SEARCH

SEARCH BY CITATION

Keywords:

  • AIDS;
  • coinfection;
  • HIV-exposed infant;
  • HIV mother-to-child transmission;
  • malaria

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Limitations and strengths
  8. Acknowledgements
  9. References

Objectives

We prospectively investigated fever symptoms and maternal diagnosis of malaria in pregnancy (MIP) in relation to child HIV infection among 2368 pregnant HIV-positive women and their infants, followed up from pregnancy until 6 weeks post-delivery in Tanzania.

Methods

Doctors clinically diagnosed and treated MIP and fever symptoms during prenatal health care. Child HIV status was determined via DNA polymerase chain reaction (PCR). Multivariable logistic regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for HIV mother-to-child transmission (MTCT) by the 6th week of life.

Results

Mean gestational age at enrolment was 22.2 weeks. During follow-up, 16.6% of mothers had at least one MIP diagnosis, 15.9% reported fever symptoms and 8.7% had both fever and MIP diagnosis. Eleven per cent of HIV-exposed infants were HIV-positive by 6 weeks. The RR of HIV MTCT was statistically similar for infants whose mothers were ever vs. never clinically diagnosed with MIP (RR 1.24; 95% CI 0.94–1.64), were diagnosed with one vs. no clinical MIP episodes (RR 1.07; 95% CI 0.77–1.48) and had ever vs. never reported fever symptoms (RR 1.04; 95% CI 0.78–1.38) in pregnancy. However, the HIV MTCT risk increased by 29% (95% CI 4–58%) per MIP episode. Infants of women with at least two vs. no MIP diagnoses were 2.1 times more likely to be HIV infected by 6 weeks old (95% CI 1.31–3.45).

Conclusions

Clinical MIP diagnosis, but not fevers, in HIV-positive pregnant women was associated with an elevated risk of early HIV MTCT, suggesting that malaria prevention and treatment in pregnant HIV-positive women may enhance the effectiveness of HIV prevention in MTCT programmes in this setting. Future studies using a laboratory-confirmed diagnosis of malaria are needed to confirm this association.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Limitations and strengths
  8. Acknowledgements
  9. References

The vast majority of HIV-infected children acquire the infection through mother-to-child transmission (MTCT) in utero, around the time of labour and delivery, or postnatally through breast feeding [1, 2]. Approximately 70% of all perinatally acquired HIV transmission occurs early (i.e. in utero, intra-partum or within 6 weeks of birth) in an exposed infant's life [2]. Previous investigations have identified several factors associated with early HIV transmission, including maternal (low CD4 cell count, high viral load and lack of antiretroviral therapy during pregnancy, mastitis and breast abscess), delivery (noncesarean section birth and absence of prophylactic nevirapine use) and child (low birth weight and prematurity) factors [2-4].

HIV and malaria infections represent the most important health problems in sub-Saharan Africa (SSA), where these infections overlap and coinfection is common [5]. An estimated 24.3 to 37% of HIV-positive pregnant women in the malaria-endemic regions of SSA are coinfected with malaria [6-8]. Malaria infection up-regulates the expression of chemokine (C-C motif) receptor 5 (CCR5) receptors in placental macrophages [9], increases peripheral and placental HIV-1 viral load [8], and thereby increases the risk of HIV MTCT for infants of pregnant HIV-positive women.

Nevertheless, there is little research on the potential contribution of coincident infections, such as malaria in pregnancy (MIP), to early HIV MTCT among HIV-exposed infants of HIV-infected women in SSA; when available, results have been inconclusive [6-8, 10-16]. In a short-term prospective study of infants born to 277 HIV-positive Kenyan women and 372 HIV-negative hospital-based controls, Inion et al. found no association between placental malaria and in utero or peripartal transmission of HIV-1 by 6 weeks [13]. Maternal placental malaria was associated with a lower risk of child HIV-positive status at 1 month of life among 207 pregnant HIV-positive women, each provided with a long-lasting insecticide-treated bed net with randomization to either intermittent preventive malaria therapy with sulfadoxyl-pyrimethamine or a placebo [17]. Another study of 512 HIV-positive mothers from Kenya found complex associations between maternal placental malaria and perinatal HIV MTCT [6]. On the one hand, low-density placental malaria was an independent protective risk factor for HIV MTCT. This association varied by maternal viral load such that, among mothers with low HIV viral load, low-density placental malaria protected against HIV MTCT, whereas, among mothers with high HIV viral loads, high-density placental parasitemia was associated with an elevated risk of HIV MTCT [6]. Further, a large, multi-site, randomized, placebo-controlled trial of antibiotics for reduction of chorioamnionitis that included pregnant HIV-positive women from three SSA countries, Malawi, Zambia and Tanzania, found no association between placental malaria and MTCT at birth [14]. However, among women with low baseline viral load, placental malaria was positively associated with HIV MTCT at birth [15]. On the other hand, a study of HIV-positive mothers from the Rakai District in Uganda found a twofold higher risk of HIV MTCT for HIV-positive mothers with placental malaria relative to those without placental malaria [7, 10]. Most recently, a small case−control study of the placentas of 40 HIV-infected mother−child pairs, which included 20 pairs in which the infants were perinatally HIV infected and 20 in which the infants were HIV-exposed but uninfected, as well as 20 HIV-uninfected mother−child pairs, reported sixfold higher odds of child perinatal HIV infection for mothers with placental malaria [11]. Both studies that found significant positive associations between in-pregnancy malaria and HIV MTCT were implemented prior to the availability of antiretroviral therapy for pregnant HIV-infected African women [10, 11].

