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Placental Malaria Increases Malaria Risk in the First 30 Months of Life

  1. Norbert G. Schwarz1,4,
  2. Ayola A. Adegnika1,4,5,
  3. Lutz P. Breitling1,4,
  4. Julian Gabor1,4,
  5. Selidji T. Agnandji1,4,
  6. Robert D. Newman7,
  7. Bertrand Lell1,4,
  8. Saadou Issifou1,4,
  9. Maria Yazdanbakhsh1,5,
  10. Adrian J. F. Luty1,4,6,
  11. Peter G. Kremsner1,4, and
  12. Martin P. Grobusch1,2,3
  1. 1Medical Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon
  2. 2Infectious Disease Unit, Division of Clinical Microbiology and Infectious Diseases, National Health Laboratory Service, South Africa
  3. 3School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
  4. 4Department of Parasitology, Institute for Tropical Medicine, University of Tübingen, Tübingen, Germany
  5. 5Department of Parasitology, Leiden University Medical Center, Leiden
  6. 6Medical Parasitology, Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands
  7. 7Malaria Branch, Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
  1. Reprints or correspondence: Prof. Martin Peter Grobusch, Infectious Diseases Unit, Div. of Clinical Microbiology and Infectious Diseases, National Health Laboratory Service, 7 York Rd., Parktown, Johannesburg 2193, South Africa (martin.grobusch{at}wits.ac.za).
 
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Abstract

Background. Plasmodium falciparum infection during pregnancy is associated with stillbirth, fetal growth restriction, and low birth weight. An additional consequence may be increased risk of malaria in early life, although the epidemiological evidence of this consequence is limited.

Methods. A cohort of 527 children were observed actively every month for 30 months after delivery. Offspring of mothers with microscopically detectable placental P. falciparum infection at the time of delivery were defined as exposed. The outcome measure was malaria (parasitemia and fever). Analyses were performed using Cox proportional hazard models and were stratified by gravidity.

Results. Overall, offspring of mothers with placental P. falciparum infection had a significantly higher risk of clinical malaria during the first 30 months of life (adjusted hazard ratio, 2.1; 95% confidence interval [CI], 1.2–3.7). The adjusted hazard ratio for offspring of multigravidae was 2.6 (95% CI, 1.3–5.3), and that for primigravidae was 1.5 (95% CI, 0.6–3.8). The offspring of placenta-infected primigravidae had no episodes of malaria during the first year of life.

Conclusions. Our findings show that active placental P. falciparum infection detected at delivery is associated with an ∼2-fold greater risk of malaria during early life, compared with noninfection. The fact that persons born to infected multigravidae rather than primigravidae appear to be at greater risk emphasizes the importance of preventing malaria in mothers of all gravidities.

Pregnancy-associated malaria due to Plasmodium falciparum is estimated to cause up to 200,000 infant deaths every year as a result of complications that include stillbirth, fetal growth restriction, and preterm delivery. The association between placental infection with the parasite and low birth weight has also been well established [1–4]. Maternal morbidity in this context most often manifests as severe anemia, often with the underlying infectious cause unrecognized. As a group, primigravidae are more susceptible to placental P. falciparum infection, and they and their offspring are therefore proportionately more affected by these adverse outcomes than are multigravidae [2, 5, 6]. Among HIV-infected women, multigravid women remain susceptible to placental P. falciparum infection [7].

Malaria attacks both occur less frequently and are less severe during the first 6 months of life than later in life [8, 9]. This is believed to be due mainly to passive transplacental acquisition of maternal IgG antibodies, although those with specificity for placental parasites do not contribute to neonatal immunity [10]. Of note, placental infection with P. falciparum is associated with reduced transfer of maternal antibodies against several pathogens. The high content of hemoglobin F in infant erythrocytes may also affect infants' susceptibility to malaria, because hemoglobin F is thought to impede plasmodial infection [11].

Placental parasitemia has been identified as a potential risk factor for anemia in several studies [12–14]. Two studies—one from Cameroon [15] and one from Tanzania [16]—provided some epidemiological evidence that there may be an association between placental parasitemia and parasitemia during infancy and early childhood. The Tanzanian study also found that the risk was greatest among multigravidae and that, among primigravidae, placental infection was actually protective against P. falciparum infection during the first year of life.

