Diagnosis & management of imported malaria in pregnant women in non-endemic countries

Though the incidence of malaria is reducing worldwide, cases reported in Europe connected to travel have remained unchanged in the last years1. Every year, there are more than 80 million travellers visiting malaria-endemic areas and many of them are women of child-bearing age2. This poses a serious question considering that pregnant women are more at risk of contracting malaria if comparing them to non-pregnant women345. Malaria in pregnancy is a relevant determinant for both maternal and foetal morbidity and mortality and is especially dangerous in those geographical areas with low rates of transmission. In these areas, women are not immune and can have a rapid progression to severe form of the disease with a higher incidence of respiratory distress and cerebral malaria26. When malaria is diagnosed early and promptly treated before its progression to severe disease, prognosis is good with full recovery1. Considering migration routes and world globalization, it will become more frequent to face diseases like malaria in non-endemic countries, therefore, clinicians worldwide will need to be ready to recognize such diseases and know how to treat them.

Epidemiology

The European Centre for Disease Prevention and Control reports 8349 malaria cases in Europe in 2018 and these data have not changed since 200878910. Near the totality of cases (99.9%) were associated with travels; instead, only a minority of cases were linked to 'baggage' malaria and blood transfusion. Autochthonous transmission was reported in many countries, in particular, Spain, Germany, the Netherlands, France, Italy and Greece1. Plasmodium falciparum (P. falciparum) is the main cause of cases signaled in Europe, especially found in people coming back from journeys in sub-Saharan Africa. On the contrary, even though malaria is not a disease frequently presented by newly arrived migrants moving to Europe for the first time, the data indicate recurrent forms of malaria in this group due to P. vivax or P. ovale1. Hence, malaria remains an issue also for those countries categorized as malaria-free because of cases arising from endemic regions. Moreover, these imported cases often determine many complications in non-endemic countries with, in particular, retarded diagnosis, costly treatment and can be associated to secondary local transmission. The involvement of non-endemic countries has also worsened the phenomenon of drug resistance and detected eradication goals11.

Risk factors

The population most sensitive to the harmful consequences of malaria is represented by pregnant women and children. The effects may be various, depending on the geographical area and the Plasmodium species involved12. Pregnant women have a higher susceptibility to this infection compared to non-pregnant women and this could be related to the immunological and hormonal changes occurring in pregnancy6. Parity and maternal age are two important determinants that can influence the risk of contracting malaria in pregnancy3. In area of high-endemicity, primigravidae are the most affected, whereas in area of low transmission all gravidities have the same risk6. In the first case, primigravidae develop antibodies to the VAR2CSA protein expressed by malaria parasites, and this protects them for the following pregnancies; this does not happen in the second case where women do not acquire immunity and consequently are exposed more easily to serious forms of the disease13.

Other important determinants influencing the gravity of the disease are represented both by the Plasmodium species and the health and nutritional conditions of people involved. Adolescents and adults living in high-transmission areas frequently develop less severe forms. On the contrary, younger children, women at their first pregnancy and travellers to areas of high endemicity are more prone to develop severe forms, which in most cases are due to P. falciparum14. Another important connection is the one involving maternal HIV infection and placental malaria. The retrovirus infection hinders the production of antibodies by the maternal immune system directed against specific antigens expressed by malaria-infected red blood cells. On the other hand, malaria infection can worsen HIV viral load and the risk of its transmission to the foetus. Further, the success of antimalarial drugs is lower in HIV-positive patients. However, anti-HIV treatment can hamper P. falciparum growth in vitro so determining lower gravity of malaria infection1516.

Clinical manifestations of malaria in pregnancy are strongly influenced by geographical area. Pregnant women in areas with a high incidence of the disease usually have no or a few symptoms because of acquired partial immunity. Women in areas of lower incidence or women who had a recent journey to a country of high endemicity develop severe forms of this disease17. These women need to start therapy as early as possible to avoid the risk of serious and potentially lethal manifestations6.

The course of the disease generally involves an incubation period varying from 10 to 21 days. The disease should be suspected in case of one or more of these events: (i) recent travel to an area of high endemicity for this disease; (ii) high body temperature and flu symptoms; (iii) low platelets count; and (iv) miscarriage and sepsis17.

