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072596 treatment of hypertension in pregnant women
D R U G T H E R A PY
The rates are higher in older women, obese women,and black women.8 The diagnosis is usually based oneither a history of hypertension before pregnancy or
A L A S T A I R J . J . W O O D , M . D . , Editor
blood-pressure elevations to at least 140/90 mm Hgbefore 20 weeks’ gestation.1
It is difficult to diagnose chronic hypertension in
TREATMENT OF HYPERTENSION
pregnant women in whom the blood pressure beforepregnancy is not known. In such cases, the diagnosis
IN PREGNANT WOMEN
is usually based on the presence of hypertension be-fore 20 weeks’ gestation. In some women, however,
hypertension before 20 weeks’ gestation may be thefirst manifestation of preeclampsia.9 Furthermore,because of the normal physiologic decrease in blood
pressure during the second trimester, many women
with chronic hypertension have normal blood pres-
nancy and are an important cause of mater-
nal and perinatal morbidity and mortality world-
In nonpregnant women and in men, hypertension
wide.1 During normal pregnancy, systolic pressure
is often classified as mild, moderate, severe, or very
changes little; however, diastolic pressure decreases
severe on the basis of either the systolic or the dia-
by an average of 10 mm Hg early in gestation (13
stolic blood pressure. During pregnancy, chronic
to 20 weeks) and rises again to prepregnancy levels
hypertension is considered either mild or severe. Al-
in the third trimester. The term “hypertension in
though there is no widely accepted definition of mild
pregnancy” describes a broad spectrum of condi-
hypertension, there is agreement that a diastolic
tions in which blood pressure varies widely. In re-
blood pressure of 110 mm Hg or higher (Korotkoff
viewing the literature on this subject, one is faced
phase V) constitutes severe hypertension.
with difficulties regarding the definitions and classi-
In babies born to pregnant women with chronic hy-
fications used to categorize hypertension in preg-
pertension, perinatal outcome is poor, mostly because
nant women,2-6 including which Korotkoff sound
(phase IV or phase V) should be used to measure di-
diagnose superimposed preeclampsia vary, however;
astolic blood pressure.1,5 All current definitions and
they have included exacerbation of hypertension, ede-
classification schemes have certain pitfalls as they re-
ma, proteinuria, hyperuricemia, or a combination of
late to clinical diagnosis and management. Neverthe-
these factors. Neither the exacerbation of hyperten-
less, a recent report by the Working Group on High
sion nor edema is a reliable indicator of superimposed
Blood Pressure in Pregnancy recommended using
preeclampsia. In the absence of renal disease, the onset
the classification system proposed by the American
of proteinuria (at least 300 mg per 24 hours) is the
College of Obstetricians and Gynecologists in 1972,2
best indicator of superimposed preeclampsia.
even though this classification is not accepted in many
Risks to the Mother and Fetus
countries outside the United States.7 In this review,hypertensive disorders of pregnancy will be divided
Pregnant women with chronic hypertension are at
into three categories: chronic hypertension, gestation-
increased risk for superimposed preeclampsia and
al hypertension, and preeclampsia (Table 1).
abruptio placentae, and their babies are at increasedrisk for perinatal morbidity and mortality.8 The like-
lihood of these complications is particularly increased
The incidence of chronic hypertension in preg-
in women with long-standing severe hypertension
nant women ranges from 1 percent to 5 percent.1
and those with preexisting cardiovascular or renaldisease.13-16 In addition, fetal and maternal morbidi-ty and mortality are higher than normal when preg-nant women have a diastolic pressure of 110 mm Hgor higher during the first trimester.14,15 Converse-
From the Division of Maternal–Fetal Medicine, Department of Obstet-
ly, the outcomes of women with mild, uncomplicat-
rics and Gynecology, University of Tennessee, 853 Jefferson Ave., Rm.
ed chronic hypertension during pregnancy and of
E102, Memphis, TN 38103, where reprint requests should be addressedto Dr. Sibai.
their babies are similar to those of normal pregnant
1996, Massachusetts Medical Society.
T h e New E n g l a n d Jo u r n a l of
Me d i c i n e
HYPERTENSIVE DISORDERS OF PREGNANCY.