We investigated the effect of placental infection in Gabonese mothers on the risk of malaria during the first 30 months of their offsprings' lives, and we investigated the role that gravidity may play in modifying this association.

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Methods

The mother-child cohort for our analysis comprised a subset of persons recruited for a study of intermittent preventive treatment for malaria in infants (IPTi) with sulphadoxine-pyrimethamine [17]. Included children were visited monthly at home if a routine clinical examination was performed, and mothers were encouraged to present to the clinical trial center at any time in the event of illness. Prerequisite for inclusion into this analysis was the availability of a placenta blood smear result.

Data for this analysis are from 2 studies that were performed by 2 independent teams; one team obtained and analyzed placenta samples, and the other performed the follow-up evaluations of children in the IPTi trial. Informed consent was obtained separately and independently for the 2 studies. People in the IPTi trial who were charged with the longitudinal follow-up of children were not aware of the placental parasite status, and data for both studies were entered separately into different databases. Technicians who assessed blood slides from children were blinded to the placental parasitemia status of the mother.

The ethics committee of the International Foundation of the Albert Schweitzer Hospital (Lambaréné, Gabon) approved both studies from which the data for this analysis originated. The trial was conducted at the Albert Schweitzer Hospital from December 2002 through April 2007. The last child was enrolled in the cohort in July 2004, before intermittent preventive treatment in pregnant women was implemented in Gabon in 2005 [18]. Malaria transmission in Gabon is perennial, with little seasonal variability. In 2000, the entomological inoculation rate was determined to be 50 infective bites per person, and 95% of all malarial infections were caused by P. falciparum [19, 20].

Placental blood specimens were obtained immediately after delivery from the intervillous spaces at the center of the placental tissue, as approached from the maternal side. Giemsa-stained thick smears were prepared. Parasite loads were quantified using a standardized microscopical method, as described elsewhere [21].

Exposure

We classified mother-child pairs as exposed to P. falciparum malaria (PM positive) if ⩾1 P. falciparum parasite was found in a placenta thick smear. They were classified as nonexposed (PM negative) if no parasites were found.

Outcome

Malaria in a child during the first 30 months of life was defined as the presence of any asexual P. falciparum parasites in a thick blood smear accompanied by a rectal temperature of ⩾38.5°C or a history of fever in the previous 48 h reported by the mother or guardian. Until mid-August 2004, malaria attacks were treated with artesunate monotherapy [22]; thereafter, they were treated with artesunate-amodiaquine [23].

Statistical Analysis

Baseline characteristics. We compared the frequency distribution of maternal and infant baseline characteristics between PM-positive and PM-negative mother-child pairs for gravidity (primigravidae vs. multigravidae), maternal age at delivery, residence area, bed net use, sex of the child, month of birth, and birth weight. We also compared the proportions lost to follow-up, the mean duration of follow-up, and the proportions according to randomization group in the IPTi trial. We used the χ2 test for categorical variables. To compare mean values for a continuous variable, we used Student's t test. To compare the median values and the distribution of nonnormally distributed continuous variables, we used the Wilcoxon rank-sum test. The analysis plan was established with prior knowledge of the absence of a statistically significant difference in malaria risk between the placebo and IPTi sulphadoxine-pyrimethamine intervention groups [17]. Nevertheless the IPTi intervention group was kept as a covariate in the multivariate models.

Outcome analysis. The outcome was analyzed for the entire study population and separately for the offspring of primigravidae and multigravidae. Outcome measures were hazard ratio (HR) for the first malaria attack and, for those children who presented with malaria within the observation period, the time to first malaria attack.

The median time to first malaria attack was then calculated for 4 different subgroups: primigravidae with PM-negative placenta specimens, primigravidae with PM-positive placenta specimens, multigravidae with PM-negative placenta specimens, and multigravidae with PM-positive placenta specimens. Follow-up time was calculated from birth to the first malaria attack, date of loss to follow-up, date of death, or date of last contact with study staff. We used Kaplan-Meier survival and Cox regression analyses to determine the unadjusted and adjusted Cox HRs for PM-positive versus PM-negative offspring. The proportional hazard assumption was assessed graphically with a Nelson Aalen plot and with a likelihood ratio test that evaluated whether HRs changed significantly for different intervals of the time scale. Time scales were split into 3, 4, 5, and 6 intervals of equal numbers of outcomes. None of these approaches suggested a violation of the proportional hazard assumption, and we concluded that Cox regression was an appropriate method to use for analysis of the data.

