The Epidemiology of Postpartum Malaria
The Epidemiology of Postpartum Malaria
Nine of 10 reviewed studies suggested that the risk for malaria infection during pregnancy decreased after delivery, and one study suggests an equivalent risk after delivery compared to pregnancy. Postpartum women had more episodes of malaria than non-pregnant, non-postpartum controls in the three studies that included a control group.
However, the results of this review must be carefully interpreted, as the majority of studies were not designed to document specifically postpartum malaria, and there was a large variability in study designs and outcomes. The use of preventive drugs is an example of such a complicating factor: in more than half (6/11) of the studies IPTp or chemoprophylaxis were used during pregnancy. Chloroquine (weekly chemoprophylaxis) and sulphadoxine-pyrimethamine (IPTp) have a long half life and women are protected from malaria until the drug concentration falls below the minimum inhibitory concentration. Depending on the timing of the last dose in pregnancy, drug half life and level of drug resistance, protection could be prolonged into the early postpartum period and may result in an underestimation of the postpartum susceptibility to malaria when compared to non pregnant non postpartum controls who did not use any prevention. In Mozambique, reduced prevalence of malaria parasitaemia at delivery and eight weeks postpartum (detected by malaria smear) was attributed to IPTp-sulphadoxine-pyrimethamine, though the last dose of IPTp was given at a mean time of 77 days before delivery. This is much longer than the one-month estimated protective effect of sulphadoxine-pyrimethamine. However, when PCR detection was used in a selection of women from the same study, it was reported that women in the IPTp group were indeed protected from malaria at delivery, but not anymore at eight weeks postpartum. Many post partum women harboured sub microscopic levels of parasites. Another effect of preventive anti-malarials during pregnancy was seen with use of weekly chemoprophylaxis. In 1985 when P.vivax was still sensitive to chloroquine in PNG, an increase in malaria incidence (P. falciparum, but especially P. vivax) was noticed in all gravidae as soon as the chloroquine chemoprophylaxis was stopped at delivery. Such a "rebound effect" was noticed in a chemoprophylaxis study from Tanzania as well as in children. Chemoprophylaxis may have suppressed parasitaemia in pregnancy to sub-microscopic levels, but when it was discontinued at delivery, the parasites became microscopically detectable. This is in agreement with the recent studies, which were able to use PCR genotyping for detection of placental and postpartum parasites.
In the reviewed studies, postpartum women had more malaria episodes than non-pregnant, non-postpartum controls making plausible the existence of a transition phase, in which the susceptibility returned to pre-pregnancy levels. From the data available, the length of such a period could not be determined. In Senegal, the increased incidence went back to pre-pregnancy levels within 90 days after delivery, but in Tanzania women still had an increased prevalence compared to controls six months after delivery. A mechanism to explain the decreased susceptibility in the post-partum period is maternal immunity. Fievet and colleagues observed an impairment in the IL-2 response, and unaffected or enhanced responses in IL-4 and interferon-gamma, in 33 women from Cameroon followed during their first pregnancy and at 6 months after delivery. This was thought to favor a general depression of cellular immunity in pregnancy, rather than a specific malaria phenomenon. The transition phase from suppressed pregnancy immunity to normal pre-pregnancy levels has also been hypothesized by others. Another mechanism to explain a transition phase is the persistence of malaria parasites from pregnancy due to inadequate treatment. Resistance of P. falciparum to chloroquine or sulphadoxine-pyrimethamine was mentioned in 55% (6/11) of articles. Ineffective treatments do not radically cure malaria infections, and these infections may recrudesce in the postpartum period. The only available P.falciparum genotyping data demonstrated that 30–50% of the postpartum infections were persistent from delivery until the postpartum period. Hence, highly effective treatment during pregnancy, or IPTp regimens with highly effective drugs would impact significantly on reducing postpartum infection as well. In addition primiparous women have less antibodies to the CSA binding parasites that cause placental malaria This could explain the increased risk of post partum malaria in primiparous women compared to multiparous mothers observed in six of seven studies reviewed.