*Defined as у1ϩ by dipstick testing on two occasions or у300 mg in a 24-hour urine collection.
ed in only three trials,22,23,26 was not reduced by
The results of two retrospective studies of preg-
treatment. Abruptio placentae was mentioned in only
nant women13,17 and randomized trials involving non-
one trial,26 in which there was no difference in fre-
pregnant women18 indicate that antihypertensive
quency between the treated and untreated groups
therapy decreases the incidence of stroke and cardio-
(1 percent in each group). In the two largest tri-
vascular complications among pregnant women with
als,21,26 the incidence of perinatal death was less than
diastolic blood-pressure values above 110 mm Hg.
2 percent in the untreated groups. Demonstrating a
There is general agreement that pregnant women
50 percent reduction in the frequency of either
with severe hypertension should receive pharmaco-
abruptio placentae or perinatal death would have re-
logic treatment,1,8,19 but whether it is beneficial to
quired the enrollment of approximately 2000 wom-
lower blood pressure in pregnant women with mild
en in each group. Therefore, the continued uncer-
essential hypertension is not known.1,8,19
tainty about the benefits of lowering blood pressure
The cardiovascular benefits of long-term therapy
in pregnant women who have mild chronic hyper-
to lower blood pressure in nonpregnant, middle-
tension is mainly due to the fact that all published
aged, and elderly subjects with diastolic pressures of
trials have been too small to detect moderate reduc-
less than 110 mm Hg (mild hypertension) are well
tions in the rates of obstetrical complications.
established.12,18 These benefits were most evident af-
Other trials have evaluated the benefits of lower-
ter four to six years of treatment in men who were
ing blood pressure in pregnant women with mild
older than 50 and those with risk factors for cardio-
chronic or gestational hypertension.27-36 Some have
vascular disease or stroke.12,18 However, most preg-
compared two different antihypertensive drugs; others
nant women with mild chronic hypertension are less
have involved a combination of drugs or compared
than 40 years old and have uncomplicated mild hy-
treatment with no treatment or a placebo (Table 3).
pertension. Therefore, treating mild chronic hyperten-sion in pregnant women is unlikely to be beneficial.
Risks of Pharmacologic Treatment
In order to improve perinatal outcomes, therapy
Antihypertensive drugs have potential adverse ef-
to lower the blood pressure in pregnant women
fects on the mother and the fetus or neonate,37 and
with mild hypertension must reduce the incidence
some of the latter may not become evident until
of preeclampsia, abruptio placentae, preterm deliv-
childhood. Antihypertensive drugs can affect the fe-
ery, and fetal or neonatal death. In the past 30 years,
tus either indirectly, by lowering uteroplacental blood
at least seven studies have compared antihyperten-
flow, or directly, by influencing the umbilical or fetal
sive therapy with either no medication or a placebo
in pregnant women with mild chronic hypertension
Methyldopa is the drug most often used to treat
(Table 2).20-26 There was a higher rate of fetal loss
chronic hypertension in pregnant women and has
during the second trimester among untreated wom-
been used most commonly in randomized trials
en in several early trials,20,21 but this finding was not
(Tables 2 and 3). Short-term treatment with meth-
confirmed in later studies.22-26 There was no decrease
yldopa (for an average of 24 days) during the third
in the frequency of superimposed preeclampsia in
trimester does not affect uteroplacental or fetal he-
five trials.21-24,26 The rate of preterm delivery, report-
modynamics.38 Furthermore, neither short-term ef-
D R U G T H E R A PY
RANDOMIZED TRIALS OF ANTIHYPERTENSIVE DRUG THERAPY IN PREGNANT WOMEN WITH MILD CHRONIC HYPERTENSION.
