Drug Treatment of Toxemia of Pregnancy —Indications and Limitations—

Clinical Medicine
Drug Treatment of Toxemia of Pregnancy
—Indications and Limitations—
JMAJ 45(3): 97–102, 2002
Yuichiro NAKAI*, Junko NISHIO** and Sachio OGITA***
Lecturer*, Research Associate**, Professor***,
Department of Obstetrics and Gynecology, Medical School, Osaka City University
Abstract:
The cause of toxemia of pregnancy is still unclear, and therefore this
condition is only treated symptomatically. Edema, hypertension, and proteinuria
are the three key elements of this condition, but drug treatment generally targets
only hypertension. Although hydralazine hydrochloride and methyldopa have long
been used as antihypertensive therapies, newer drugs such as calcium antago-
nists have also become used frequently in recent years. The clinical use of these
drugs, however, raises major issues, since some of them are contraindicated for
pregnant women because of excessive fear of adverse drug reactions in the fetus.
Conventional diuretics may cause excessive hemoconcentration during pregnancy,
and therefore, it has become common practice to use them only in the puerperium.
Since toxemia of pregnancy is viewed, in a sense, as chronic disseminated intra-
vascular coagulation (DIC), anticoagulant therapy with aspirin is a treatment option.
This paper describes practical drug treatment of toxemia of pregnancy and the
issues involved in light of the aforementioned considerations.
Key words:
Toxemia of pregnancy; Treatment; Antihypertensive drugs
cussion of sedatives and anticonvulsants.
Introduction
The etiology and pathology of toxemia of
Considerations in Drug Treatment of
pregnancy still remain to be clarified, and tox-
Toxemia of Pregnancy
emia of pregnancy even now is jokingly called
a disease in theory only. Treatment of this con-
1. Concept of toxemia of pregnancy and
dition is, therefore, no more than symptomatic
pathologic states subject to drug treatment
treatment.
The cause of toxemia of pregnancy is still
The present paper outlines the use of drugs in
unclear, and therefore its treatment is restricted
the treatment of toxemia of pregnancy, focus-
to symptomatic treatment. The triad of this con-
ing on antihypertensive drugs with some dis-
dition comprises hypertension, proteinuria, and
This article is a revised English version of a paper originally published in
the Journal of the Japan Medical Association (Vol. 124, No. 7, 2000, pages 989–992).
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Y. NAKAI et al.
edema. Edema localized in lower limbs is not
Table 1
Antihypertensive Drug Therapies for Severe
considered to adversely affect the pregnancy,
Toxemia of Pregnancy
and hence is not the target of treatment. How-
Efficacy rate
No. of cases
ever, edema associated with hypoproteinemia,
(%)
which is often accompanied by pleural effusion
No. of patients on medication
140
52.1
or ascites, should not be left untreated. If main-
Calcium antagonists
70
52.8
tenance of pregnancy is required for a pro-
- or / -blockers
29
48.3
longed period, additional protein supplements
Hydralazine hydrochloride
78
56.4
are necessary. However, since no radical treat-
Methyldopa
17
58.8
ment is available for the cause of hypoprote-
Furosemide
12
66.7
ACE inhibitors
3
66.7
inemia, i.e., leakage of protein into the urine,
except for termination of pregnancy, the preg-
(Including overlapping medication)
(Adapted from reference1))
nancy should be terminated as needed after
judging whether the fetus is viable outside the
uterus.
Hypertension can be treated with various
technical difficulties, the reality is that they will
antihypertensive drugs. Thus, hypertension in
not make a profit.
toxemia of pregnancy is the best target of drug
Japan Society for the Study of Toxemia of
therapy in this condition. However, in such
Pregnancy has discussed this matter at great
cases, placental function is often decreased,
length to establish guidelines for the use of
and fetal development delayed. These cases
these drugs to provide appropriate medical
may often require termination of pregnancy as
care. However, at present, when we consider
fetal distress becomes apparent along with the
the prognosis of a markedly immature fetus,
progression of pregnancy.
obstetricians have no way to maintain a preg-
nancy other than using drugs for which preg-
2. Considerations in drug treatment in
nancy is specified as a contraindication or to be
pregnancy and puerperium
handled similarly to a specific contraindication,
Drug treatment of this condition does have
as long as the safety of the drug has been widely
effects on the fetus during pregnancy and the
accepted (Table 1).1)
neonate via milk, which should be considered.
