels!
but occasionally t&is is not so$ <n suc& cases! ia2epam! 8-1/ mg
given intravenously! or amobarbital! up to .8/ mg given
intravenously! may be use$ T&e patient s&oul be c&ec0e
every 5 &ours to be sure t&at eep tenon refle9es are present!
respirations are at least 1.6min! an urine output &as been at
least 1// m: uring t&e preceing 5 &ours$ T&e antiote for
magnesium sulfate overose is 1/ m: of 1/> calcium c&lorie or
calcium gluconate given intravenously$ T&e remeial effect
occurs ,it&in secons$
P&enytoin is not as effective as magnesium for t&e prevention of
eclamptic sei2ures; &o,ever! it may be use safely in settings in
,&ic& t&ere is a ris0 in using magnesium! suc& as patients ,it&
myast&enia gravis$
Dia2epam causes respiratory epression! &ypotonia! poor
feeing! an t&ermoregulatory problems in t&e ne,born$ @lso!
t&e soium ben2oate preservative competes ,it& bilirubin for
albumin bining! t&us preisposing t&e infant to 0ernicterus$
.$ Control of &ypertensionIT&ere is controversy about ,&et&er
or not uteroplacental bloo flo, is autoregulate$ "ost evience
inicates t&at t&e uterine vasculature is ma9imally vasoilate
at all times$ T&erefore! most p&ysicians believe t&at reuctions
in maternal bloo pressure ten to ecrease uteroplacental
perfusion an caution against treatments t&at ,ill cause large!
precipitate rops in mean arterial pressure$ @nti&ypertensive
rugs are usually given if t&e iastolic bloo pressure e9cees
11/ mm Hg$ T&e goal is to bring t&e iastolic bloo pressure into
t&e 9/-1// mm Hg range$
a$ Hyrala2ineIT&e rug of c&oice is &yrala2ine! a irect
arteriolar vasoilator t&at causes a seconary baroreceptor)
meiate sympat&etic isc&arge resulting in tac&ycaria an
increase cariac output$ T&is latter effect is important because
it increases uterine bloo flo, an blunts t&e &ypotensive
response! ma0ing it ifficult to give an overose$ <f late
ecelerations of fetal &eart rate o occur after &yrala2ine
aministration! t&ey usually respon to flui)loaing!
aministration of o9ygen! turning t&e patient on &er sie! an
iscontinuing o9ytocin$ Hyrala2ine is metaboli2e by t&e liver!
an in patients ,it& slo, acetylation! it &as a longer uration$
T&e ose is 8 mg given intravenously every 18-./ minutes$ T&e
onset of action is 18 minutes! t&e pea0 effect occurs ,it&in 7/-
4/ minutes! an t&e uration of action is 5-4 &ours$ Sie effects
inclue flus&ing! &eaac&e! i22iness! palpitations! angina! an
an iiosyncratic lupusli0e synrome in patients ta0ing more t&an
.// mg6 c&ronically$ <n more t&an 98> of cases of
preeclampsia! &yrala2ine ,ill be effective in controlling bloo
pressure$ Ot&er agents &ave been substitute for &yrala2ine!
most commonly labetalol! nifeipine! an ia2o9ie$
b$ :abetalolI:abetalol is a nonselective beta bloc0er an
postsynaptic a1)arenergic bloc0ing agent available for bot& oral
an intravenous aministration$ <ntravenous labetalol is given
every 1/ minutes as follo,sA t&e first ose is ./ mg! t&e secon
is 5/ mg! an subse1uent oses are E/ mgIto a ma9imum
cumulative osage of 7// mg or until bloo pressure is
controlle$ <t may also be given as a constant infusion$ Onset of
action is in 8 minutes! pea0 effect is in 1/-./ minutes! an
uration of action ranges from 58 minutes to 4 &ours$
Lteroplacental bloo flo, appears to be unaffecte by
intravenous labetalol$ <nitial e9perience inicates it to be ,ell)
tolerate by mot&er an fetus$
c$ JifeipineIJifeipine! a calcium c&annel bloc0er! can be
aministere in a bite)an)s,allo, tec&ni1ue to lo,er bloo
pressure acutely$ <t is a po,erful arteriolar vasoilator ,it& t&e
main problem being overs&oot &ypotension$ 'or t&is reason! it
probably s&oul not be use in patients ,it& intrauterine gro,t&