MEAN WK OF
in whom severe hypertension devel-oped despite treatment
fects on the fetus or neonate26 nor long-term effects
treated with diuretics; whether therapy should be
during infancy39 have been reported after the long-
continued during pregnancy is controversial.1,14,26
term use of methyldopa in pregnancy. In contrast,
The working group concluded that therapy to con-
atenolol has definite adverse effects on uteropla-
trol blood pressure should be continued in women
cental and fetal hemodynamics,40 as well as on fetal
who are already receiving a diuretic or in those treat-
growth.25 The data concerning the potential adverse
ed before 20 weeks’ gestation.1 Diuretic therapy is
effects of other beta-adrenergic–antagonist drugs
particularly useful in pregnant women with salt-sen-
during pregnancy are conflicting.26-28,30-36 Moreover,
sitive hypertension or with left ventricular diastolic
there are no studies of the long-term effects on the
dysfunction; however, it should be discontinued
infant of beta-adrenergic–antagonist drugs during
if preeclampsia develops or there is evidence of re-
duced fetal growth.1 Early initiation of prenatal care
A meta-analysis of nine randomized trials compar-
and close medical supervision are the keys to a suc-
ing diuretic therapy with no treatment in a total of
cessful outcome of pregnancy in such cases.1,13,26
7000 normotensive pregnant women found no dif-
The decision to initiate drug therapy in a woman
ference in the incidence of adverse effects on the
with chronic hypertension should take into account
mother or neonate between the two groups.41 This
the severity of the hypertension, the potential risk of
overview did not evaluate the effects of diuretics on
damage to target organs, and the presence or ab-
fetal growth. Diuretic therapy in pregnant women
sence of preexisting cardiovascular disease.8,12 The
with mild chronic hypertension is associated with a
initial drug of choice is methyldopa. If there are con-
lower-than-normal degree of plasma volume expan-
traindications to its use (such as drug-induced liver
sion, which may be detrimental to fetal growth.23
damage) or if it is ineffective or cannot be tolerated,
Administration of drugs that inhibit angioten-
labetalol or nifedipine can be given.
sin-converting enzyme during pregnancy is contrain-dicated because these drugs are associated with fe-
tal growth retardation, oligohydramnios, congenital
Gestational hypertension is defined as the develop-
malformations, neonatal renal failure, and neonatal
ment of high blood pressure without other symptoms
death.42 There is little experience with the long-term
of preeclampsia after 20 weeks’ gestation in a previ-
administration of calcium-channel–blocking drugs to
ously normotensive woman. In some women, gesta-
pregnant women with hypertension.8,36 Therefore,
tional hypertension may be an early manifestation of
their effects on the fetus and neonate are unknown.
preeclampsia, whereas in others it may be an earlysign of unrecognized chronic hypertension.1,3,5 Gen-
Management of Chronic Hypertension
erally, the outcome of pregnancy in women with ges-
Women with chronic hypertension should be eval-
tational hypertension is good without drug therapy.
uated before conception so that drugs that may haveadverse effects on the fetus (such as angiotensin-
converting–enzyme inhibitors and atenolol) can be
Preeclampsia has traditionally been described as the
replaced by other drugs such as methyldopa or la-
occurrence of hypertension, edema, and proteinuria
betalol. Many women with chronic hypertension are
after 20 weeks’ gestation in a previously normoten-
T h e New E n g l a n d Jo u r n a l of
Me d i c i n e
RANDOMIZED TRIALS OF ANTIHYPERTENSIVE DRUG THERAPY IN PREGNANT WOMEN WITH ALL FORMS OF MILD HYPERTENSION.*
NO. OF OF GESTATION
Fewer side effects in combined-treatment
Fewer cesarean sections in treatment group
Less proteinuria and lower birth weights in
More admissions to neonatal intensive care
*These trials included women with chronic hypertension, gestational hypertension only, or preeclampsia.
