INTRODUCTION
Sub-Saharan Africa, a region where intestinal helminth infection is endemic in both rural and urban areas, is also burdened by malaria infection. 1,2 The overlapping distribution of these parasitic infections results in high rates of co-infection.3 In pregnancy, there is a transient depression of cell-mediated immunity that allows fetal allograft retention but also interferes with resistance to various infectious diseases.4 Cellular immune responses to Plasmodium falciparum antigens, for example, are depressed in pregnant women. 5,6 Pregnant women in malaria-endemic areas are highly susceptible to malaria, and this is true especially in primigravid women.7 There is evidence that P. falciparum strains exist that have specifically high affinity to placental receptors such as choriondroitin sulfate A (CSA) and therefore are sequestered in the placenta.8 With successive pregnancies, women are subsequently exposed to a variety of strains of malaria and develop efficient mechanisms to control infection and prevent disease. 8,9 Primigravidae and secundigravidae women have little or no immunity against the strains and hence suffer adverse consequences. 10
In sub-Saharan Africa, malaria in pregnancy contributes to 15% of maternal anemia, 14% of low-birthweight (LBW) infants, 30% of preventable LBW, 70% of intrauterine growth retardation, 36% of premature deliveries, and 8% of infant mortality. 11 A study carried out in Gabon reported P. falciparum prevalence of 57% in pregnant women, with primigravidae women having significantly higher prevalence (64%) than women in their second pregnancy (40%).7 The connection between malaria and anemia in pregnancy is well established, but intestinal helminths, specifically hookworms, have also been shown to be associated with anemia in pregnancy. 12 The mechanism for induction of anemia by intestinal helminths other than hookworms and Trichuris is not clearly understood, but it has been suggested that helminth infections lead to decreased erythropoiesis through NO release. Because NO can reduce erythrocyte deformability, 13,14 it could lead to increased red blood cell destruction. 15 A study in Gabon showed a prevalence of intestinal helminths of 66% in pregnant women compared with a prevalence of 36% in non-pregnant women. 16 The findings of the Gabon study showed a susceptibility pattern of pregnant women to intestinal helminth infection that has not been described in other studies.
Although there have been only a few studies on these co-infections in pregnant women; one study in Nigeria showed that > 45% of Plasmodium-infected pregnant women also harbored various intestinal helminths. This co-infection was associated with low hemoglobin level, especially among primigravid women. 17
Despite the increasing interest in the associations between helminths and malaria with anemia in pregnancy, few studies have assessed the occurrence of malaria and intestinal helminth co-infection in pregnancy and its risk factors. To our knowledge, the prevalence of Plasmodium and intestinal helminth co-infection in pregnant women and its risk factors in Ghana have not been previously reported.
MATERIALS AND METHODS
Study site and population.
The study was conducted in Kumasi, the capital of the Ashanti region of Ghana. Kumasi is the second largest city in Ghana, with a population of 1.2 million. 18 The climate in Kumasi is tropical, with two rainy seasons: April to June and September to October. The Ashanti region has an intense perennial malaria transmission, with the predominant parasite being P. falciparum.18
Ethical considerations.
The study protocol was approved before its implementation by the Institutional Review Board of the University of Alabama at Birmingham and the Committee on Human Research, Publications and Ethics, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi.
Data collection.
This was a cross-sectional study of women presenting for delivery at two hospitals in Kumasi, the Komfo Anokye Teaching Hospital (KATH) and the Manhyia Polyclinic, during November and December 2006. All women who had a singleton, uncomplicated pregnancy were invited to participate. Women were identified from admission records. After informed consent was obtained, a questionnaire was administered by a trained interviewer. The questionnaire included information on demographic characteristics (age, education, socioeconomic status, residence, and toilet facilities), obstetric history for current and previous pregnancies (stillbirth, ectopic pregnancy, preterm delivery, and LBW), illnesses, and treatments during the current pregnancy. Questionnaire content was derived from a model questionnaire recommended for use by Roll Back Malaria Monitoring and Evaluation Reference group (malaria indicator survey, women’s questionnaire). 19 Obstetric information was obtained from the women’s antenatal care (ANC) charts. ANC charts provided information on gestational age at first ANC visit, number of antenatal care visits, gestational age as assessed by palpation or ultrasound at first ANC visit, tetanus immunization, malaria prophylaxis, antihelminthic medication, illnesses, and treatment during pregnancy. A single blood sample was collected in EDTA by venipuncture for determination of malaria antigen. Stool samples were obtained for determination of intestinal helminths.