Complications of malaria in pregnancy

Malaria infection in pregnancy is associated with serious negative consequences on both mother and foetus. The principal foetal effects are foetal growth restriction, abortions, stillbirth and neonatal death18. In pregnancy, the augmented risk of contracting infection and having negative consequences due to the disease is related to the accumulation of infected red blood cells in the placenta. In P. falciparum infection, this accumulation is favoured by the binding between the protein VAR2CSA, an antigen expressed by infected red blood cells and the placental chondroitin sulphate A. Placental sequestration of infected erythrocytes leads to an inflammatory response which has been associated with negative consequences, especially foetal growth restriction, maternal anaemia and pregnancy loss19202122.

Symptoms of severe malaria in pregnancy

Malaria in pregnancy requires multi-speciality involvement, including physicians, obstetricians and paediatricians37. Among all symptoms typical of severe malaria, the most frequent conditions for pregnant women are hypoglycemia and pulmonary oedema37. Low blood glucose can be associated with quinine treatment, which causes marked hyperinsulinaemia. The maternal clinical manifestations vary from no symptoms to cold sweats, impaired state of consciousness, epilepsy and are often accompanied by foetal distress. Acute pulmonary oedema is also frequent. It occurs mainly within one week of the birth with chest signs and an augmented breath frequency. Other conditions are severe anaemia, which is added to the anaemia typical of pregnancy. Foetal distress, LBW and foetal death are usual. Post-partum haemorrhage and puerperal sepsis are common. Frequently symptomatic falciparum malaria can favour the onset of uterine contractions and therefore trigger a premature labour with a poor prognosis3338.

Diagnosis

The gold standard for malaria diagnosis in clinical practice remains the microscopic examination of serial blood films. Afterwards, new techniques have been introduced, in particular rapid diagnostic tests which are sensitive to all types of Plasmodium. However, these do not reach the sensitivity and specificity of the classical method and, in particular, these cannot determine parasite count which is a key factor in determining prognosis and therapy39. In conclusion, the new methods must be considered as a support to the conventional ones and not as their substitutes.

Malaria prevention in pregnancy

Expectant women travelling towards areas of high risk should use specific anti-malarial interventions. These include strategies to reduce the risk of mosquito bites and specific drugs for chemoprophylaxis and therapy, especially in endemic areas.These strategies of prevention are necessary for all women travelling in areas of high endemicity and include reducing possible exposure to mosquitoes by living in protected environments avoiding to stay outdoors during the night, protecting body skin with clothes and using treated bednets with (pyrethroids like permethrin)42. Further use of chemoprophylaxis is necessary and strictly recommended. Chloroquine is the drug of choice for prophylaxis when travelling to regions where resistance to this medicine has not been described. When chloroquine is administered in the prophylactic dosage, there are no foetal risks described43. The only other drug approved for chemoprophylaxis is mefloquine (MQ), which can be used if resistance to chloroquine is present43. Doxycycline must not be used by expectant women because of negative effects on foetal teeth and bones caused by tetracycline, a medicine belonging to the same category43. Furthermore, primaquine is not recommended in pregnancy because it can induce haemolytic anaemia in a foetus with favism. All these precautions and therapies are recommended for women seeking pregnancy, and there is no need for them to wait for a precise time frame before starting pregnancy after chemoprophylaxis43.

Therapies

Conclusions

Malaria in pregnancy is a cause of concern globally. There are both maternal and foetal risks associated, especially in non-endemic areas, such as western countries, where there is little immunity against malaria. In these areas, there is a higher risk of developing severe forms that can lead to life-threatening conditions for the mother such as respiratory distress, cerebral malaria or even death, if not recognized and treated promptly. For the foetus also several adverse effects have been described such as stillbirth and LBW. Taking into account the wide migration flows and the high number of people travelling every year to endemic areas, malaria should be considered a global health problem, increasingly involving western countries. Clinicians worldwide need to be prepared for this emerging disease in non-endemic countries. A desirable situation would be that clinicians can give adequate advice to women travelling to endemic areas in terms of prevention, as well as being able to promptly recognize and treat all pregnant patients. This will reduce severe complications for both mother and child.