Power calculation. The sample size of the source study had been determined on the basis of considerations pertaining to the randomized controlled trial intervention effect [17]. With use of a method described by Rothman and Boice [24], given the observed number of exposed children (n=50), a total number of 527, a malaria risk in PM-negative children of 14%, the power to detect a significant association with a 2-sided α of .05 for rate ratios of 2.0, 2.5, and 3.0 was 0.70, 0.93, and 0.99, respectively.

However, with use of a method described by Collet [25] designed to estimate the power of a log-rank test (equivalent to a Cox model with the proportional hazard assumption fulfilled), the expected study power was lower: given the observed number of malarial events (n=91) and proportion of PM-exposed offspring (50 of 527), the power to detect a statistically significant association with a 2-sided α of .05 for HRs of 2.0, 2.5, and 3.0 was 0.49, 0.73, and 0.87, respectively.

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Results

Between December 2002 and July 2004, a total of 527 children were enrolled in the study at birth and were observed for 30 months. The total duration of follow-up was 949 person-years at risk, corresponding to a mean duration of follow-up of 21.6 months. Three hundred forty-seven children (66%) completed the 30-month follow-up period. Of the 180 children who did not complete the entire follow-up period, the majority (167) were lost to follow-up because of migration from the study area. For 9 children, the parents withdrew their consent; 4 children died. The placental blood sample obtained at delivery contained P. falciparum parasites in 50 cases. Ninety-one children (17%) experienced at least 1 malaria episode. Eight percent of those who completed the entire study period and 12% of those lost to follow-up before they reached the end of the 30-month follow-up period were offspring of PM-positive mothers (P=.12). The (unadjusted) HR for malaria for subjects who did not complete the study (178 person-years at risk) versus those who did (770 person-years at risk) was 1.6 (95% CI, 0.9–2.6).

table 1 shows mothers' and infants' characteristics for the entire mother-child birth cohort and separately for PM-negative and PM-positive mother-child pairs. The mean birth weight for offspring of PM-positive mothers was significantly lower than that for offspring of PM-negative mothers. Figure 1 shows how many hospital deliveries were noted during the recruitment period, how many children were recruited into the IPTi study, and how many had placenta samples available.

Figure 1
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Figure 1

Study flow chart starting with all hospital deliveries during the study period in 1 of the 2 hospitals in Lambaréné, Gabon, 2002–2004. IPIi, intermittent preventive treatment for malaria in infants.

The mean time to the first case of parasitemia in offspring of multigravidae was 13.2 months (range, 3.9–29.7 months) in PM-negative offspring and 15.8 months (range, 1.9–27.0 months) in PM-positive offsprings. In offspring of primigravidae, the mean values were 14.6 months (range, 4.1–29.3 months) in PM-negative offspring and 15.3 (range, 11.9–19.8 months) in PM-positive offspring. Although the risk of malaria did not differ between children who were randomized to an IPTi intervention (which consisted of sulphadoxine-pyrimethamine given at months 3, 9, and 15) and those who received placebo (Cox HR, 1.0; 95% CI, 0.7–1.6), the association between placental malaria and malaria in the child was only statistically significant for children who were randomized to receive the sulphadoxine-pyrimethamine intervention (adjusted Cox HR, 3.0; 95% CI, 1.5–6.0); the adjusted Cox HR for the placebo group was 1.0 (95% CI, 0.3–3.7). The exploratory nature of these models and the somewhat biologically implausible nature of this effect modification nevertheless led us to proceed as laid out in the original analysis protocol, which did not allow for separate analyses based on IPTi intervention group but did allow for adjustment according to the intervention group.

The earliest recorded malaria attack among offspring of PM-positive primigravidae occurred at 12 months of age, which was much later than in the other 3 subgroups. This pattern is illustrated clearly in the cumulative incidence curves for primigravidae (figure 2C), with multiple attacks recorded in the PM-negative group from 4 months onward, with an incidence curve diverging from that of the PM-positive group until month 12, when the curves cross. The cumulative incidence curves for the entire study population (figure 2A) show that the curves for offspring of PM-positive mothers are consistently above those for offspring of PM-negative mothers, reflecting their higher overall risk of experiencing malaria. Figure 2B illustrates that this difference in risk between the groups is strongest for offspring of multigravidae.