To protect the post partum mother and her neonate from malaria, an additional treatment dose of highly effective treatment at delivery may be considered as part of the IPTp strategy. Self-treatment may affect the presence of parasitaemia, but this was only reported in two manuscripts. Self-treatment effects are likely to vary with the quality of the drug, the dose and duration of treatment.
A limitation of this review is that in most published articles microscopy was used to detect malaria, whereas microscopy failed to detect 75% of the PCR detected parasitaemia during the postpartum period in a recent study. The same study reports that 20 (77%) out of the 26 women with positive placenta-paired samples had not received treatment during labour because parasitaemia was sub-microscopic. The authors concluded that such untreated sub-microscopic infections persist until the postpartum period and reported a five-fold higher risk (95% CI 2.49-10.63) of P. falciparum infection eight weeks after delivery in women with sub-microscopic placental malaria. This relation between placental and postpartum malaria was not shown in, for example, the study from Senegal, where microscopy was used. However, at the same time, in the same area, but in the general population, high levels of sub-patent P. falciparum levels (two third of microscopically negative slides) were reported, using PCR. Clearly, more investigation is needed to determine the burden of sub-microscopic malaria infections around delivery and in the post partum period.
There was an increased number of symptomatic infections in the postpartum period in Senegal and Gabon. Asymptomatic untreated (sub-microscopic) infections in pregnancy may have become symptomatic after delivery, or asymptomatic episodes were detected and reported as symptomatic due to accompanying fever, as women in the postpartum period are prone to febrile co-morbidities such as mastitis and endometritis. In both studies, the incidence of asymptomatic malaria episodes did not increase as much as for symptomatic episodes.
Data on non-falciparum species and the risk of postpartum infection has only been described for PNG. At least for P. vivax and P. ovale it would be very useful to know more about the postpartum risks for infection as primaquine, the only available drug for eradication of the liver stage of these species, cannot be used during pregnancy. Postpartum detection may provide a window of opportunity for primaquine therapy so that these species do not relapse in subsequent pregnancies.
Discussion
Nine of 10 reviewed studies suggested that the risk for malaria infection during pregnancy decreased after delivery, and one study suggests an equivalent risk after delivery compared to pregnancy. Postpartum women had more episodes of malaria than non-pregnant, non-postpartum controls in the three studies that included a control group.
However, the results of this review must be carefully interpreted, as the majority of studies were not designed to document specifically postpartum malaria, and there was a large variability in study designs and outcomes. The use of preventive drugs is an example of such a complicating factor: in more than half (6/11) of the studies IPTp or chemoprophylaxis were used during pregnancy. Chloroquine (weekly chemoprophylaxis) and sulphadoxine-pyrimethamine (IPTp) have a long half life and women are protected from malaria until the drug concentration falls below the minimum inhibitory concentration. Depending on the timing of the last dose in pregnancy, drug half life and level of drug resistance, protection could be prolonged into the early postpartum period and may result in an underestimation of the postpartum susceptibility to malaria when compared to non pregnant non postpartum controls who did not use any prevention. In Mozambique, reduced prevalence of malaria parasitaemia at delivery and eight weeks postpartum (detected by malaria smear) was attributed to IPTp-sulphadoxine-pyrimethamine, though the last dose of IPTp was given at a mean time of 77 days before delivery. This is much longer than the one-month estimated protective effect of sulphadoxine-pyrimethamine. However, when PCR detection was used in a selection of women from the same study, it was reported that women in the IPTp group were indeed protected from malaria at delivery, but not anymore at eight weeks postpartum. Many post partum women harboured sub microscopic levels of parasites. Another effect of preventive anti-malarials during pregnancy was seen with use of weekly chemoprophylaxis. In 1985 when P.vivax was still sensitive to chloroquine in PNG, an increase in malaria incidence (P. falciparum, but especially P. vivax) was noticed in all gravidae as soon as the chloroquine chemoprophylaxis was stopped at delivery. Such a "rebound effect" was noticed in a chemoprophylaxis study from Tanzania as well as in children. Chemoprophylaxis may have suppressed parasitaemia in pregnancy to sub-microscopic levels, but when it was discontinued at delivery, the parasites became microscopically detectable. This is in agreement with the recent studies, which were able to use PCR genotyping for detection of placental and postpartum parasites.