retaration or abnormal fetal &eart rate patterns$ Profoun
&ypotension may be reverse by volume aministration or
intravenous calcium$ @lt&oug& nifeipine appears to &ave muc&
potential! it re1uires furt&er assessment of its use in pregnancy$
$ Soium nitroprussieISoium nitroprussie causes e1ual
egrees of vasoilatation in arteries an veins ,it&out
autonomic or central nervous system effects$ <ts onset of action
is 1$8-. minutes! t&e pea0 effect occurs in 1-. minutes! an t&e
uration of action is 7-8 minutes$ <t is an e9cellent rug for
minute)to)minute control in an intensive care unit setting$ <t
may be titrate against a segmental epiural bloc0 for labor or
cesarean section$ <t is recommene t&at t&e rug not be
aministere intravenously over a perio longer t&an 7/ minutes
in t&e unelivere mot&er because of t&e ris0 of cyanie an
t&iocyanate to9icity in t&e fetus$
e$ Trimet&ap&anITrimet&ap&an! a ganglionic bloc0er! is use
acutely by anest&esiologists to lo,er bloo pressure prior to
laryngoscopy an intubation for general anest&esia$ @ reporte
fetal sie effect is meconium ileus$
f$ JitroglycerinIJitroglycerin given intravenously is a
preominantly venular vasoilator t&at appears to be safe for
t&e fetus$ <t is only a moerately po,erful anti&ypertensive
agent$
'luis suc& as 8> e9trose in Ringer3s lactate! 1.8-18/ m:6&! are
given intravenously$ @ S,an)Gan2 cat&eter is &elpful in patients
,it& pulmonary eema! massive &emorr&age! or oliguria
unresponsive to a 1///)m: flui c&allenge$ @nalgesia ,it&
intravenous meperiine or butorp&anol is given in small oses
every 1-. &ours$ :ocal anest&esia ,it& or ,it&out puenal bloc0
may be use for vaginal elivery$
T&e use of epiural anest&esia in patients ,it& preeclampsia is
some,&at controversial$ T&e problem is suen &ypotension ue
to pooling of bloo in t&e venous capacitance vessels seconary
to sympat&etic bloc0ae$ Ho,ever! ,it& t&e almost universal
use of epiural anest&esia for cesarean section! it &as been
,iely use in preeclamptic patients$ <f t&ere is no evience of
fetal compromise *by fetal &eart rate criteria+! if t&ere is no
coagulopat&y present! if t&e patient is pre&yrate! an if a
segmental activation tec&ni1ue is use by an e9perience
anest&esiologist! epiural anest&esia may be use for labor an
elivery or for cesarean section$ <f t&ese criteria are not met!
t&en balance general anest&esia is preferre for cesarean
section$ Spinal anest&esia is consiere contrainicate for
,omen ,it& severe preeclampsia$
C$ POSTP@RTL" TR(@T"(JT
Some of t&e constraints of t&erapy no longer apply once elivery
&as occurre! eg! soium nitroprussie or iuretics may be use$
Since .8> of eclamptic sei2ures occur postpartum! patients ,it&
preeclampsia are maintaine on magnesium sulfate for .5 &ours
after elivery$ P&enobarbital! 1./ mg6! is sometimes use in
patients ,it& persistent &ypertension in ,&om spontaneous
postpartum iuresis oes not occur or in ,&om &yperrefle9ia
persists after .5 &ours of magnesium sulfate$ @lternatively!
magnesium sulfate may not be continue for 74-5E &ours$
Hypertension may not resolve until 4 ,ee0s postpartum$ <f t&e
iastolic bloo pressure remains consistently above 1// mm Hg
for .5 &ours postpartum! any number of anti&ypertensive agents
coul be given! incluing a iuretic! calcium c&annel bloc0er!
@C( in&ibitor! central alp&a agonist! or beta)bloc0er$ T&e bloo
pressure s&oul be c&ec0e in t&e staning position to avoi t&e
possibility of ort&ostatic &ypotension$ @t follo,)up after 1 ,ee0!
t&e nee for continuing anti&ypertensive t&erapy may be
reevaluate$
Prognosis
"aternal eat&s ue to preeclampsia)eclampsia are rare in t&e
Lnite States! but eat& may be cause by cerebral
&emorr&age! aspiration pneumonia! &ypo9ic encep&alopat&y!