In general, when medication for toxemia of
Drug treatment in pregnancy is also greatly
pregnancy is necessary after delivery, it is also
restricted at present due to the increased risk
often the case that breastfeeding is not permit-
of malpractice suits and enforcement of the
ted to allow the mother to rest. Many drugs are,
Product Liability Law in Japan. As an extreme
unfortunately, secreted into breast milk and
example, some drugs whose administration in
adversely affect the infant thus requiring the
pregnant women is permitted in western coun-
prohibition of breastfeeding. However, lacta-
tries are contraindicated for pregnant women
tion should not immediately be allowed to stop,
in Japan. The end result in some cases may
because if the period of medication is to be
be that the only way obstetricians can protect
short, breastfeeding can be commenced after
themselves from legal liability is to tell the
the end of medication.
patient that the condition is untreatable and
advise termination of the pregnancy in light of
Use of Antihypertensive Drugs and
the poor prognosis for the fetus. A further issue
Considerations
that must be addressed is that clinical trials in
pregnant women are difficult to perform, and
1. Goal of pressure lowering and precautions
even if a pharmaceutical company overcomes
It is necessary to maintain sufficient placental
98
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DRUG TREATMENT OF TOXEMIA OF PREGNANCY
blood flow during pregnancy. In cases of tox-
medication if possible, and injections should be
emia of pregnancy, increased blood pressure
used only during labor or when pressure must
actually contributes to maintenance of placen-
be rapidly reduced. Oral therapy should begin
tal circulation. In particular, placental function
with an initial dose of 30–40 mg/day, and should
is often markedly lowered in patients with this
not exceed 200 mg/day. Although the package
condition, accompanied by delayed fetal devel-
insert specifies intramuscular or gradual intra-
opment in the uterus. In such cases, caution
venous injection of 1 A (20 mg) when the injec-
should be taken to avoid an excessive drop in
tion formulation is used, an intravenous drip
pressure because a drop in maternal blood pres-
infusion is recommended for patients in the
sure may lead to fetal distress. The target blood
obstetric field, particularly during pregnancy.
pressure reading is 140/90 mmHg, taking into
Although this drug is reportedly unstable in
consideration the minimum blood pressure nec-
glucose solution, usually 1 or 2 A dissolved in
essary for maintaining placental blood flow, and
500 ml of 5% glucose solution are used for
blood pressure should not be allowed to fall
patients with toxemia of pregnancy, in order to
below this level. In addition, candidates for anti-
avoid an overdose of sodium. The infusion rate
hypertensive therapy should be restricted to
should be controlled while monitoring blood
those patients with severe toxemia of pregnancy
pressure. This drug is difficult to use after deliv-
and a blood pressure of over 160/100 mmHg
ery because of its transfer into milk.
to 180/110 mmHg, and the therapy should be
The safety of methyldopa during pregnancy
given only while the patient is hospitalized.
and breastfeeding has not yet been established.
It should also be kept in mind that the objec-
However, its use is indicated when the benefit
tive of antihypertensive therapy for toxemia of
surpasses the risk, and is useful in lowering
pregnancy during pregnancy is to avoid eclamp-
blood pressure in the puerperium. However,
sia and hypertensive encephalopathy while main-
only oral formulations are available for this
taining fetal well-being.
drug, and therefore difficult to use when pres-
sure must be rapidly lowered or during labor.
2. Antihypertensive drugs used to
Therapy should begin with an initial daily dose
treat toxemia of pregnancy
of 1–3 tablets (250–750 mg), which should be
(1) Drugs commonly used to treat toxemia of
increased by 250 mg at intervals of several days.
pregnancy
The maintenance dose is 250–2,000 mg/day,
Antihypertensive drugs commonly used to
taken as divided doses. Quick increases in the
treat toxemia of pregnancy include hydralazine
dose are necessary in toxemia of pregnancy
hydrochloride (Apresoline®) and methyldopa
since it takes a considerable time to achieve a
(Aldomet®).
