Malaria in pregnancy is a obstetric, social and medical
problem requiring multidisciplinary and multidimensional solution.
Pregnant women constitute the main adult risk group for malaria and
80% of deaths due to malaria in Africa occur in pregnant women and
children below 5 years. In Africa, perinatal mortality due to
malaria is at about 1500/day. In areas where malaria is endemic,
20-40% of all babies born may have a low birth weight. Malaria in
pregnancy is a Priority Area in Roll Back Malaria strategy.
Malaria
and pregnancy are mutually aggravating conditions. The physiological
changes of pregnancy and the pathological changes due to malaria
have a synergistic effect on the course of each other, thus making the
life difficult for the mother, the child and the treating physician.
P. falciparum malaria can run a turbulent and dramatic course in
pregnant women. The non- immune, primi gravidae are usually the most
affected. In pregnant women the morbidity due to malaria includes
anemia, fever illness, hypoglycemia, cerebral malaria, pulmonary edema,
puerperal sepsis and mortality can occur from severe malaria and
haemorrhage. The problems in the new born include low birth weight,
prematurity, IUGR, malaria illness and mortality.
Malaria in Pregnancy : Double Trouble
More common |
Malaria is more common in pregnancy compared to the general
population. Immuno suppression and loss of acquired immunity to
malaria could be the causes. |
More atypical |
In pregnancy, malaria tends to be more atypical in presentation.
This could be due to the hormonal, immunological and hematological
changes of pregnancy. |
More severe |
Due to the hormonal and immunological changes, the parasitemia tends
to be 10 times higher and as a result, all the complications of
falciparum malaria are more common in pregnancy compared to the
non-pregnant population. |
More fatal |
P. falciparum malaria in pregnancy being more severe, the
mortality is also double (13 %) compared to the non-pregnant
population (6.5%). |
Selective treatment |
Some anti malarials are contra indicated in pregnancy and some may
cause severe adverse effects. Therefore the treatment may become
difficult, particularly in cases of severe P. falciparum
malaria. |
Other problems |
Management of complications of malaria may be difficult due to the
various physiological changes of pregnancy. Careful attention has to
be paid towards fluid management, temperature control, etc. Also
decisions regarding induction of labour may be difficult and
complex. Foetal loss, IUGR, and premature labour are common. |
Pathophysiology
The
pathophysiology of malaria in pregnancy is greatly due to the altered
immunity and availability of a new organ called placenta in
pregnancy. A dramatic breakdown of acquired immunity occurs in
pregnancy, especially in primigravidae. (Paradoxically, fully effective
antimalaria immunity is transferred to the child!) Various hypotheses
have been put forth to explain the pathophysiology of malaria in
pregnancy.
Hypothesis - 1: Loss of antimalarial immunity is consistent with the
general immunosupression of pregnancy viz; reduced lymphoproliferative
response, sustained by elevated levels of serum cortisol. This is
designed to prevent the fetal rejection but renders the pregnant woman
susceptible to infection. However, this does not explain the diminished
susceptibility to malaria experienced by multigravid women.
Hypothesis - 2: What is lost is cell mediated immunity, but what is
transferred is the passive antibody mediated immunity and therefore the
pregnant mother suffers.
Hypothesis - 3: Placenta is a new organ in the primigravidae and
allows the parasites to by-pass the existing host immunity or allows
placenta specific phenotypes of P. falciparum to multiply.
Development of placenta specific immunity may thus explain the decreased
susceptibility in multigravidae.
Recently, it has been discovered that multigravid women can form
strain-independent antibodies against CSA-specific parasites, and they
demonstrate greatly diminished parasite load. The unique susceptibility
of primigravids to placental infection can be explained by their immune
inexperience with the parasite subpopulation.