t&romboembolism! &epatic rupture! renal failure! or anest&etic
accient$ <t is important to stress t&at iatrogenic complications
increase if multiple rugs are given$ <f t&e patient truly &a
preeclampsia! t&e ris0 of recurrence is less li0ely *77>+ t&an if
s&e &a c&ronic &ypertension mista0en for preeclampsia$ <n t&e
latter situation! t&e ris0 of recurrence is 1uite &ig& *=/>+$ <n
stuies t&at inclue multiparas ,it& preeclampsia! t&e
recurrence rate in t&e ne9t pregnancy is as &ig& as =/>$ <n one
stuy of primigravias ,it& eclampsia! only 77> &a some
&ypertensive isorer in any subse1uent pregnancy; in most
cases! t&e conition ,as not severe! but .> i &ave recurrence
of eclampsia$
T&e effect of preeclampsia)eclampsia on subse1uent
evelopment of c&ronic &ypertension is ebatable$ Confusion
may result from a mista0en iagnosis of preeclampsia in ,omen
,it& unerlying renal isease or c&ronic &ypertension$ <n one
stuy of ,omen ,it& eclampsia uring t&eir first pregnancy ,&o
,ere follo,e for more t&an 5/ years! no increase ,as seen in
t&e incience of &ypertension or eat&s ue to cariovascular
isease or ot&er causes$ "ultiparas ,it& eclampsia &a a muc&
&ig&er incience of subse1uent &ypertension an eat&s ue to
cariovascular isease an ot&er causes$ <t seems reasonable to
conclue t&at t&e ris0 of recurrent eclampsia in subse1uent
pregnancies is not &ig& enoug& to recommen against future
pregnancies$ Preeclampsia oes not cause permanent amage!
preispose to c&ronic &ypertension! or aversely affect t&e long)
term &ealt& of t&e mot&er$
CHROJ<C HMP(RT(JS<OJ
T&e incience of c&ronic &ypertension varies among ifferent
populations! ranging from /$8-5> an averaging .$8>$ C&ronic
&ypertension in pregnancy is usually iiopat&ic *E/>+ or ue to
renal isease *./>+! t&oug& t&ese figures may reflect insufficient
investigation$ @ number of renal iseases may be causative! t&e
most common being c&ronic glomerulonep&ritis! interstitial
nep&ritis! iabetic glomerulosclerosis! <g@ nep&ropat&y! an
renal artery stenosis$
Clinical 'inings
@$ SM"PTO"S @JD S<GJS
Patients ,it& c&ronic &ypertension ten to be over 7/ years of
age! obese! an multiparous! ,it& associate meical problems
suc& as iabetes or renal isease$ T&e incience is &ig&er in
blac0 ,omen an in ,omen ,it& a family &istory of
&ypertension$ @ ,oman ,&o &as elivere one or more infants
an &as &ypertension in t&is pregnancy most li0ely &as c&ronic
&ypertension$ T&e typical patient &as &ypertension ,it&out
ot&er signs of preeclampsia *eg! proteinuria or nonepenent
eema+$ T&e iagnosis is mae on t&e basis of ocumente
&ypertension before conception or before ./ ,ee0s3 gestation or
persistence of &ypertension after t&e puerperium *4 ,ee0s+$ T&e
iagnosis of c&ronic &ypertension s&oul be confirme by
multiple measurements incluing &ome an6or out)of)office
bloo pressure reaings as recommene in T&e Si9t& Report of
t&e Noint Jational Committee on Prevention! Detection!
(valuation! an Treatment of Hig& %loo Pressure$ <f
&ypertension is severe *stage 7! systolic pressure 1E/ mm Hg or
iastolic pressure 11/ mm Hg+! t&e patient s&oul be evaluate
for reversible causes$ #&et&er ,orsening &ypertension
represents superimpose preeclampsia or &ypertension
associate ,it& renal isease is sometimes ifficult to
etermine$ Pree9isting renal isease alone may &ave all t&e
manifestations of preeclampsia *&ypertension! eema!
proteinuria! an &yperuricemia+$ Renal biopsy ,oul confirm t&e
iagnosis but is usually not necessary! because t&e ecision to
eliver can be base on ifficulty of bloo pressure control!
renal function! an fetal ,ell)being$ 'or t&e same reasons! renal
biopsy is usually not performe for t&e ,or0)up of proteinuria or
elevate serum creatinine in pregnancy$
%$ :@%OR@TORM! R)R@M! @JD (:(CTROC@RD<OGR@PH<C 'inings
T&e (CG may s&o, left ventricular &ypertrop&y in 8-1/> of
patients$ (levate serum creatinine! ecrease creatinine
clearance! an proteinuria are also present in about 8-1/> of
patients ,it& c&ronic &ypertension$ T&e c&est 9)ray is usually
normal! t&oug& it may reveal cariomegaly$ Patients ,it& left
ventricular &ypertrop&y or elevate serum creatinine are at
increase ris0 for eveloping superimpose preeclampsia$
Patients ,it& cariomegaly ue to eit&er &ypertensive
cariovascular isease or congestive cariomyopat&y are at
increase ris0 for superimpose preeclampsia! pulmonary
eema! an arr&yt&mias$
Complications
@$ "@T(RJ@: CO"P:<C@T<OJS
T&e main complication of c&ronic &ypertension is superimpose
preeclampsia! ,&ic& occurs in about one)t&ir of patients$
Patients ten to eteriorate faster ,it& superimpose
preeclampsia t&an ,it& preeclampsia alone$ T&ere is an
increase ris0 of abruptio placentae ,it& c&ronic &ypertension
*/$5-1/>+$ @ssociate ,it& t&is conition is t&e ris0 of
isseminate intravascular coagulation! acute tubular necrosis!