In the reviewed studies, postpartum women had more malaria episodes than non-pregnant, non-postpartum controls making plausible the existence of a transition phase, in which the susceptibility returned to pre-pregnancy levels. From the data available, the length of such a period could not be determined. In Senegal, the increased incidence went back to pre-pregnancy levels within 90 days after delivery, but in Tanzania women still had an increased prevalence compared to controls six months after delivery. A mechanism to explain the decreased susceptibility in the post-partum period is maternal immunity. Fievet and colleagues observed an impairment in the IL-2 response, and unaffected or enhanced responses in IL-4 and interferon-gamma, in 33 women from Cameroon followed during their first pregnancy and at 6 months after delivery. This was thought to favor a general depression of cellular immunity in pregnancy, rather than a specific malaria phenomenon. The transition phase from suppressed pregnancy immunity to normal pre-pregnancy levels has also been hypothesized by others. Another mechanism to explain a transition phase is the persistence of malaria parasites from pregnancy due to inadequate treatment. Resistance of P. falciparum to chloroquine or sulphadoxine-pyrimethamine was mentioned in 55% (6/11) of articles. Ineffective treatments do not radically cure malaria infections, and these infections may recrudesce in the postpartum period. The only available P.falciparum genotyping data demonstrated that 30–50% of the postpartum infections were persistent from delivery until the postpartum period. Hence, highly effective treatment during pregnancy, or IPTp regimens with highly effective drugs would impact significantly on reducing postpartum infection as well. In addition primiparous women have less antibodies to the CSA binding parasites that cause placental malaria This could explain the increased risk of post partum malaria in primiparous women compared to multiparous mothers observed in six of seven studies reviewed.
To protect the post partum mother and her neonate from malaria, an additional treatment dose of highly effective treatment at delivery may be considered as part of the IPTp strategy. Self-treatment may affect the presence of parasitaemia, but this was only reported in two manuscripts. Self-treatment effects are likely to vary with the quality of the drug, the dose and duration of treatment.
A limitation of this review is that in most published articles microscopy was used to detect malaria, whereas microscopy failed to detect 75% of the PCR detected parasitaemia during the postpartum period in a recent study. The same study reports that 20 (77%) out of the 26 women with positive placenta-paired samples had not received treatment during labour because parasitaemia was sub-microscopic. The authors concluded that such untreated sub-microscopic infections persist until the postpartum period and reported a five-fold higher risk (95% CI 2.49-10.63) of P. falciparum infection eight weeks after delivery in women with sub-microscopic placental malaria. This relation between placental and postpartum malaria was not shown in, for example, the study from Senegal, where microscopy was used. However, at the same time, in the same area, but in the general population, high levels of sub-patent P. falciparum levels (two third of microscopically negative slides) were reported, using PCR. Clearly, more investigation is needed to determine the burden of sub-microscopic malaria infections around delivery and in the post partum period.
There was an increased number of symptomatic infections in the postpartum period in Senegal and Gabon. Asymptomatic untreated (sub-microscopic) infections in pregnancy may have become symptomatic after delivery, or asymptomatic episodes were detected and reported as symptomatic due to accompanying fever, as women in the postpartum period are prone to febrile co-morbidities such as mastitis and endometritis. In both studies, the incidence of asymptomatic malaria episodes did not increase as much as for symptomatic episodes.
Data on non-falciparum species and the risk of postpartum infection has only been described for PNG. At least for P. vivax and P. ovale it would be very useful to know more about the postpartum risks for infection as primaquine, the only available drug for eradication of the liver stage of these species, cannot be used during pregnancy. Postpartum detection may provide a window of opportunity for primaquine therapy so that these species do not relapse in subsequent pregnancies.
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