sufficient drop in blood pressure. However, it is
Hydralazine hydrochloride is reported to be
difficult to control pressure during pregnancy
associated with teratogenicity in mice, and it has
employing this therapy.
been suggested that there is a risk of throm-
(2) Antihypertensive therapy with other drugs
bocytopenia in human fetuses. This drug should
to treat toxemia of pregnancy
be used during pregnancy only when the benefit
a. Calcium antagonists
would surpass the risk. Oral formulations of
Calcium antagonists not only have a depres-
this drug are easy to use, with toxemia of preg-
sor effect through inhibition of smooth muscle
nancy specified as an indication in the package
contraction, but also seem to improve uterine
insert. Injectable formulations of the drug are
and placental blood flow through inhibition of
indicated for hypertensive emergencies includ-
uterine muscle contraction. Therefore, these
ing eclampsia. In general, pressure control dur-
drugs can be used to treat patients with tox-
ing pregnancy should be attempted with oral
emia of pregnancy before delivery. However,
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Y. NAKAI et al.
these agents have been found to be teratogenic
depressor effect can be expected from this drug.
in animal experiments. Deformities generally
In addition, recent investigations have indicated
occur in the early stage of pregnancy, but it is
that increased vascular permeability and hemo-
reasonable to think that these agents may be
concentration are among the pathological fea-
administered in the second or third trimester of
tures of toxemia of pregnancy. The view that
pregnancy. However, the instructions for use
use of this drug during pregnancy worsens pla-
of nifedipine (Adalat®) list pregnant women in
cental circulation by promoting hemoconcent-
the contraindications. In addition, the package
ration is becoming widely accepted. However,
insert for nicardipine (Perdipine®) states that
potent diuresis is necessary for water retention
the drug should not be used in pregnant women,
such as puerperal pulmonary edema, and there-
although it is not listed as a contraindication.
fore active use of this drug is recommended,
In light of these problems, we do not neces-
in addition to d-mannitol and supplementation
sarily recommend calcium antagonist therapy.
therapy for postpartum hypoalbuminemia.
However, they have potent depressor and uter-
Since the safety of Lasix® has not been estab-
ine contraction-inhibiting effects, and sublin-
lished, the use of this drug in the early stage of
gual administration of nifedipine 5–10 mg is
pregnancy is limited to cases where the benefit
extremely effective in immediately lowering
surpasses the risk. In addition, the risk of hemo-
blood pressure. A survey of the Japan Society
concentration is specified for trichlormethiazide
for the Study of Toxemia of Pregnancy (Table
(Fluitran®), but it may be used during pregnancy
1) revealed that calcium antagonists are fre-
when the benefit surpasses the risk.
quently used for treatment of severe cases of
d. Angiotensin converting enzyme (ACE)
toxemia of pregnancy, ranking next to hydra-
inhibitors
lazine hydrochloride.
ACE inhibitors are used frequently in the
b.
-Blockers and / -blockers
field of internal medicine. However, the renin-
These classes of drugs have the advantage
angiotensin system is enhanced during preg-
in that they do not cause reflex tachycardia. 1
nancy and since one of the pathological fea-
blockade can be anticipated, but drugs having
tures of toxemia of pregnancy is that the degree
-blocking actions as well are also used for
of such enhancement is lower than in normal
preventing peripheral circulatory failure. The
pregnancy, medication with this series of drugs
-blockers include atenolol (Tenormin®), and
may be problematic. Furthermore, influences
the / -blockers include labetalol (Trandate®).
on the fetal kidney and severe oligohydramnios
The possibility of causing delayed fetal devel-
due to decreased fetal urine volume have been
opment in the uterus has been raised for ateno-
reported. Thus, ACE inhibitors are considered
lol, but since it is easy to use, it is indicated
to be unsuitable as drugs to be used during
when the benefit surpasses the risk. On the
pregnancy as an antihypertensive agent. The
other hand, as noted in the package insert,
Captopril® package insert states that the drug
labetalol is not to be used in pregnant women,
should not be used in pregnant women. How-
with this population included in the list of
ever, it also states that if it is used due to the
contraindications because its safety in pregnant
lack of an alternative, administration should be
women has not been confirmed yet. It may
minimal, and the condition of the fetus and the
be safer to use drugs with high 1 selectivity
volume of amniotic fluid should be monitored.
because 2-stimulants are generally used to
inhibit uterine contractions.