or renal cortical necrosis$
T&e effect of pregnancy on c&ronic renal isease is uncertain$
@lt&oug& t&ere are fe, ata for patients ,it& severe isease!
limite evience suggests t&at if renal function is ,ell preserve
*creatinine F 1$8 mg6:+! pregnancy oes not c&ange t&e course
of renal isease! but if renal insufficiency e9ists prior to
pregnancy *creatinine C 1$8 mg6:+! t&e ecline in renal
function may be more rapi t&an e9pecte$
%$ '(T@: CO"P:<C@T<OJS
T&e fetus &as a .8-7/> ris0 of prematurity an a 1/-18> ris0 of
gro,t& restriction$ Preeclampsia tens to occur after 75 ,ee0s3
gestation! so t&at prematurity is not a great concern$
Preeclampsia superimpose on c&ronic &ypertension fre1uently
occurs earlier *at .4-75 ,ee0s+! an in suc& cases! fetuses are at
ouble ?eopary for prematurity an intrauterine gro,t&
retaration$ <n aition! t&ere is a ris0 of stillbirt& or
intrapartum fetal istress ue to abruptio placentae or c&ronic
intrauterine asp&y9ia$
Treatment
@$ COJTRO: O' HMP(RT(JS<OJ
"ost aut&orities agree t&at anti&ypertensive t&erapy ,ill
ecrease t&e incience of stro0e an &eart failure in pregnant
patients ,it& iastolic bloo pressures e9ceeing 11/ mm Hg$
T&e real controversy concerns t&e value of anti&ypertensive
t&erapy of mil &ypertension *appro9imately 98> of pregnant
patients ,it& c&ronic &ypertension &ave mil &ypertension+$ One
stuy emonstrate t&at treatment of iastolic bloo pressures
of 1/5-118 mm Hg in men ecrease cariovascular morbiity
*myocarial infarction! congestive &eart failure! an stro0e+ in
?ust 1/ mont&s$ Patients ,it& iastolic pressures of 95-1/5 mm
Hg s&o,e benefits of t&erapy only after 8 years &a elapse$
T&erefore no benefits of anti&ypertensive t&erapy for mil
c&ronic &ypertension coul be e9pecte uring t&e 9 mont&s of
pregnancy! an t&erapy cannot be ?ustifie by t&e same
arguments use in general internal meicine$ Some aut&ors
claim t&at anti&ypertensive t&erapy for mil c&ronic
&ypertension ,ill ecrease t&e incience or elay t&e onset of
superimpose preeclampsia! t&us lo,ering perinatal mortality
an morbiity rates$ Ot&ers claim t&ere is no benefit an
consierable ris0$ Since t&is issue is still unresolve! a revie, of
some of t&e recent clinical stuies is &elpful *see Reference
section+$
Several oral agents may be consiere if &ypertension is to be
treate$
1$ T&ia2ie iureticsIT&ia2ie iuretics &ave been reporte to
cause a number of &armful maternal an fetal sie effects! t&e
main one being plasma volume contraction$ Stuies in
nonpregnant patients s&o, t&at t&ia2ies &ave acute an c&ronic
effects$ @cutely! t&ey cause a 8-1/> ecrease in plasma volume!
,&ic& lo,ers cariac output an bloo pressure in t&e first 7-8
ays$ Over t&e ne9t 5-4 ,ee0s! renal compensatory mec&anisms
return t&e plasma volume to,ar normal but not pretreatment
levels$ @t t&e same time! cariac output returns to pretreatment
levels! but total perip&eral resistance stays lo,$ T&us! t&e acute
bloo pressure)lo,ering effect of t&ia2ies is ue to volume
contraction$ T&e sustaine anti&ypertensive effect is t&oug&t to
involve mobili2ation of e9cess soium from t&e arterial ,all$
T&is leas to ,iening of t&e vascular lumen an possibly to a
ecrease in t&e vascular responsiveness to enogenous
catec&olamines$ One set of researc&ers s&o,e t&at plasma
volume contraction occurs in early pregnancy in &ypertensive
patients on c&ronic t&ia2ie t&erapy$ #&en t&e t&ia2ie ,as
stoppe! normal p&ysiologic volume e9pansion occurre; if t&e
t&ia2ie ,as continue! plasma volume e9pansion ,as minimal
*1E> mean increase in patients ta0ing t&ia2ies versus 8.> mean
increase in patients in ,&om iuretics ,ere iscontinue early in
pregnancy+$ Perinatal outcome ,as t&e same in bot& groups$
@not&er consieration is t&e volume e9pansion cause by
anti&ypertensive agents$ <t may be t&at t&e soium an ,ater
retention prouce by anti&ypertensive agents offsets t&e
volume contraction cause by t&e t&ia2ie$ <n summary!