sive woman. The differences between preeclampsia
These changes result in reduced perfusion of the
and gestational hypertension are summarized in Ta-
placenta, kidneys, liver, and brain. Endothelial dys-
ble 1. In general, preeclampsia is defined as hyper-
function (resulting in vasospasm, altered vascular
tension plus hyperuricemia or proteinuria, and it is
permeability, and activation of the coagulation sys-
categorized as mild or severe primarily on the basis
tem) could explain many of the clinical findings in
of the degree of elevation in blood pressure, the
women with preeclampsia.4 Indeed, many of the ab-
degree of proteinuria, or both. At present, there is
normalities described in such women are due pri-
no consensus regarding the definition of mild hyper-
marily to reduced perfusion rather than to hyper-
tension, severe hypertension, or severe proteinuria.1-6
Nonetheless, emphasis on either hypertension or pro-teinuria may minimize the clinical importance of
Risks of Preeclampsia to the Mother and Fetus
a number of other disturbances in various organ
The chief risks to the woman entailed by pre-
systems.4 For example, some women with the syn-
eclampsia are convulsions, cerebral hemorrhage,
drome of hemolysis, elevated serum liver-enzyme
abruptio placentae with disseminated intravascular
concentrations, and low platelet counts (HELLP)
coagulopathy, pulmonary edema, renal failure, liver
have life-threatening complications (pulmonary ede-
hemorrhage, and death. The risks to the fetus in-
ma, acute renal failure, or liver rupture) but little or
clude severe growth retardation, hypoxemia, acido-
no hypertension and minimal proteinuria.43 In ad-
sis, prematurity, and death. The frequency of these
dition, among women with preeclampsia who later
complications depends on the duration of gestation
have convulsions (eclampsia), 20 percent have a
at the onset of preeclampsia, the presence or absence
diastolic blood pressure below 90 mm Hg or no
of associated medical complications, the severity of
proteinuria.44 Some women with preeclampsia have
the preeclampsia, and the quality of medical man-
symptoms and signs that are mistakenly thought to
agement. In women with mild preeclampsia who are
indicate the presence of other disorders (Table 4).
closely followed,45-48 the risk of convulsions is 0.2percent, that of abruptio placentae is 1 percent, and
that of fetal or neonatal death is less than 1 percent.
One of the earliest abnormalities noted in women
The incidence of fetal growth retardation (birth
in whom preeclampsia later develops is the failure
weight, Ͻ10th percentile) is 5 to 13 percent, and
of the second wave of trophoblastic invasion into
that of preterm delivery ranges from 13 percent to
the spiral arteries of the uterus. As a result of this
54 percent — depending on the duration of gesta-
defect in placentation, there is failure of the cardio-
tion at onset and the presence or absence of pro-
vascular adaptations (increased plasma volume and
teinuria.45-48 Conversely, maternal and fetal or neo-
reduced systemic vascular resistance) that are char-
natal morbidity and mortality are substantial among
acteristic of normal pregnancy. In preeclampsia, both
women with eclampsia,44,49,50 those with the HELLP
cardiac output and plasma volume are reduced,
syndrome,43,51 and those in whom preeclampsia oc-
whereas systemic vascular resistance is increased.1
D R U G T H E R A PY
preeclampsia and a cervix favorable for induction at
term (Bishop’s score, Ͼ6), delivery should be induced
to avoid possible maternal and fetal complications.1,3 In
contrast, there is no agreement about the managementof mild preeclampsia earlier in pregnancy. In particular,
there is disagreement about the need for bed rest, pro-
longed hospitalization, antihypertensive drug therapy,
Bed rest, whether at home or in the hospital, is
commonly recommended for women with mild pre-
eclampsia.55 The purported benefits of bed rest in-
clude the reduction of edema, improved fetal growth,
Exacerbation of systemic lupus erythematosus
prevention of progression to severe preeclampsia, and
improved outcomes of pregnancy.45-47 In three ran-
domized trials, however, there were no benefits to
bed rest at home or in the hospital among women
with mild gestational hypertension,56-58 although bed
rest at home reduced the number of days of hospi-talization.56-58 In one trial, however, more womentreated at home had progression to severe diseaseand needed preterm delivery.58 Moreover, none ofthese trials were large enough to evaluate the risks
Management of Preeclampsia
of eclampsia, abruptio placentae, and fetal or neona-
Early diagnosis, close medical supervision, and
timely delivery are the cardinal requirements of the
At least 10 randomized trials evaluating drug treat-
management of preeclampsia; delivery is the ulti-
ment in women with mild gestational hypertension
mate cure.1,3 Once the diagnosis is established, sub-
or preeclampsia remote from term have been report-
sequent management should be based on the initial
ed (Table 5).40,46,47,59-66 In eight of these trials, anti-
evaluation of maternal and fetal well-being. On the
hypertensive drug therapy was compared with either
basis of the results of this evaluation, a decision is
no medication or a placebo, and in two trials dif-
then made regarding hospitalization, expectant man-
ferent antihypertensive drugs were compared.40,62 In
agement, or delivery, with the following factors tak-
some trials,59,63-65 the frequency of proteinuria, pro-
en into account: the severity of the disease process,
gression to severe disease, and neonatal respiratory
the status of mother and fetus, and the length of
distress syndrome was higher when the women were
gestation. Irrespective of the management strategy
not treated, but these findings were not confirmed
chosen, the ultimate goal must first be the safety of
in other trials.46,47,60 The effects of treatment on the
the mother and, second, the delivery of a live infant
length of pregnancy, on fetal growth, and on the in-
who will not require intensive and prolonged neona-
cidence of preterm delivery varied. Therefore, there
is no clear benefit to drug treatment in women withmild gestational hypertension or preeclampsia.