Hypothesis - 4: Pregnant women display a bias towards type- 2
cytokines and are therefore susceptible to diseases requiring type 1
responses for protection like TB, malaria, leishmaniasis etc. However,
in infected pregnant women a change of balance of the local placental
environment from TH2 to TH1 has been observed, consistent with large
number of monocytes in infected placenta. IL-10 levels are decreased,
while IFN-g
, IL-2, and TNF-α
levels-hallmarks of a type-1 cytokine response-are elevated. These
pro-inflammatory cytokines account for the pathology of maternal
malaria: Elevated levels of TNF-
α
are associated with severe maternal anemia; symptomatology of malaria
and localized cytokine elevation contributes to adverse pregnancy
outcomes.
Role
of Placenta, the NEW ORGAN of pregnancy:
P.
falciparum has the unique ability of cytoadhesion and adhesion
molecules such as CD36 and intercellular adhesion molecule-1 may be
involved in the development of severe malaria in children and
non-pregnant adults. Chondroitin sulfate A and hyaluronic acid have been
identified as the adhesion molecules for parasite attachment to
placental cells. The putative ligand expressed by the parasite is PfCSA-L
and it has been found to be antigenically conserved among global cases
of maternal malaria, suggesting a unique subpopulation of P.
falciparum that do not bind to CD36. The parasites sequester along
the surface of the placental membrane, specifically the trophoblastic
villi, extravillous trophoblasts, and syncytial bridges. Intervillous
spaces are filled with parasites and macrophages, interfering with
oxygen and nutrient transport to the foetus. Villous hypertrophy and
fibrinoid necrosis of villi (complete or partial) have been observed.
All the placental tissues exhibit malarial pigments (with or even
without parasites). These changes impede oxygen-nutrient transfer and
can cause general hemorrhaging. These changes contribute to the
complications experienced by both mother and child.
Pregnancy-malaria and intensity of transmission: Clinical
presentation and severity of malaria in pregnancy differ in areas of
high transmission and low transmission due to differences in the level
of immunity. In high endemic areas, acquired immunity is high, mortality
is less common, asymptomatic and incidental parasitemia are not
uncommon. Sequestration of MP in the placenta and long standing
placental malaria occur and peripheral blood may be negative for MP.
Higher parasitemia, particularly in II and III trimester; anemia and
altered placental integrity result in less nutritional support leading
to LBW, abortion, stillbirth, premature birth and low birth weight, and
excess infant mortality/morbidity. These problems are more common in
first and second pregnancies as the parasitemia level decreases with
increasing number of pregnancy. HIV infection extends this to all
pregnancies and makes it worse. The strategy for management of malaria
in pregnant population in areas of high transmission include
intermittent treatment and use of insecticide treated bednets.
In
areas of low transmission, the problems are dramatically different. The
risk of malaria infection during pregnancy is greater and can result in
maternal death and spontaneous abortion in up to 60% of cases. Low birth
weight can occur even in cases of treated malaria; however, silent
malaria rather rare. The strategy involves measures to avoid malaria by
ITMs/chemoprophylaxis and early diagnosis and prompt treatment of cases.
Table: Comparison of occurrence of complications in areas of high and
low transmission
|
Complication |
High Transmission |
Low transmission |
Hypoglycemia |
- |
++ |
|
Severe Anemia |
+++ |
+++ |
|
Pulmonary oedema |
- |
++ |
|
ARF |
- |
++ |
|
Hyperpyrexia |
+ |
+++ |
|
Placental malaria |
+++ |
+++ |
|
LBW babies |
+++ |
+++ |
|
Abortions |
- |
+++ |
|
Congenital malaria |
- |
+++ |
Clinical features:
Atypical manifestations of malaria are more common in pregnancy,
particularly in the 2nd half of pregnancy.
Fever: Patient may have different patterns of fever - from
afebrile to continuous fever, low grade to hyper pyrexia. In 2nd
half of pregnancy, there may be more frequent paroxysms due to
immunosuppression.
Anemia: In developing countries, where malaria is most
common, anemia is a common feature of pregnancy. Malnutrition and
helminthiasis are the commonest causes of anemia. In such a situation,
malaria will compound the problem. Anemia may even be the presenting
feature of malaria and therefore all cases of anemia should be tested
for MP. Anemia as a presenting feature is more common in partially
immune multigravidae living in hyperendemic areas.