iuretics o not prevent preeclampsia or eclampsia$ T&ia2ie
iuretics are contrainicate in patients ,it& pure
preeclampsia$ T&ey may &ave a place in t&e treatment of
patients ,it& c&ronic &ypertension; &o,ever! ,it& t&e
availability of more po,erful anti&ypertensive agents suc& as
nifeipine an labetalol! t&eir use is eclining$
.$ "et&ylopaI"et&ylopa! a central a)arenergic agonist! is
t&e only anti&ypertensive rug ,&ose long)term safety for
mot&er an fetus &as been ae1uately assesse$ <t reuces total
perip&eral resistance ,it&out causing p&ysiologically significant
c&anges in &eart rate or cariac output$ <f met&ylopa is use
alone! flui retention an loss of anti&ypertensive effect are
fre1uent$ 'or t&is reason! met&ylopa is usually combine ,it& a
iuretic for treatment of nonpregnant patients$ <t is usually
starte at a ose of .8/ mg 7 times a ay an increase to .
g6$ Pea0 plasma levels occur .-7 &ours after aministration;
t&e plasma &alf)life is about . &ours! an t&e ma9imum effect
occurs 5-4 &ours after an oral ose$ "ost of t&e agent is
e9crete via t&e 0iney$ T&e most commonly reporte sie
effects are seation an postural &ypotension$ #it& prolonge
t&erapy! 1/-./> of patients evelop a positive irect Coombs3
test! usually after 4-1. mont&s of t&erapy$ Hemolytic anemia
occurs in fe,er t&an 8> of t&ese patients an is an inication to
stop t&e rug$ 'ever! liver function abnormalities!
granulocytopenia! an t&rombocytopenia &ave occurre rarely$
7$ CloniineICloniine is anot&er central a)arenergic agonist$
Treatment is usually starte at /$1 mg t,ice aily an increase
in increments of /$1-/$. mg6 up to .$5 mg6$ %loo pressure
eclines 7/-4/ mm Hg ,it& use of cloniine! ,it& a ma9imum
effect in .-5 &ours an a uration of action of 4-E &ours$ Renal
bloo flo, an t&e glomerular filtration rate are preserve! but
cariac output falls$ T&is is attributable to a ecrease in venous
return seconary to systemic vasoilatation an braycaria$
Cariac output respons normally to e9ercise$ Rerostomia an
seation are t&e most fre1uently encountere sie effects$
#it&ra,al of cloniine prouces a &ypertensive crisis t&at
respons ,ell to reinstitution of t&e rug$ T&ere is not as muc&
information on cloniine in pregnancy as t&ere is on met&ylopa;
one large stuy foun it to be e1uivalent to met&ylopa$
5$ Calcium c&annel bloc0ersICurrently available calcium
c&annel bloc0ers inclue nifeipine! verapamil! iltia2em!
nicaripine! israipine! amloipine! an feloipine$ T&ey cause
irect arteriolar vasoilation by selective in&ibition of slo,
in,ar calcium c&annels in vascular smoot& muscle$ Since
calcium c&annel bloc0ers affect suc& a funamental cellular
response! t&eir t&erapeutic applications are ,ie)ranging! from
angina pectoris to premature labor$ Jifeipine is t&e calcium
c&annel bloc0er most ,iely use in pregnancy$ Jinety percent
of oral nifeipine is absorbe from t&e gastrointestinal tract$
@fter moerate first)pass liver metabolism! t&e bioavailability is
48-=/>$ Onset of action after bite)an)s,allo, aministration is
about 7 minutes$ T&e rug &as an initial fast &alf)life of .$8-7
&ours an a terminal slo, &alf)life of 8 &ours$ <t is almost
completely metaboli2e by t&e liver an e9crete 9/> by t&e
0iney an 1/> by t&e liver$ Sie effects inclue &ypotension!
