Malaria in Pregnancy

Pregnant women are more susceptible to malaria than the general population: they are more likely to become infected, suffer a recurrence, develop severe complications and to die from the disease. This is thought to be due to general impaired immunity plus a diminution of acquired immunity to malaria in endemic areas. Developing severe anaemia secondary to malaria increases the risk of maternal death - at least 10, 000 maternal deaths per annum are thought to be attributable in Sub-Saharan Africa.¹ Maternal malarial infection has serious consequences for the fetus - it is highly likely to cause miscarriage, stillbirth, premature delivery and low birth weight, increasing risk of infant death. Regardless of symptoms, the presence of plasmodial parasites in a pregnant woman's body will have a negative impact on her and her fetus' health. Restricting treatment to symptomatic pregnant women is an inadequate strategy to reduce the morbidity and mortality associated with malaria.²

Malaria in pregnancy is different to the disease in the non-pregnant state. Placental malaria occurs where P. falciparum infected erythrocytes accumulate in the intervillous space of the placenta but may be rare or absent in the peripheral circulation. This can make diagnosis by light microscopy of blood films more difficult. Complications of malaria tend to affect women more severely in their first and second pregnancies. Immunity is thought to develop with antibodies to the surface adhesion molecules of infected red blood cells.³

Treatment can be more difficult due to restrictions on anti-malarial agents. Many are unlicensed in pregnancy due to lack of clinical trials involving this important population, for fear of damaging the fetus. There is frequently a lack of good post-marketing surveillance where these drugs are routinely used in pregnancy. The situation is worse when considering chemoprophylaxis.⁴
Concurrent HIV infection worsens this scenario significantly: HIV increases susceptibility to malarial infection and the presence of malaria causes an increase in HIV viral load.⁵

Producing good estimates of the global burden of malaria is difficult due to poor numerator (number of women affected by malaria in pregnancy) and denominator (population at risk) data. However:

• In sub-Saharan Africa, the area most burdened by malaria, the disease is thought to cause 400,000 cases of severe maternal anaemia and between 75,000-200,000 infant deaths annually.¹ 25 million pregnant women are believed to be at risk of P. falciparum infection per annum in this region and 25% have evidence of placental infection at the time of delivery.⁶
• Malaria makes a large but unquantifiable contribution to low birth weight in infants in the developing world, a major cause of morbidity and mortality in infants and children. Preventing malaria in pregnant low gravid women:
  • Reduces severe maternal anaemia by 38%
  • Reduces low birth weight by 43%
  • Reduces perinatal mortality by 27%⁶

Preventing and treating malaria in pregnancy can be a key intervention to improving maternal, fetal and child health globally and is linked to 3 of the Millennium Development Goals (MDG-3 Maternal Health, MDG-4 Child Health, MDG-5 Combating infectious disease).⁷

Risk factors⁶

• Primigravida women are at highest risk of malarial infection in high transmission areas (this effect is less marked in low transmission areas and absent in epidemic regions) and at highest risk of serious complications (this effect is also seen in women with one previous birth).⁸ The effect of gravida on complication risk is negated by concurrent HIV infection.⁵
• Younger maternal age (particularly adolescence) carries a higher risk of infection and adverse effects.
• Second trimester carries the highest risk of infection.
• Some studies suggest the increased risk disperses quickly after delivery, others that the first two months' post-partum continue to carry an increased risk of infection.

Atypical presentation of malaria is common in pregnancy, particularly in the 2nd and 3rd trimesters, so a high index of suspicion should be maintained in susceptible pregnant mothers.

• A travel history should be taken in any pregnant woman with unexplained fever or anaemia.
• Fever may be absent, low grade or very high and may not behave in the classical quartian/tertian fashion.
• Anaemia is a common feature and may be the only clue to the illness in mature primigravidae living in endemic areas.
• Splenomegaly may occur but tends to regress in 2nd half of pregnancy.
• Complications (see below), along with features of cerebral malaria (impaired consciousness, seizures) and jaundice can be the presenting features of an acute, severe illness.

As for malaria in general, plus:

• Rhesus incompatibility
• CMV infection
• Herpes infection
• Rubella
• Toxoplasmosis
• Syphilis

Diagnosis of falciparum malaria in pregnancy can be particularly difficult due to placental sequestration of parasites - seek expert help.

• Thick and thin films for malarial parasites should be examined and the degree of parasitaemia determined. Parasites may not be detectable on peripheral blood films.
• FBC, U&E, blood glucose and LFTs including bilirubin levels should also be checked.
• CXR may reveal cases of pulmonary oedema.
• PCR tests are available.
• There are an increasing number of rapid diagnostic tests (RDTs) for malaria. Thus far, problems with inter-species cross-reactivity, variable sensitivity at high/low levels of parasitaemia, false positives/negatives and other difficulties mean that none have been approved by the US Food and Drug Administration, although they continue to be sold to travellers for self-testing and are widely used.

If malaria is suspected in a pregnant patient, refer immediately to secondary/tertiary care where infectious disease, obstetric and neonatal care is on hand and intensive care facilities, if needed.