Laboratory procedures.
Determination of malaria antigen in plasma was done using the Malaria Antigen Celisa assay (Cellabs, Brookvale, Australia). The Malaria Antigen Celisa is a monoclonal antibody-based assay specific for P. falciparum malaria. The assay detects a merozoite antigen that circulates in the blood for up to 14 days after infection and detects P. falciparum infection at parasitemias as low as 0.001%, with a sensitivity of ~98% and a specificity of > 96%. 20 Determination of hookworms, Ascaris lumbricoides, and Trichuris trichura was done using the Kato-Katz thick smear technique (WHO 1991), whereas Strongyloides stercoralis samples were processed using the Baermann method. 21 Stool samples were processed within 12 hours of collection and examined microscopically within 1 hour of preparation to avoid missing hookworm ova.
Statistical analysis.
Data analysis was performed using SAS software version 9.1 (SAS Institute, Cary, NC). Differences in socio-demographic and obstetric characteristics by single and by co-infection status were assessed using χ2 tests. Because there were either no differences or very minimal differences between women with a single infection (malaria only or helminth only) and women with no infection, all analyses described below pertain to co-infection in comparison to no infection. Correlation analyses were performed to identify potential multicollinearity between independent variables. To determine risk factors for co-infection, we used multiple logistic regression. Variables that were statistically significant at P < 0.05 on bivariate analysis and those known to be associated with malaria and helminth infections based on previous studies were entered into the models using the backward stepwise technique. 22 Separate models were run for primigravid and multigravid women, because variables, such as pregnancy interval, are only applicable to one group. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for each variable entered into the model.
A total of 785 women were eligible for the study, and all consented. However, we obtained P. falciparum Celisa and intestinal helminth results for 746 (95.0%) and conducted analyses on these 746 women.
RESULTS
Participant characteristics.
Overall, the mean age of the women was 26.8 years (range: 15–48 years); 22.1% had no formal education, and 23.6% had a weekly income of < 100,000 Ghanaian cedis (US$10; Table 1). Almost one third of the women (30.2%) were primigravidae. Seventy-three percent had been prescribed sulfadoxine pyrimethamine (SP) for malaria prophylaxis, whereas only 3% had been prescribed anthelminthics. When stratified by co-infection, a larger proportion of younger, poorer (< 100,000 cedis weekly), single, primigravid women, women without toilet facilities, and women with a pregnancy interval of < 1 year were co-infected compared with their counterparts (Table 1).
Parasite prevalence.
The overall prevalence of P. falciparum was 36.3% (N = 271; Table 2). Of the 746 women, 19.7% (N = 147) tested positive for P. falciparum only, 9.1% (N = 68) tested positive for helminths only, and 16.6% (N = 124) were co-infected. Women who had any intestinal helminth infection were almost five times (OR = 4.8, 95% CI = 3.4–40) as likely to be infected with P. falciparum as women with no worm infection (Table 2). Women infected with A. lumbricoides and hookworms were also as likely to be infected with P. falciparum as uninfected women.
Risk factors for malaria and/or intestinal helminth infections.
Young age at pregnancy (< 20 years) and low income were significantly associated with either malaria or intestinal helminth infections (Table 3). Primigravid women had a 60% increased risk of malaria (OR = 1.6, 95% CI = 1.1–2.7).
Risk factors for malaria and intestinal helminth co-infection.
Risk factors for co-infection are shown in Table 4. Young age at pregnancy was strongly associated with an increased risk of co-infection (OR = 6.2). Single women and primigravid women also had an increased risk of co-infection. Young age at pregnancy, low income, and being single were each associated with increased odds of co-infection among both primi- and multigravid women, but the strength of the associations differed considerably between the two groups (Table 4). Young primigravid women had 5.2-fold increased odds of co-infection, whereas the odds ratio for multigravid women was 3.2. Weekly income of < 200,000 cedis was associated with a 2.4-fold increased odds of co-infection among multigravid women and 1.6 times increased odds among primigravidae. Single primigravid women had 3.1-fold increased odds of co-infection, whereas the odds ratio for multigravidae women was 2.1. Pregnancy interval of < 1 year was associated with a 3.7-fold increased odds of co-infection among multigravid women.