&eaac&e! flus&ing! tac&ycaria! an an0le eema$ Since
magnesium sulfate is also a calcium c&annel bloc0er! t&e use of
bot& nifeipine an magnesium sulfate toget&er coul be
potentially &a2arous *eg! &ypotension+$ Jifeipine &as been
use in several &uman stuies comparing its tocolytic effect ,it&
ritorine$ <t &as also been use bot& acutely an c&ronically as
an anti&ypertensive agent in pregnancy$ <n t&e largest stuy to
ate! one set of researc&ers ranomly treate .// preeclamptic
patients ,it& nifeipine an be rest or be rest alone$ T&ere
,as no prolongation of pregnancy or improve perinatal
outcome in t&e nifeipine group! but uncontrolle &ypertension
as an inication for elivery ,as reuce$ %ecause it is suc& a
po,erful an epenable agent! nifeipine is becoming
increasingly popular for anti&ypertensive t&erapy in pregnancy$
8$ Pra2osinIPra2osin is a competitive bloc0er of t&e
postsynaptic a1)arenergic receptor$ <t causes vasoilatation of
bot& t&e resistance an capacitance vessels! reucing cariac
preloa an afterloa$ <t lo,ers bloo pressure ,it&out
significantly lo,ering &eart rate! cariac output! renal bloo
flo,! or t&e glomerular filtration rate$ <t is almost e9clusively
metaboli2e in t&e liver$ @ppro9imately 9/> of t&e rug is
e9crete via bile into t&e feces$ <t appears to be more slo,ly
absorbe an its &alf)life slig&tly prolonge uring pregnancy$ <n
one stuy! t&e meian time to pea0 concentration ,as 148
minutes in pregnant ,omen an 1./ minutes in men of similar
age$ T&e mean elimination &alf)life ,as 1=1 minutes in pregnant
,omen an 17/ minutes in men$ Pra2osin may cause a first)ose
p&enomenon c&aracteri2e by suen &ypotension 7/-9/ minutes
after t&e initial ose$ T&is can be avoie by limiting t&e first
ose to 1 mg given ?ust prior to betime$ @nimal stuies &ave
emonstrate no teratogenic effects$ Pra2osin is not a very
po,erful agent an &as usually been combine ,it& t&e beta
bloc0er o9prenolol in obstetric stuies$ <n one stuy pra2osin ,as
use alone or in combination ,it& o9prenolol in 55 pregnant
,omen$ Jo fetal abnormalities or averse effects ,ere note$
@not&er set of researc&ers use pra2osin ,it& or ,it&out
o9prenolol to treat pregnancy &ypertension beginning before 75
,ee0s3 gestation$ Jone of t&e .. patients &a significant
maternal or fetal sie effects attributable to rug t&erapy$
@lt&oug& available since 19=4! pra2osin &a not been ,iely
use in pregnancy$
4$ Hyrala2ineIHyrala2ine is an e9cellent rug for intravenous
t&erapy of &ypertension in pregnancy$ <t is an arteriolar
vasoilator t&at causes a seconary baroreceptor)meiate
sympat&etic response! increasing &eart rate an cariac output$
Ho,ever! it is poorly tolerate orally as a single agent$
Prominent sie effects are &eaac&e! tac&ycaria! palpitations!
flui retention! an a lupusli0e synrome ,&en c&ronic osage
e9cees .// mg6$ "any of t&e un,ante sie effects are
minimi2e ,&en it is use ,it& a iuretic! met&ylopa! or a beta
bloc0er; &o,ever! use of multiple agents is iscourage in
pregnancy$ Dosage is initiate at 1/ mg 5 times aily an
increase to .// mg6$
=$ %eta bloc0ersI%eta bloc0ers ,ere introuce in t&e 194/s
an &ave been use in pregnancy to treat migraine &eaac&e!
&ypertrop&ic obstructive cariomyopat&y! mitral valve prolapse!
Graves3 isease! an &ypertension$ %eta bloc0ers are usually not
ae1uate to control severe &ypertension an are fre1uently
combine ,it& a iuretic! a vasoilator! or bot&$ %eta bloc0ers
&ave been associate ,it& neonatal braycaria! &ypoglycemia!
&yperbilirubinemia! intrauterine gro,t& retaration! respiratory
epression! bloc0ing of tac&ycariac response to &ypo9ia! an
increase in uterine muscle tone causing ecrease uterine bloo
flo,$ T&e fre1uency of t&ese sie effects is un0no,n$ T&oug&
clinical e9perience is accumulating! t&e safety of beta bloc0ers
in pregnancy &as not yet been clearly establis&e$ T&eir use
re1uires t&oug&tful ris0)benefit analysis an clinical ?ugment$
<nfants of mot&ers ta0ing beta bloc0ers s&oul be place in an
intermeiate care unit after elivery to be monitore for sie
effects$
E$ :abetalolIT&e lo, incience of sie effects! lac0 of
teratogenicity! maintenance of uterine bloo flo,! an lo,
propensity to cross t&e placenta ma0e labetalol attractive for
treatment of pregnant ,omen$ One ranomi2e stuy foun it
offere no avantages over met&ylopa in &ypertensive
pregnancy$ @not&er stuy compare t&e use of labetalol plus
&ospitali2ation versus &ospitali2ation alone in t&e management
of .// milly preeclamptic ,omen$ Jo benefit ,as
emonstrate in t&e labetalol)treate group; in aition! t&e
incience of SG@ infants ,as &ig&er in t&at group$ :abetalol is
starte at 1// mg 7-5 times aily an increase to a ma9imum
osage of .5// mg6$ Sie effects are minor an inclue
tremulousness an &eaac&e$
9$ @C( in&ibitorsIT&e 'D@)approve angiotensin)converting
en2yme in&ibitors inclue captopril! enalapril! lisinopril!