Women with preeclampsia require close observa-
tion because the disorder may worsen suddenly. The
Severe preeclampsia may be rapidly progressive,
presence of symptoms (such as headache, epigastric
resulting in sudden deterioration in the status of
pain, and visual abnormalities) and proteinuria
both mother and fetus, so that prompt delivery is rec-
increases the risks of both eclampsia and abruptio
ommended regardless of the duration of gestation.3,67
placentae; women with these findings require close
Prompt delivery is clearly indicated when there is im-
observation in the hospital.45-47 Outpatient manage-
minent eclampsia, multiorgan dysfunction, or fetal
ment may be considered if compliance is expected to
distress or when severe preeclampsia develops after
be good, hypertension is mild, and the fetus is nor-
34 weeks.68 Early in gestation, however, prolonga-
mal. The management should include close monitor-
tion of pregnancy with close monitoring may be in-
ing of the mother’s blood pressure, weight, urinary
dicated in order to improve neonatal survival and
protein excretion, and platelet count, as well as of fe-
reduce short-term and long-term neonatal morbid-
tal status.1 In addition, the woman must be informed
ity.9,53,54,69 In three recent clinical trials in women
about the symptoms of worsening preeclampsia.48 If
with severe preeclampsia remote from term, neona-
there is evidence of disease progression, hospitaliza-
tal morbidity and mortality were reduced with con-
servative management.53,54,69 Nevertheless, because
There is general agreement that in women with mild
only 116 women were assigned to conservative man-
T h e New E n g l a n d Jo u r n a l of
Me d i c i n e
RANDOMIZED TRIALS OF ANTIHYPERTENSIVE DRUG THERAPY IN WOMEN
WITH GESTATIONAL HYPERTENSION OR PREECLAMPSIA.
MEAN WK OF
MEAN WK OF
agement in these trials, and because such manage-
distress with hydralazine, several investigators have
ment entails risk to the mother and fetus, conserva-
recommended using other drugs to treat severe pre-
tive management must be considered only at tertiary
eclampsia (Table 6).69,70,72-79 In nine randomized tri-
perinatal centers and must include very close moni-
als in which hydralazine (or dihydralazine) was com-
pared with another drug, only one found that side
The primary objective of treatment in women with
effects and treatment failure were more frequent in
severe hypertension and preeclampsia is to prevent
cerebral complications such as encephalopathy andhemorrhage. The threshold for treatment is usually
Anticonvulsant Drug Therapy
a sustained diastolic blood pressure of 110 mm Hg
Women with preeclampsia have an increased risk
or higher.3,67-70 Some experts recommend initiating
of convulsions.1,80 The degree of risk depends on the
treatment at diastolic blood-pressure values of 105
severity of the preeclampsia and on the characteris-
mm Hg or even lower,1 whereas others use mean ar-
tics of the woman.80 For many years, authorities in
terial pressure greater than 125 mm Hg as the thresh-
the United States have recommended that magne-
sium sulfate be given prophylactically during labor
The aim of therapy is to keep the mean arterial
and post partum to all women with preeclampsia.80,81
pressure below 126 mm Hg (but not less than 105
In contrast, authorities in other countries consider
mm Hg) and the diastolic pressure below 105
lowering the maternal blood pressure to be adequate
mm Hg (but not less than 90 mm Hg).1,71 The ini-
prophylaxis.82-84 This controversy is not surprising,
tial treatment of choice in women who have severe
since the incidence of eclampsia in women with pre-
hypertension during the peripartum period is hy-
eclampsia is extremely low and varies greatly among
dralazine given intravenously in 5-mg bolus dos-
different groups of women.80-85 For example, in two
es.1,3,71 The dose may be repeated as needed every 20
large, observational studies in the United States, the
minutes up to a cumulative total of 20 mg. If this
average rate of eclampsia among 13,924 women with
amount of hydralazine does not achieve the desired
preeclampsia who received prophylaxis with magne-
therapeutic response, or if the mother has side ef-
sium sulfate was 0.26 percent,80 which does not dif-
fects such as tachycardia, headache, or nausea, labet-
fer substantially from the rate of 0.18 percent among
alol (20 mg intravenously) or nifedipine (10 mg
3885 women with preeclampsia who did not receive
orally) may be given. Because of concern about fetal
D R U G T H E R A PY
RANDOMIZED TRIALS OF ANTIHYPERTENSIVE-DRUG THERAPY IN PREGNANT WOMEN
More effective blood-pressure control in
More effective blood-pressure control in
Similar effects on placental and umbilical
Similar effects on placental flow-velocity
*Severe hypertension was defined as a diastolic blood pressure у110 mm Hg.