• Drugs should be used at adequate doses and according to clinical condition and local resistance patterns. Drug safety is paramount in pregnancy:
  • Chloroquine and quinine can be used safely in any part of the pregnancy, but resistance is common.
  • Artemisinins appear to be safe in the second and third trimesters.⁹
  • Mefloquine and pyrimethamine/sulphadoxine are safe in second and third trimesters.
  • Primaquine, tetracycline, doxycycline and halofantrine are contraindicated.
  Current UK treatment guidelines¹⁰ suggest the use of quinine and clindamycin in place of doxycycline.
• Recurrence of malaria is common in pregnancy and resistance frequently reduces the usefulness of anti-malarials.¹¹ Primaquine (for eradication of P. vivax or P. ovale hypnozoites) is contraindicated in pregnancy so following treatment, a pregnant woman should take weekly chloroquine prophylaxis until after delivery.
• Fluid replacement needs to be very carefully monitored to prevent pulmonary oedema.
• If anaemia requires transfusion (Hb < 7-8 g/dl) then packed cells are preferred to avoid fluid overload.
• The complications of malaria should be carefully and aggressively managed.
• Involve the obstetric team early in case of premature labour.

Maternal complications

In endemic/high-transmission areas for malaria, baseline immunity to malaria is decreased by pregnancy. Sufferers are more likely to experience severe anaemia. A non-immune pregnant woman (or one with low immunity from a low-transmission area) is likely to develop a severe form of the illness and complications.

• Anaemia tends to occur between 16-29 weeks - due to haemolysis of parasitised cells and increased demands of pregnancy ± folate/iron deficiency. 5-10% of pregnant African women have severe anaemia, of which 26% is thought to be attributable to malaria.⁶ Severe anaemia eliminates any physiological reserve to cope with haemorrhage, making women more likely to die in childbirth.
• Acute pulmonary oedema occurs much more commonly in pregnant women and may be the presenting feature. It carries a high mortality and is typically seen in the second and third trimesters.
• Hypoglycaemia - this complication of malaria is much more common in pregnancy. It can be aggravated by treatment with parenteral quinine.
• Cerebral malaria is much common in pregnant women.¹²
• Disseminated intravascular coagulation can occur and carries a high mortality.

Fetal complications

Both P. falciparum and P. vivax can cause complications that affect the fetus. Fetal mortality is estimated at 15% for P. vivax and around 30% for P. falciparum. Common problems for the fetus include:¹³

• Spontaneous abortion
• Premature delivery - affects around 15-20%
• Still birth - affects around 4%
• Intrauterine growth retardation - affects around 20%
• Low birth weight - common

Neonatal and infant problems related to malaria include:⁶

• Increased mortality rates
• Congenital malaria
• Anaemia
• Increased rates of other infections
• Undernutrition

Congenital malaria may occur by transplacental spread but has always been considered rare in children born in endemic areas and is more common in offspring of non-immune mothers with malaria. Treatment of the mother may not eradicate parasites from the fetus due to lower drug levels. Congenital malaria tends to present with fever, irritability, feeding difficulties, hepatosplenomegaly, jaundice or anaemia. It is most commonly due to infection with P. malariae and can be diagnosed by blood films of cord or heel-prick blood within a week after birth. Always consider congenital malaria in the differential of a febrile infant in the first 3 months of life of mothers who have travelled to or immigrated from malarial areas.¹⁴

Longer-term developmental problems related specifically to malaria during pregnancy are harder to unpick from those related to low birth weight. It is thought that there may be long term consequences such as short stature and an increased risk of metabolic disease in adulthood.⁶

It is difficult to estimate exact morbidity and mortality rates due to the heterogeneity of severity but with non-immune patients there is a high risk of acute, severe complications and death if the illness is not diagnosed and treated quickly.

Endemic regions

• Intermittent preventive treatment (IPT) with sulphadoxine/pyrimethamine is an effective preventative strategy¹⁵ and even in areas of increasing resistance, two dose IPT still offers significant benefit to the semi-immune, HIV negative pregnant woman.¹⁶ Whilst no drug can be considered completely safe in pregnancy, IPT has a favourable risk-benefit profile used in endemic areas.¹⁷
• Insecticide treated nets are effective, easy to administer and may be used to protect the newborn.¹⁸
• A vaccine specific for pregnancy-associated malaria may be possible to develop based on variant surface antigens expressed by P. falciparum under these conditions.¹⁹

Travel from non-endemic regions^20,21

Non-immune women should be strongly discouraged from travelling to malarial zones due to the high risk of infection and complications. If unavoidable, then advise:

• Avoidance of mosquito bites (remain indoors dusk to dawn, clothing precautions etc.) - note that pregnant women are more attractive to mosquitoes than non-pregnant ones.²²
• Use of DEET-based repellants but avoid concentrations of >50%.
• Rigorous use of insecticide-impregnated nets.
• Chemoprophylaxis during pregnancy:
  • Chloroquine and proguanil - safe in all trimesters of pregnancy but give poor protection in many geographical areas due to drug-resistant P. falciparum. Supplement proguanil in pregnancy with 5 mg folic acid daily.
  • Mefloquine - caution advised. Whilst it appears unlikely that mefloquine is associated with adverse fetal outcomes in the second and third trimesters, there is a lack of data surrounding its use in the first trimester. Its use may be justified in the first trimester where there is a high risk of resistant falciparum malaria - seek expert advice.
  • Doxycycline- contraindicated in pregnancy.
  • Atovaquone and proguanil - lack of evidence on safety in pregnancy.
  Advise that time following the completion of certain antimalarials should be allowed before seeking to conceive:
  • Mefloquine - 3 months
  • Doxycycline - 1 week
  • Atovaquone and proguanil - 2 weeks