Maternal malaria and gravidity interact to modify infant susceptibility to malaria

Abstract

Background: In endemic areas, placental malaria due to Plasmodium falciparum is most frequent and severe in first-time mothers, and increases the risk of infant mortality in their offspring. Placental malaria may increase the susceptibility of infants to malaria parasitemia, but evidence for this effect is inconclusive.

Methods and findings: During 2002-2004, we monitored parasitemia in 453 infants, including 69 who were born to mothers with placental malaria, in a region of northeastern Tanzania where malaria transmission is intense. We used a Cox proportional hazards model to evaluate the time from birth to first parasitemia, and a generalized estimating equations logistic regression model to evaluate risk of any parasitemia throughout the first year of life. Compared with infants whose mothers did not have placental malaria at delivery ("PM-negative"), offspring of mothers with placental malaria at delivery ("PM-positive") were 41% more likely to experience their first parasitemia at a younger age (adjusted hazard ratio [AHR] = 1.41, 95% confidence interval [CI] 1.01-1.99). The odds of parasitemia throughout infancy were strongly modified by the interaction between placental malaria and gravidity (p for interaction = 0.008, Type 3 likelihood ratio test). Offspring of PM-negative primigravidae had lower odds of parasitemia during infancy (adjusted odds ratio [AOR] = 0.67, 95% CI 0.50-0.91) than offspring of PM-negative multigravidae, and offspring of PM-positive primigravidae had the lowest odds (AOR = 0.21, 95% CI 0.09-0.47). In contrast, offspring of PM-positive multigravidae had significantly higher odds of parasitemia (AOR = 1.59, 95% CI 1.16-2.17).

Conclusion: Although parasitemia is more frequent in primigravid than multigravid women, the converse is true in their offspring, especially in offspring of PM-positive women. While placental malaria is known to increase mortality risk for first-born infants, it surprisingly reduced their risk of parasitemia in this study. Placental malaria of multigravidae, on the other hand, is a strong risk factor for parasitemia during infancy, and therefore preventive antimalarial chemotherapy administered to multigravid women close to term may reduce the frequency of parasitemia in their offspring.

Figure 1. Kaplan-Meier Estimate of the Probability of Surviving without Parasitemia

The graph shows the age at first parasitemia in offspring of PM-positive mothers (solid line) versus PM-negative mothers (dashed line). Infants born to PM-positive mothers experience their first parasitemia at a significantly younger age than infants of PM-negative mothers (log rank, p = 0.02).

Figure 2. Kaplan-Meier Estimate of the Probability of Surviving without Parasitemia and Adjusted Estimate Using a Cox Model

The graphs show the unadjusted (left panels) and adjusted (right panels) age at first parasitemia in first-born (A and B), second-born (C and D), or third-born or subsequent (E and F) offspring of PM-positive mothers (solid lines) versus PM-negative mothers (dashed lines). PM is associated with a significantly younger age at the time of first parasitemia among offspring of multigravidae (log rank, p = 0.01), but not among offspring of primigravidae (log rank, p = 0.48) or secundigravidae (log rank, p = 0.06). Adjustment estimates using a Cox model did not change statistical significance in any gravidity group.

Figure 3. Age-Specific Parasite Positivity

These graphs show age-specific parasite positivity of all blood slides obtained from infants born to primigravid women (dashed lines) versus secundigravid or multigravid women (solid lines). The frequency of parasitemia among offspring of PM-negative mothers (A and B) or offspring of PM-positive mothers (C and D) is presented according to whether the slides were collected during the low-transmission season (A and C) or high-transmission season (B and D). Low transmission of malaria around Muheza occurs from November through April, and high transmission occurs from May through October. Parasitemia was more frequent among the offspring of secundigravid and multigravid women versus primigravid women when PM was present at delivery. This relationship was observed in all age groups except neonates, and was observed in both low- (C) and high- (D) transmission seasons. Figures represent frequency of positivity for all slides collected during the study period, including slides collected subsequent to treatment.