†Single values are means; inclusive values are ranges.
‡Inclusive values are ranges; plus–minus values are means ϮSD; single values are means.
§The value was not reported.
Two randomized trials have evaluated prophylaxis
sions in women with eclampsia.87 All women with
with magnesium sulfate in women with preeclamp-
eclampsia should therefore receive magnesium sul-
sia.81,84 In one trial of an antihypertensive drug plus
fate during labor and delivery and for at least 24
magnesium sulfate in 112 women with severe pre-
eclampsia and antihypertensive therapy alone in 116,84there was one case of eclampsia in the magnesium
Prevention of Preeclampsia
sulfate group and none in the other group. In the
For many years, salt restriction and diuretic drugs
other trial,81 magnesium sulfate and phenytoin were
have been used to prevent preeclampsia. It is now
compared for the prevention of eclampsia in 2137
known that dietary sodium restriction during preg-
women with mild preeclampsia. There were 10 cases
nancy reduces blood volume without reducing the
of eclampsia (1 percent) in the phenytoin group and
frequency of hypertension.88 The results of a review
none in the magnesium sulfate group.
of early studies of women at risk for preeclampsia
The routine use of magnesium sulfate prophylaxis
suggested that low doses of aspirin reduced the in-
in all women with preeclampsia has been ques-
cidence and severity of preeclampsia.89 However, the
tioned.85,86 Nevertheless, if a decision is made to treat
results of two large, multicenter, randomized trials
such women prophylactically during labor and deliv-
in nulliparous women90 and women at various de-
ery, magnesium sulfate is the ideal therapy.1,80,81 More-
grees of risk for preeclampsia91 do not support the
over, in a recent large-scale trial, magnesium sulfate
use of aspirin in pregnancy. The results of epidemi-
was superior to both phenytoin and diazepam for
ologic studies have suggested an inverse association
the treatment and prevention of recurrent convul-
between dietary calcium intake, on the one hand,
T h e New E n g l a n d Jo u r n a l of
Me d i c i n e
and maternal blood pressure and the incidence of
Redman CWG. Controlled trials of antihypertensive drugs in pregnan-
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Leather HM, Humphreys DM, Baker PB, Chadd MA. A controlled
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Redman CWG. Fetal outcome in trial of antihypertensive treatment in
during pregnancy to be effective in reducing the risk
of hypertension,93 but its effects on preeclampsia (de-
Arias F, Zamora J. Antihypertensive treatment and pregnancy outcome
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VEER NARMAD S OUTH GUJ ARAT UNIVE RSIT Y, S URAT First Year M. Sc. Biotechnology BIOPHYSICS 1.1 Interference: Interference, coherence and coherent sources, interference by division of wavefront, interference by division of amplitude 1.2 Diffraction: Fresnel and Fraunhoffer diffraction, fraunhoffer diffraction due to (i) single slit (ii) double slit (iii) circular aperture, resol
Ivermectin fact sheet Ivermectin was the first of the avermectins to be used in veterinary medicine and has been widely used as an endectocide in a variety of species, including humans, for 30 years [1, 2]. A macrolide antibiotic in the avermectin group, it is an agonist for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and can be administered orally, topically or by injectio