DISCUSSION
This study showed that young age (< 20 years), low income, being single, and being primigravid were each independently associated with increased odds of co-infection among the women. These associations were present when assessed separately for primi- and multigravid women, but the strength of associations varied considerably for the two groups of women.
Women living in malaria-endemic areas have an increased risk of P. falciparum infection during pregnancy.7 However, although parasite prevalence and density are higher among pregnant women compared with non-pregnant women, infection with P. falciparum is usually asymptomatic. 23 Malarial parasites accumulate within the intervillous spaces of the placenta, leading to placental malaria. Women enrolled in this study were asymptomatic for malaria.
This study confirmed that malaria is a major problem among pregnant women in Ghana (36.3% prevalence). Our findings are in accordance with findings from other West African areas: 21.9% in Cameroon 24 and 63% in Ghana. 25 The WHO recommends two doses of SP for malaria prophylaxis in pregnancy. However, although malaria is endemic in Ghana, 18 26.4% of the women in this study did not receive an SP prescription during ANC and only 34.2% received two doses.
An overall prevalence of 25.7% was observed for intestinal helminth infections. In many sub-Saharan African countries, women consume soil during pregnancy, and a study in Kenya found that 73% of pregnant women ate soil regularly. 26 This habit might contribute to intestinal helminth infections. 27,28 The relatively high prevalence of helminth infections in this Ghanaian population could also be indicative of poor sanitation and improper sewage disposal, as shown by the fact that 37.9% of the participants had no toilet facilities in their homes. The prevalence rates of A. lumbricoides (12.3%) and hookworm (7.9%) were higher than those of other helminths, an observation that has been made in other studies in sub-Saharan Africa. 23,29,30 Our studies for intestinal helminths used only one stool sample from each woman; hence, the proportion of women with low-intensity infections could have been misclassified as uninfected. 31 The prevalence of helminth infections is therefore likely to be underestimated in this study.
Approximately 16.6% of the participants in this study were co-infected with P. falciparum and intestinal helminths. Of the women who had malaria, > 45% also had some type of worm infection. A study in Nigeria 17 observed a similar rate. In this study conducted in a malaria-endemic area, it was observed that participants with intestinal helminth infections were almost five times as likely to have P. falciparum infection as women with no helminth infection. The presence of helminths is usually associated with socio-economic confounders, which have been controlled for in this study, and the observed results are not likely to be caused by chance. Findings from a Thailand study found an increase in the prevalence of clinical malaria in individuals with helminth infections. 32 Awareness of the importance of co-infections is increasing, and suggestions have been made that helminth infection may influence susceptibility to other infections, including malaria 33,34 and HIV. 34,35 Several hypotheses have been put forth to explain this observation. It has been suggested that helminth infection creates a cytokine milieu favorable to the production of non-cytophilic antibodies, thus making individuals more susceptible to clinical malaria. 36 It is also thought that the presence of T-regulatory cells is amplified during helminth infection, and if present in sufficient numbers, could induce a non-specific suppression, 37 making individuals susceptible to infections such as malaria.
Our results indicate that the occurrence of A. lumbricoides infection and malaria are strongly associated. The mechanism behind this association is not clearly understood, but could be that Th2 profile-associated immunoglobulin E production seen in ascaris infection could down-modulate Th1 antimalarial immune responses, resulting in increased risk of malaria infection. 38
Risk factors for malaria infection were young age, low income, and primigravidae, whereas risk factors for intestinal helminth infection were young age and low income. The risk factors for malaria and intestinal helminth co-infection were identified to be young age, low income, being single, short pregnancy interval, and primigravidae.
The susceptibility of pregnant women to malaria infection is well established. 39,40 Findings from previous studies showed that primigravidae women are the most susceptible to P. falciparum infection.7,41,42 It has been shown in previous studies also that age is associated with malaria, with younger women more at risk. 7,40
The relationship between income and helminth infections has been observed in previous studies. 43,44 In this study, younger women (< 20 years) tended to have low income.