Splenomegaly: Enlargement of the spleen may be variable. It may
be absent or small in 2nd half of pregnancy. A preexisting
enlarged spleen may regress in size in pregnancy.
Complications: Complications tend to be more common and more
severe in pregnancy. A patient may present with complications of malaria
or they may develop suddenly. Acute pulmonary edema, hypoglycemia and
anemia are more common in pregnancy. Jaundice, convulsions, altered
sensorium, coma, vomiting / diarrhoea and other complications may be
seen.
Complications of malaria in pregnancy:
Anemia:
Malaria can cause or aggravate anemia. It could be due to the following
causes:
-
Hemolysis of parasitised red blood cells.
-
Increased demands of pregnancy.
-
Profound hemolysis can aggravate folate deficiency.
Anemia
due to malaria is more common and severe between 16-29 weeks. It can
develop suddenly, in case of severe malaria with high grades of
parasitemia. Pre existing iron and folate deficiency can exacerbate the
anemia of malaria and vice versa.
Anemia
increases perinatal mortality and maternal morbidity and mortality. It
also increases the risk of pulmonary oedema. Risk of post-partum
haemorrhage is also higher.
Significant anemia (Hemoglobin <7-8 g%) may have to be treated with
blood transfusion. In view of the increased fluid volume in pregnancy,
it is better to transfuse packed cells than whole blood. Rapid
transfusion, particularly whole blood, may cause pulmonary oedema.
Acute pulmonary
oedema:
Acute
pulmonary oedema is also a more common complication of malaria in
pregnancy compared to the non-pregnant population. It may be the
presenting feature or can develop suddenly after several days. It is
more common in 2nd and 3rd trimesters.
It can
develop suddenly in immediate post-partum period due to auto transfusion
of placental blood with high proportion of parasitised RBC’s and sudden
increase in peripheral vascular resistance after delivery.
It is
aggravated by pre existing anemia and hemodynamic changes of pregnancy.
Acute
pulmonary oedema carries a very high mortality.
Hypoglycemia:
This is
another complication of malaria that is peculiarly more common in
pregnancy. The following factors contribute to hypoglycemia:
-
Increased demands of hypercatabolic state and infecting parasites.
-
Hypoglycemic response to starvation.
-
Increased response of pancreatic islets to secretory stimuli (like
quinine) leads to hyperinsulinemia and hypoglycemia..
Hypoglycemia in these patients can remain asymptomatic and may not be
detected. This is because, all the symptoms of hypoglycemia are also
caused by malaria viz. tachycardia, sweating, giddiness etc. Some
patients may have abnormal behaviour, convulsions, altered sensorium,
sudden loss of consciousness etc. These symptoms of hypoglycemia may be
easily confused with cerebral malaria. Therefore, in all pregnant women
with falciparum malaria, particularly those receiving quinine, blood
sugar should be monitored every 4-6 hours. Hypoglycemia can be recurrent
and therefore constant monitoring is needed.
In
some, it can be associated with lactic acidosis and in such cases
mortality is very high. Maternal hypoglycemia can cause fetal distress
without any signs.
Immuno suppression:
Immunosuppression in pregnancy poses special problems. It makes malaria
more common and more severe. And to add to the woes, malaria itself
suppresses immune response.
Hormonal changes of pregnancy, reduced synthesis of immunoglobulins,
reduced function of reticulo endothelial system are the causes for
immunosuppression in pregnancy. This results in loss of acquired
immunity to malaria, making the pregnant more prone for malaria. Malaria
is more severe with higher parasitemia. Patient may have more frequent
paroxysms of fever and frequent relapses.
Secondary infections (UTI and pneumonias) and algid malaria (septicaemic
shock) are more common in pregnancy due to immunosuppression.
Risks for the foetus:
Malaria
in pregnancy is detrimental to the foetus. High grades of fever,
placental insufficiency, hypoglycemia, anemia and other complications
can all adversely affect the foetus. Both P. vivax and P.
falciparum malaria can pose problems for the foetus, with the
latter being more serious. The prenatal and neonatal mortality may vary
from 15 to 70%. In one study, mortality due to P. vivax malaria during
pregnancy was 15.7% while that due to P. falciparum was 33%.