Figure 2
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Figure 2

Kaplan-Meier curves for the cumulative incidence of first malaria attacks in children during their first 30 months of life for offspring of Plasmodium falciparum malaria (PM)–positive mothers (dashed lines) versus offspring of PM-negative mothers (solid lines), Gabon, 2002–2004. A, Whole study population (527 subjects, with 91 first malaria events; P=.002, by log-rank test for equality of survivor functions). B, Offspring of multigravidae (395 subjects, with 63 first malaria events; P=.002, by log-rank test for equality of survivor functions). C, Offspring of primigravidae (132 subjects, with 28 first malaria events; P=.45, by log-rank test for equality of survivor functions).

Overall, offspring of PM-positive mothers had a higher risk of malaria during the first 30 months of life, with an unadjusted HR of 2.3 (95% CI, 1.3–3.9) (table 2). After adjustment for gravidity, residence area, quartile of birth month , IPTi, and bed net use (table 3), the HR was slightly lower (2.1; 95% CI, 1.2–3.7). The adjusted HR for offspring of multigravidae was 2.6 (95% CI, 1.3–5.3), and that for primigravidae was 1.5 (95% CI, 0.6–3.8). table 4 provides an overview of the characteristics of and outcomes in all 3 studies, including ours, examining the association between placental P. falciparum infection and either P. falciparum parasitemia or malaria in young children.

Table 1
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Table 1

Baseline characteristics of study participants, Gabon, 2002–2004.

Table 2
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Table 2

Unadjusted hazard ratios (HRs) for risk of first episode of malaria during the first 30 months of life, Gabon, 2002–2004.

Table 3
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Table 3

Adjusted hazard ratios (HRs) for risk of first episode of malaria during the first 30 months of life for the entire study population and separately for multi- and primigravidae, Gabon, 2002–2004.

Table 4
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Table 4

Comparison of studies on the association between Plasmodium falciparum placental infection at delivery and parasitemia or malaria in the offspring.

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Discussion

Main findings. Our data indicate that infants born to mothers with placental P. falciparum infection at delivery have a greater risk of malaria in early life than do those born to mothers with uninfected placenta.

Main findings in the context of other studies. Two studies, similar in design to the one we report here, have examined the association between placental P. falciparum infection and either P. falciparum parasitemia or P. falciparum malaria in young children. The outcome in our study was malaria. In a study from Cameroon [15], there was no statistically significant difference regarding the appearance of at least 1 malaria attack between infants born to PM-positive mothers (47%) and infants born to PM-negative mothers (39%) during the first 24 months of life (P=.60); however, from the age of 4 months to 18 months, the prevalence of parasites in the monthly thick smear was higher among the offspring of PM-positive mothers, and this difference was statistically significant for offspring aged 5–8 months.

In a study from northeastern Tanzania [16], gravidity (primigravidity vs. multigravidity) modified the effect of placental parasitemia on the probability of parasitemia during the first year of life. Among a total of 453 infants, 69 were born to a mother with placental parasitemia. The risk of parasitemia during the first year of life in children of PM-positive multigravid mothers was higher than for children of PM-positive primigravid women and of PM-negative women of all gravidities. Conversely, the risk was decreased in infants of PM-positive primigravid mothers, even when compared with PM-negative women. In our study, placental P. falciparum infection increased the malaria risk during the first 30 months of life among offspring of both primigravidae and multigravidae. The effect, however, was found to be stronger for offspring of multigravidae. None of the 6 malaria attacks recorded among offspring of PM-positive primigravidae occurred before the end of the first year of their life. Thus, although our findings indicate that all offspring of PM-positive mothers, regardless of gravidity, are at increased risk of malaria in their first 30 months of life, the first such attacks among offspring of primigravid women did appear to be delayed.

A possible explanation for the study's findings is that women with placental malaria infection came from households where malaria was common and that the child's increased risk was partly attributable to this higher rate of exposure. However, immunological mechanisms may be important as well: placental P. falciparum infection has been reported to reduce the transfer of maternal antibodies to the newborn [26–30].

