Assessing the burden of pregnancy-associated malaria under changing transmission settings

Abstract

Background: The clinical presentation of pregnancy-associated malaria, or PAM, depends crucially on the particular epidemiological settings. This can potentially lead to an underestimation of its overall burden on the female population, especially in regions prone to epidemic outbreaks and where malaria transmission is generally low.

Methods: Here, by re-examining historical data, it is demonstrated how excess female mortality can be used to evaluate the burden of PAM. A simple mathematical model is then developed to highlight the contrasting signatures of PAM within the endemicity spectrum and to show how PAM is influenced by the intensity and stability of transmission.

Results: Both the data and the model show that maternal malaria has a huge impact on the female population. This is particularly pronounced in low-transmission settings during epidemic outbreaks where excess female mortality/morbidity can by far exceed that of a similar endemic setting.

Conclusion: The results presented here call for active intervention measures not only in highly endemic regions but also, or in particular, in areas where malaria transmission is low and seasonal.

Figure 1

Spleen rate, Epidemic Figure (EF), and relative female mortality of all age groups between 1914 and 1943 for all districts in the Punjab. Relative female mortality (as % × 10, dotted line), defined as the ratio of female to male mortalities, correlates well with both malaria indices spleen rate (dashed line) and Epidemic Figure (solid line). The values of the EF and relative female mortality for 1918, during the influenza epidemic, were estimated, based on the linear regression results with the spleen rate (r = 0.76 and r = 0.64 respectively).

Figure 2

Relative female to male fever mortality by age group for all Punjab districts (1908 to 1917). Excess female fever mortality increase in the 5-9 age group, and remains high during the female reproductive age, only returning to levels comparable to males in the age groups over 40 years. Standard deviations are highest for the 20-29 year age group. Apart from malaria, excess female fever mortality will be associated with perinatal bacterial infections. The slope in the decline of excess mortality between the 10 to 14 and the 30 to 39 year age group could signify a specific pregnancy-associated immunity.

Figure 3

Relative female fever mortality in all Punjab's 26 districts for the epidemic year 1917 showing the effect of prior exposure on PAM induced morbidity during epidemic outbreaks. For malaria exposure of the districts prior to 1917, the average annual Epidemic Figures (EF) between 1902 and 1916 for each district were used. One outlier (red diamond) was excluded from the polynomial regression (blue line). Spearman rank coefficient r = -0.645, R² = 0.4595, P < 0.0005 (with outlier: r = -0.519, R² = 0.3725, P < 0.007).

Figure 4

Flow diagram showing the movements between different compartments within the model. It is assumed that girls become reproductively active at an average age of 1/m. Depending on transmission intensity they contract malaria with probability λ, with a proportion a dying as a direct result of the disease. Women who do not contract PAM at their first or subsequent pregnancies remain susceptible and move between different classes of nursing at a rate c, where 1/c is the average length of time between succeeding pregnancies, until they cease to be reproductively active.

Figure 5

The effects of transmission intensity on excess female morbidity and its contribution from multigravidae. As the rate of transmission, λ, goes up, the excess female morbidity, E (blue line), initially increases but plateaus at medium levels of λ. At the same time, the contribution from multigravidae to excess morbidity (red line) declines as a greater proportion of women will contract PAM during their earlier pregnancies. Parameter values: μ = 1/40, m = 1/14, c = 1, B = 1/40, α = 0.1, H = 10.

Figure 6

Effect of seasonal transmission on excess morbidity in primigravidae and multigravidae at different background transmission rates. The left panel illustrates a scenario of low background transmission between seasonal (or epidemic) outbreaks (λ₀ = 0.01), whereas the right panel depicts a situation with moderate level of year-round transmission (λ₀ = 0.2). The top row (a, b) shows the excess morbidity from primigravidae; the middle row (c, d) shows the excess morbidity of multigravid women, clearly indicating that higher background transmission significantly reduces excess morbidity from multigravid women during epidemic outbreaks. The bottom row (e, f) compares the maximum in excess morbidity from primi- and multigravidae (E_M and E_P, respectively) for the two background transmission rates with a stable transmission setting under equivalent maximum transmission rates, clearly demonstrating the effect of unstable transmission on multigravid women. Parameter values: μ = 1/40, m = 1/14, c = 1, B = 1/40, α = 0.1, H = 10, k = 10.

Figure 7

The effect of prior exposure on PAM induced morbidity during epidemic outbreaks. High year-round transmission results in most women experiencing PAM some time during their first pregnancies and offers a high degree of protection within the multigravidae class. Low levels of transmission on the other hand leave women of all parities vulnerable to the disease, causing a high degree of excess morbidity during large epidemics. Parameter values: μ = 1/40, m = 1/14, c = 1, B = 1/40, α = 0.1, H = 10, k = 10, λ_S = 0.5-λ₀.