Spontaneous abortion, pre mature birth, still birth, placental
insufficiency and IUGR (temporary / chronic), low birth weight, fetal
distress are the different problems observed in the growing foetus.
Transplacental spread of the infection to the foetus can result in
congenital malaria.
Congenital malaria:
Congenital
malaria due to transplacental or peripartal infection of the fetus is
being increasingly reported in has been reported in 8–33% of pregnancies
from both malaria-endemic and nonendemic areas.[9-15] It has been
reported following maternal infections with all four species of human
plasmodium, althighu most cases are reported following P. falciparum
or P. vivax malaria.[5,16,17] In nonendemic countries, P.
malariae may cause a disproportionately higher number of congenital
malaria cases due to its longer persistence in the host.[16] [Also
See]
In
endemic areas symptomatic malaria in the neonate is rare, despite a high
incidence of maternal parasitemia and placental malaria, as maternally
derived IgG and the high proportion of fetal hemoglobin inhibit parasite
development.[16,17] In endemic areas a high prevalence of neonatal
parasitemia has been reported, with majority of the parasitemic newborns
being asymptomatic; however, the mortality was found to be higher in the
parasitemic newborns compared with the aparasitemic and in the
symptomatic compared with the asymptomatic.[11-15] On the other, infants
born to nonimmune mothers with malaria at the time of labour may develop
parasitemia and illness in the first few weeks of life. Congenital
malaria usually manifests between the second and eighth weeks of life
(as early as 1 day or delayed by weeks or months)[10] with symptoms such
as fever, anorexia, lethargy, anemia, and hepatosplenomegaly etc.
Features suggestive of neonatal sepsis such as irritability, poor
feeding, regurgitation, loose stools, jaundice, and occasionally
drowsiness, restlessness, and cyanosis, may also be seen. However,
complications seen in nonimmune adults have not been reported in
congenital malaria.[17]
The diagnosis of
congenital malaria can be confirmed by a smear for MP from cord blood or
heel prick, anytime within a week after birth (or even later if post-partum,
mosquito-borne infection is not likely). Differential diagnoses include
Rh. incompatibility, infections with CMV, Herpes, Rubella, Toxoplasmosis,
and syphilis.
P. vivax malaria in
pregnancy:
There are very few documented studies on P.
vivax malaria in pregnancy. It appears to be more common in primigravidae than
multigravidae. Parasite densities are similar in pregnant and non-pregnant states. It may
be associated with mild anaemia and increased risk of low birth weight and not associated
with abortion, stillbirth or a reduction of the duration of pregnancy. Benefit of
chemoprophylaxis has not been established.
Management of
Malaria in Pregnancy:
Management of malaria in pregnancy
involves the following three aspects and equal importance should be attached to all the
three.
- Treatment of malaria
- Management of complications
- Management of labour
Treatment of malaria:
Treatment of malaria in pregnancy
should be energetic, anticipatory and careful.
Energetic:
-
Don't waste any time.
-
It is better to admit all cases of P.
falciparum malaria.
-
Assess severity- General condition,
pallor, jaundice, BP, temperature, hemoglobin, Parasite count, SGPT, S. bilirubin,
S. creatinine, Blood sugar.
Anticipatory: Malaria in pregnancy
can cause sudden and dramatic complications. Therefore, one should always be looking for
any complications by regular monitoring.
Careful: The physiologic changes
of pregnancy pose special problems in management of malaria. In addition, certain drugs
are contra indicated in pregnancy or may cause more severe adverse effects. All these
factors should be taken into consideration while treating these patients.
-
Choose drugs according to severity of the
disease/ sensitivity pattern in the locality.
-
Avoid drugs that are contra indicated
-
Avoid over / under dosing of drugs
-
Avoid fluid overload / dehydration
-
Maintain adequate intake of calories.