Seventy-one percent of women < 20 years of age were primigravidae, and > 45% earned < 100,000 cedis (US$ 10) per week. These three factors seem to be interdependent in this study. Low income predisposes to helminth infection, 43,44 whereas gravidity and age (young age corresponded with lower gravidity) predispose to P. falciparum infection7,41 and therefore risk for co-infection. Being single was also a risk factor for co-infection. Being single in most cases means low income, and low income can be a predisposing factor to infections, such as malaria and intestinal helminths. It has been observed that P. falciparum strains may get sequestered in the placenta.8 With successive pregnancies, women are subsequently exposed to a variety of strains of malaria and develop efficient mechanisms to control infection and prevent disease. 8,9 Primigravidae women have little or no immunity against the strains and hence suffer adverse consequences. 10
The strengths of the study include the relatively large sample size and the fact that the hospitals from which the women were recruited cater to women of all socio-economic status. Methodologic limitations include the use of one stool sample from each woman for determination of intestinal helminth infections and the limit of generalizability of the findings to all pregnant women in the region who deliver in the hospital. A proportion of women with low-intensity hookworm infections could have been misclassified as uninfected. Also, hookworms shed eggs intermittently; therefore, the prevalence of this infection is likely to be underestimated in this study.
This study shows relatively high prevalence rates of malaria, intestinal helminths, and co-infection in pregnant women in Kumasi, Ghana. This high prevalence of malaria, intestinal helminths, and co-infection have implications for public health practice in that pregnant women in endemic areas should be the focus of control efforts to prevent malaria and intestinal helminths, especially in the ANC setting.
Demographic and obstetric characteristics of 746 Ghanaian women, by malaria and intestinal helminth infection status, 2006
Associations between malaria and intestinal helminth infection among 746 pregnant Ghanaians, 2006
Risk factors for Plasmodium falciparum and intestinal helminth infections
Risk factors for Plasmodium falciparum and Intestinal helminth co-infection
Address correspondence to Pauline E. Jolly, Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, 1665 University Boulevard, RPHB 217, Birmingham, AL 35294-0022. E-mail: jollyp@uab.edu
Authors’ addresses: Nelly J. Yatich, Jiang Yi, Pauline E. Jolly, Department of Epidemiology, School of Public Health, University of Alabama at Birmingham (UAB), 1665 University Boulevard, RPHB 217, Birmingham, AL 35294. Tsiri Agbenyega, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana. Archer Turpin, Komfo Anokye Teaching Hospital, Kumasi, Ghana. Julian C. Rayner, Division of Infectious Diseases, School of Medicine, University of Alabama at Birmingham (UAB), 845 19th Street South, BBRB 220, Birmingham, AL 35294. Jonathan K. Stiles, Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA 30310. William O. Ellis, Department of Biochemistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana. Ellen Funkhouser, Division of Preventive Medicine, School of Medicine, University of Alabama at Birmingham (UAB), 1717 11th Avenue S, MT 611, Birmingham, AL 35294. John E. Ehiri, Department of Maternal and Child Health, School of Public Health, University of Alabama at Birmingham (UAB), 1665 University Boulevard, RPHB 302, Birmingham, AL 35294. Jonathan H. Williams, College of Agriculture and Environmental Sciences, University of Georgia, 1109 Experiment Street, Stuckey Building, Rm. 148, Griffin, GA 30223.
Acknowledgments: The authors thank Joshua Dugbartey for help with data collection and Ezra Mereng, Janet Kibet, and Dan Bunei for help with data entry. The authors thank Lincoln Gankpala for assistance with processing of samples, plasma preparation, and shipping and Dr. Curtis Jolly for helping with collecting and sorting of samples. We also thank the staff at the labor wards of Komfo Anokye Teaching Hospital and Manhyia Polyclinic and laboratory technicians for assisting in many ways to realize this work. Special thanks go to all the pregnant women who participated in this study. The authors thank Dr. Thomas Kruppa, Professor Ohene Adjei, and other laboratory personnel at the KCCR (KNUST) for use of their laboratory facilities.
Financial support: This research was supported by USAID Grant LAG-G-00-96-90013-00 for the Peanut Collaborative Support Research Program and the UAB Framework Program for Global Health, Grant R25TW007501, Fogarty International Center, National Institutes of Health.
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