At the cellular immunological level, placental parasitemia sensitizes fetal immune cells; however, the mechanisms are complex, and a causal relationship between such sensitization and the outcome of postnatal P. falciparum infection remains to be proven [31–34].

Secondary findings. A statistically significantly higher proportion of primigravidae than multigravidae had parasitized placentas, and their offspring had significantly lower birth weights. The association between placental parasitemia and lower birth weights is consistent with findings of studies conducted elsewhere in sub-Saharan Africa [2, 6] and in a study conducted in another region of Gabon [5].

Limitations. The mothers who are PM positive may have been at higher risk for malaria because of some sort of elevated exposure risk. Their offspring could then be at greater risk because of a shared environment. For future studies with a similar aim, we recommend assessment of the malaria exposure level for households (e.g., by assessing the malaria risk of siblings). However, the evidence of modification of the effect that placental parasitemia has on the child's malaria risk through gravidity during the first year of life makes it less likely that the observed associations result only from confounding. The exploratory analyses we performed revealed some evidence of modification of the association between placental parasitemia and malaria risk in infants related to the IPTi intervention. We conjecture that this is a purely chance statistical finding with no biologically plausible explanation. The analytical plan was developed with prior knowledge of the outcome of the IPTi intervention trial, which demonstrated no difference in the risk of malaria between sulphadoxine-pyrimethamine recipients and placebo recipients [17]. Therefore, we chose not to perform analyses of the relationship between placental parasitemia and infants' malaria risk separately for the randomization groups of the IPTi trial (apart from the adjusted HRs shown in Results).

Earlier “chronic” infection, which is known to potentially influence the outcome of a pregnancy exposure, could have been assessed by histological examination of placenta samples. The only published data we are aware of on gravidity-associated distribution is in the original article on histological classification by Bulmer et al. [35], in which the authors indicate that chronic infection was more prevalent among primiparae; this finding is somewhat confused by the fact that the authors also segregated cases of chronic infection into active and past infections. A cooperating working group showed that the strongest alterations to the immunological activity of cord blood mononuclear cells (measured as Toll-like receptor ligand–inducible IFN-γ production) appear to be associated with placental infections acquired in the last months of gestation (i.e., acute rather than “chronic” infection) [36].

Thirty-four percent of all children included in the study did not complete the 30-month follow-up period. The percentage of exposed (PM-positive) children and the rate of malaria was slightly and nonsignificantly higher among persons who did not complete the entire 30-month follow-up period. The HIV infection status of mothers and children in our study was not known.

With 527 children observed, our cohort is, to our knowledge, the largest cohort used to examine the association between placental malaria and malaria risk during infancy and early childhood and the first in a study to focus exclusively on malaria as an outcome. However, it was necessary to stratify subjects by gravidity and to adjust for several variables, reducing the cell sizes in the analysis. For example, we recorded only 6 clinical malaria attacks among primigravidae of PM-positive mothers. More studies are needed, and larger cohorts would clearly be desirable.

Conclusions. Because primigravidae are correctly seen as the most vulnerable group with respect to plasmodial infection–related complications, prevention of malaria during pregnancy should be focused on primigravidae as a group. Our findings, however, indicate that the offspring of PM-positive multigravidae have a proportionately increased risk of malaria during early life. This is consistent with the higher parasitemia risk in offspring of PM-negative multigravidae found in a recent Tanzanian study [16]. In our view, this emphasizes the importance of preventing malaria in mothers of all gravidities.

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Acknowledgments

We thank Larry Slutsker for his thoughtful comments on the draft manuscript and all children and their parents or primary caretakers for participation in this study.

Financial support. Bill and Melinda Gates Foundation (28574), the German Ministry of Education and Research (01KA0202), the German Academic Exchange Service (A/02/18261 to A.A.A., D/02/46952 to N.G.S., A/05/23966 to S.T.A.), and The Netherlands Foundation for the Advancement of Tropical Research (W93–385 20077).

Potential conflicts of interest. All authors: no conflicts.

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Footnotes

  • The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

  • Received March 25, 2008.
  • Accepted June 19, 2008.
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  1. Clin Infect Dis. (2008) 47 (8): 1017-1025. doi: 10.1086/591968
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