Anti malarials in pregnancy:
All trimesters: Chloroquine;
Quinine; Artesunate / Artemether / Arteether
2nd trimester: Mefloquine;
Pyrimethamine / sulfadoxine
3rd trimester:
Mefloquine; ?Pyrimethamine / sulfadoxine
Contra indicated: Primaquine;
Tetracycline; Doxycycline; Halofantrine
Management of
complications:
[See Treatment of Severe P.
falciparum malaria]
Acute Pulmonary Oedema: Careful
fluid management; back rest; oxygen; diuretics; ventilation if needed.
Hypoglycemia: 25-50% Dextrose,
50-100 ml I.V., followed by 10% dextrose continuous infusion. If fluid overload is a
problem, then Inj. Glucagon 0.5-1 mg can be given intra muscularly. Blood sugar should be
monitored every 4-6 hours for recurrent hypoglycemia.
Anemia: Packed cells should be
transfused if hemoglobin is <5g%.
Renal failure: Renal failure could
be pre-renal due to unrecognised dehydration or renal due to severe parasitemia. Treatment
involves careful fluid management, diuretics, and dialysis if needed.
Septicaemic shock: Secondary
bacterial infections like urinary tract infection, pneumonia etc. are more common in
pregnancy associated with malaria. Some of these patients may develop septicaemic shock,
the so called 'algid malaria'. Treatment involves administration of 3rd generation
cephalosporins, fluid replacement, monitoring of vital parameters and intake and output.
Exchange transfusion: Exchange
transfusion is indicated in cases of severe falciparum malaria to reduce the parasite
load. Patient’s blood is removed and it is replaced with packed cells. It is
especially useful in cases of very high parasitemia (helps in clearing) and impending
pulmonary oedema (helps to reduce fluid load).
Management of
labour:
Anemia, hypoglycemia, pulmonary oedema,
and secondary infections due to malaria in full term pregnancy lead to problems for both
the mother and the foetus. Severe falciparum malaria in full term pregnancy carries a very
high mortality. Maternal and fetal distress may go unrecognised in these patients.
Therefore, careful monitoring of maternal and foetal parameters is extremely important and
pregnant women with severe malaria are better managed in an intensive care unit.
Falciparum malaria induces uterine
contractions, resulting in premature labour. The frequency and intensity of contractions
appear to be related to the height of the fever. Fetal distress is common and often
unrecognised. Therefore only monitoring of uterine contractions and fetal heart rate may
reveal asymptomatic labour and foetal tachycardia, bradycardia or late deceleration in
relation to uterine contractions, indicating fetal distress. All efforts should be made to
rapidly bring the temperature under control, by cold sponging, anti pyretics like
paracetamol etc.
Careful fluid management is also very
important. Dehydration as well as fluid overload should be avoided, because both could be
detrimental to the mother and/or the foetus. In cases of very high parasitemia, exchange
transfusion may have to be carried out.
If the situation demands, induction of
labour may have to be considered. Once the patient is in labour, foetal or maternal
distress may indicate the need to shorten the 2nd stage by forceps or vacuum
extraction. If needed, even caesarian section must be considered.
Treatment of vivax malaria in pregnancy:
In pregnancy, use of primaquine is
contraindicated. Therefore to
prevent the relapse of vivax malaria from reactivation of hypnozoites in the liver,
suppressive chemoprophylaxis with chloroquine is recommended. Tablet Chloroquine 500 mg
weekly should be administered to all such patients until delivery. At that
point, a complete treatment with full therapeutic dose of chloroquine and primaquine
should be administered.
Vaccine against malaria in pregnancy: Although
a general malaria vaccine appears to be a distant possibility, there is much hope for a
vaccine against placental malaria. The administration of excessive soluble CSA to pregnant
women has proven to drastically reduce parasite adhesion; however, in excess levels, this
soluble protein is severely nephrotoxic. Studies have demonstrated that the administration
of chondroitinase AC can effectively reduce parasite adhesion by 95%. This preliminary
data is being further tested in combination with therapeutic use of monoclonal antibodies
to CSA
Also see Chemoprophylaxis
|