Use of Sedatives and Anticonvulsants
c. Diuretics
Furosemide (Lasix®) was once used regularly
Sedatives are used for the purpose of lower-
to reduce edema in toxemia of pregnancy, but no
ing blood pressure by rest or to prevent the
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DRUG TREATMENT OF TOXEMIA OF PREGNANCY
onset of eclampsia. Phenobarbital (Phenobal®)
Table 2
Maternal Indications of Pregnancy Termination2)
and chlorpromazine (Contomin®) are commonly
1. Premature delivery or premature rupture of membrane
used sedatives. Since the fetus is also affected,
2. Eclamptic attack or encephalopathy
caution is necessary for the diagnosis of fetal
3. Pulmonary edema
distress on the fetal cardiotocogram.
4. Acute renal failure
If eclampsia is imminent or has developed,
5. Persistent thrombocytopenia
intravenous administration of diazepam
6. Poor control of maternal blood pressure
(Cercine®) is effective. Combined use of an
7. HELLP syndrome
intravenous drip infusion of magnesium sulfate
(Magnesol®) is also recommended.
Chinese herbal medicines in patients with tox-
Other Drugs
emia of pregnancy, such as those documenting
1. Anticoagulant therapy
that the prophylactic use of Sairei-to in patients
Since toxemia of pregnancy is, in a sense,
with a history of severe toxemia of pregnancy
chronic disseminated intravascular coagulation
was equivalent to aspirin in preventing the
(DIC), anticoagulant therapy is a treatment
onset of another episode of toxemia of preg-
option for toxemia of pregnancy. Decreased
nancy. However, these are not standard clinical
antithrombin III (ATIII) and increased fibrin
studies using a sufficiently large number of
degradation products (FDP) are common find-
patients or a strict method of double blinding.
ings, and ATIII supplementation is often
required. Gabexate mesilate (FOY®) is used
Limitations of Drug Treatment
when DIC has developed. Attempts to use
ATIII and heparin as therapies for toxemia of
It is true that drug treatment of toxemia of
pregnancy have been reported in recent years.
pregnancy during pregnancy has its limitations,
These therapies are used to inhibit the for-
particularly in light of the effect on the fetus. In
mation of microthrombi. Aspirin, which has a
general, this condition often improves after
platelet aggregation-inhibition action, is used
pregnancy has ended. Therefore, artificial ter-
to prevent the occurrence of this condition.
mination of pregnancy may be chosen if the
Usually, Bufferin® for children, at a dose of 1
fetus can live outside the uterus, but no abso-
tablet/1 to 2 days, is given. Although the use-
lute guidelines have been set down to help
fulness of this prophylactic method is docu-
make this choice. The maternal indications for
mented in the high-risk group, the efficacy is
pregnancy termination proposed by Miyake et al.
not clear in the low-risk group for prevention
are shown in Table 2 as a reference.2)
of toxemia of pregnancy.
Conclusion
2. Other drugs used for toxemia of pregnancy
Dipyridamole (Persantin®) may be used for
Drug treatment of toxemia of pregnancy is still
the treatment of proteinuria as another drug
restricted to symptomatic therapies. Although
therapy for toxemia of pregnancy. Chinese
it is true that there are many limitations due to
herbal medicines such as Sairei-to have also
considerations of the effect on the fetus and
been prescribed, but they have not been found
other factors, a favorable prognosis for the
to be effective in the treatment of severe tox-
mother and the fetus even in severe cases is
emia of pregnancy for which drug treatment is
now becoming achievable with the careful use
generally indicated.
of drugs.
There are a number of reports on the use of
Better treatment targeted at the cause of tox-
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emia of pregnancy including anticoagulant ther-
REFERENCES
apy, hopefully will be developed in the future.
1)
Hidaka, A. et al.: Journal of Japan Society for
the Study of Toxemia of Pregnancy 1998; 6:
203–214. (in Japanese)
2)
Miyake, Y. et al.: Shusanki Igaku 1995; 25:
1628–1631. (in Japanese)
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