fosinopril! ramipril! bena2epril! an 1uinapril$ T&ey are ,iely
use as first)line t&erapy for &ypertension because t&ey
ecrease systemic vascular resistance an &ave fe, sie effects$
"ost of t&e reporte e9periences ,it& @C( in&ibitors in
pregnancy are ,it& captopril or enalapril$ <n &uman pregnancy
t&ese agents &ave been associate ,it& several fetal an
neonatal complications incluing &ypotension! gro,t&
retaration! oligo&yramnios! anuria! renal failure!
malformations! stillbirt&! an neonatal eat&$ @lt&oug& t&ey
&ave been successfully use in pregnancy! t&ey s&oul be
avoie in pregnant ,omen$
%$ (''(CTS O' @JT<HMP(RT(JS<K(S OJ %R(@ST'((D<JG
:ittle is 0no,n about t&e p&armaco0inetics of anti&ypertensive
rugs in &uman breast mil0$ <n general! rugs t&at are lipi)
soluble! un)ioni2e! an not protein boun are foun in
significant levels in breast mil0$ Specific recommenations
concerning some of t&e more important agents are as follo,sA
T&ia2ie iuretics s&oul be avoie! since t&ey ecrease mil0
prouction an &ave been use in t&e past to suppress lactation$
Ho,ever! no electrolyte abnormalities &ave been foun in
infants of mot&ers ta0ing t&ia2ies$ "et&ylopa is probably safe
uring breastfeeing! since lo, plasma levels are foun in t&e
infants$ (9cept for propranolol! t&e ot&er beta)bloc0ing agents
are foun in &ig&er concentrations in breast mil0 t&an in
maternal plasma$ T&erefore! propranolol ,oul probably be t&e
rug of c&oice if a beta bloc0er ,as neee$ Jevert&eless!
accumulate e9perience ,it& various beta bloc0ers &as s&o,n
only very lo, rug concentrations in breast mil0$ Cloniine is
foun in very small amounts in breast mil0$ Captopril appears to
be safe uring breast)feeing because only small amounts are
foun in breast mil0$ Data on t&e ot&er rugs are insufficient to
serve as a basis for recommenations$
C$ G(J(R@: O%ST(TR<C "@J@G("(JT
<n ta0ing t&e meical &istory of t&e &ypertensive pregnant
patient! particular attention s&oul be pai to t&e uration of
&ypertension! use of anti&ypertensive meications! &istory of
renal or &eart isease! an t&e outcome of previous pregnancies$
P&ysical e9amination s&oul inclue a careful funuscopic
e9amination! listening for renal artery bruit! an c&ec0ing t&e
orsalis peis pulses for coarctation of t&e aorta$ T&e bloo
pressure s&oul be measure in t&e sitting position$ <f t&e
blaer of t&e bloo pressure cuff oes not completely encircle
t&e arm! a falsely &ig& bloo pressure reaing may be obtaine$
<n t&is situation! a t&ig& cuff s&oul be use$
@t t&e first prenatal visit! baseline laboratory stuies s&oul be
obtaine for organ systems li0ely to be affecte by c&ronic
&ypertension or to eteriorate uring pregnancy$ Tests s&oul
inclue *but are not limite to+ rinalysis; complete bloo count;
measurements of bloo urea nitrogen! creatinine! serum
electrolytes! uric aci! calcium! an p&osp&orus; liver function
tests; (CG; an .5)&our urine collection for creatinine clearance
an total protein$ <f significant &eart isease is suspecte! a
c&est 9)ray *,it& t&e abomen s&iele+ or ec&ocariogram
s&oul be obtaine$ @ 7)&our oral glucose tolerance test is
esirable! since as many as one)fourt& of patients may &ave
unrecogni2e iabetes$ <f &yperglycemia or ,ie bloo pressure
s,ings are evient! .5)&our urine testing for vanillylmanelic
aci an metanep&rines is recommene to rule out
p&eoc&romocytoma$ T&e patient may be given a regular iet
,it&out salt restriction an s&oul be follo,e every .-7 ,ee0s
until 7/ ,ee0s3 gestation an t&en ,ee0ly t&ereafter$
Gestational age can be ocumente an an SG@ infant etecte
,it& serial ultrasoun e9aminations starte early in pregnancy$
'etal ,ell)being may also be assesse ,it& t&e nonstress test
an amniotic flui ine9 starting at 75 ,ee0s or ,&enever t&e
patient evelops superimpose preeclampsia$ Superimpose
preeclampsia is iagnose on t&e basis of ,orsening
&ypertension *7/ mm Hg systolic or 18 mm Hg iastolic rise+
toget&er ,it& eit&er nonepenent eema or proteinuria$ Some
of t&e more fre1uent inications for early elivery inclue
superimpose preeclampsia! unerlying meical problems suc&
as iabetes or renal insufficiency! abnormal antepartum fetal
&eart rate! an a gro,t& restricte fetus$ @ patient ,it&
,orsening &ypertension may be given betamet&asone to
accelerate fetal lung maturity if t&e lecit&inAsp&ingomyelin ratio
is less t&an . an if elivery can be elaye for 5E-=. &ours after
t&e first ose$
Prognosis
Pregnancy outcome is usually favorable in patients ,it& mil
c&ronic &ypertension! an perinatal survival rates of 98-9=> can
be e9pecte$ T&e main complications are superimpose
preeclampsia! abruptio placentae! prematurity! an intrauterine
gro,t& retaration$ <f t&e patient &as severe &ypertension in t&e
first trimester! onset of superimpose preeclampsia before .E
,ee0s3 gestation! renal insufficiency prior to pregnancy!
&ypertensive cariovascular isease! or congestive
cariomyopat&y! t&e prognosis is more guare$ T&ese patients
re1uire close follo,)up of multiple clinical an laboratory
parameters$ T&e p&ysician must be certain t&at t&ese patients
can be relie upon to ta0e t&eir meication$ T&ey may re1uire a
long perio of &ospitali2ation an are more li0ely to re1uire
cesarean elivery$ T&eir fetuses are at significant ris0 for
prematurity! gro,t& retaration! an eat&$
CH@PT(R R('(R(JC(S
%osio P" et alA "aternal central &emoynamics in &ypertensive
isorers of pregnancy$ Obstet Gynecol 1999;95A9=E$
%roc0elsby NC et alA T&e effects of vascular enot&elial gro,t&
factor on enot&elial cellsA a potential role in preeclampsia$ @m
N Obstet Gynecol .///;1E.*1Pt 1+A1=4$
Goling NA @ ranomi2e trial of lo, ose aspirin for primiparae
in pregnancy$ T&e Namaica :o, Dose @spirin Stuy Group$ %r N
Obstet Gynaecol 199E;1/8A.97$
Herrera N@! @revalo)Herrera "! Herrera SA Prevention of
preeclampsia by linoleic aci an calcium supplementationA a
ranomi2e controlle trial$ Obstet Gynecol 199E;91A8E8$
:evine RNA S&oul t&e efinition of preeclampsia inclue a rise in
iastolic bloo pressure of 18 mm HgS @m N Obstet Gynecol
.///;1E.A..8$
:evine RN et alA Trial of calcium to prevent preeclampsia$ J (ngl
N "e 199=;77=A49$
"ills N: et alA Prostacyclin an t&rombo9ane c&anges preating
clinical onset of preeclampsiaA a multicenter prospective stuy$
N@"@ 1999;.E.A784$
"orriss "C et alA Cerebral bloo flo, an cranial magnetic
resonance imaging in eclampsia an severe preeclampsia$ Obstet
Gynecol 199=;E9A841$
Ranta K et alA Jitric o9ie prouction ,it& preeclampsia$ Obstet
Gynecol 1999;97A55.$
Report of t&e Jational Hig& %loo Pressure (ucation Program
#or0ing Group on Hig& %loo Pressure in Pregnancy$ @m N Obstet
Gynecol .///;1E7AS1$
Rotc&ell M( et alA %arbaos :o, Dose @spirin Stuy in Pregnancy
*%:@SP+A a ranomi2e trial for t&e prevention of pre)eclampsia
an its complications$ %r N Obstet Gynaecol 199E;1/8A.E4$
Sibai %"A Prevention of preeclampsiaA a big isappointment$ @m
N Obstet Gynecol 199E;1=9A1.=8$
Sibai %" et alA Ris0 factors associate ,it& preeclampsia in
&ealt&y nulliparous pregnancy$ T&e Calcium for Preeclampsia
Prevention *CP(P+ Stuy Group$ @m N Obstet Gynecol
199=;1==A1//7$
T&e Si9t& Report of t&e Noint Jational Committee on Prevention!
Detection! (valuation! an Treatment of Hig& %loo Pressure$
@rc& <ntern "e 199=;18=A.517$
Taylor RJA Revie,A immunobiology of preeclampsia$ @m N
Repro <mmunol 199=;7=A=9$
Copyrig&t