In the light of these mixed findings and the persisting need to understand the potential role of maternal malarial morbidity during pregnancy in early HIV MTCT in the post-highly active antiretroviral therapy (HAART) era [18], we undertook this prospective cohort study to re-examine the hypothesis that maternal malarial morbidity during pregnancy is positively associated with MTCT. To this end, we used data collected between 2004 and 2008 among HIV-positive mothers whose children were enrolled in a trial of micronutrient supplementation in Dar es Salaam, Tanzania.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Limitations and strengths
  8. Acknowledgements
  9. References

Study population

This was a prospective cohort study of 2368 singleton, live-born infants whose mothers were HIV-positive, long-term residents of Dar es Salaam, Tanzania. The women were recruited during pregnancy and followed through delivery until the child's 24th month of life as part of a micronutrient trial. The study was conducted between June 2004 and May 2008. Per standard of care, all mothers received daily prenatal folate and iron supplements and malaria prophylaxis using sulfadoxine-pyrimethamine (SP) at 20 and 30 weeks of pregnancy. At the beginning of the study, maternal antiretroviral (ARV) medication was limited to nevirapine administered prophylactically during labour to prevent intra-partum HIV transmission. Beginning in July 2005, mothers were routinely evaluated for eligibility for HAART as a consequence of wider drug availability through the President's Emergency Plan for AIDS Relief (PEPFAR) and other programmes. Per standard of care, all newborns received nevirapine within 72 h of birth and were prescribed cotrimoxazole for prevention of bacterial pneumonia until age 6 months. Beyond 6 months of life, only breast feeding and HIV-positive children remained on cotrimoxazole. Mothers who were unable to return for follow-up, who had multiple births, or whose children had serious congenital anomalies that would interfere with study procedure compliance were excluded from participation in the trial.

Ethical clearance for the conduct of the parent study was provided by the institutional review boards of the Harvard School of Public Health and Muhimbili University of Health and Allied Sciences. The mothers of all children provided written informed consent for their own and the child's participation in the trial.

Outcome definition

Child HIV serostatus at 6 weeks was the primary outcome for this study and was assessed by a DNA polymerase chain reaction (PCR) test using the Amplicor HIV-1 DNA Prototype version 1.5 assay (Roche Diagnostics, Branchburg, NJ, USA).

Primary exposure/determinant: malaria in pregnancy

We classified mothers as having clinical MIP when treatment with antimalarial drugs was provided after a doctor's diagnosis of malaria. Specifically, clinical malaria was diagnosed during prenatal health care via a combination of a doctor's clinical assessment of the patient's presenting symptoms as being consistent with malaria and laboratory confirmation of parasitaemia (where possible). Where laboratory tests were performed, trained laboratory technicians prepared and read thin blood smears stained with Giemsa. Each slide was read in three different fields, and the parasite density per cubic millimetre was estimated from the number of parasites per 200 leucocytes. Of note, in this resource-limited setting, doctors' diagnosis of malaria based on patient symptoms is common practice. Therefore, this malaria case definition, although sensitive for identification of malaria, is necessarily limited by lower specificity [19].

For analytical purposes, clinical MIP diagnosis was operationally defined in one of three ways: (a) dichotomously as ever vs. never MIP during index pregnancy, (b) as an ordinal determinant with no, one, two or at least three malarial episodes to estimate the relative risk (RR) of HIV MTCT per unit increment in maternal MIP diagnosis, or (c) as a determinant that compares the HIV MTCT risk for infants of mothers who had at least one MIP diagnosis with that for infants whose mothers had no MIP diagnoses.

Confounders

Several classes of potential confounders of the malaria−HIV MTCT relationship were defined and adjusted for in multivariable analyses.

  1. Maternal health status. 
    Five indicators of maternal health during pregnancy at study enrolment were defined. These included (a) immune-deficient status (CD4 cell count < 350 vs. > 350 cells/uL); (b) anaemia (haemoglobin < 8.5, 8.5 to < 11 or > 11 g/dL); (c) HIV World Health Organization (WHO) disease stage (1 vs. ≥ 1); (d) use vs. non-use of HAART, and (e) number of fever symptoms reported by patients and documented by a doctor or nurse during the index pregnancy.
  2. Maternal sociodemographic factors. 
    Marital status, maternal age (in years) and socioeconomic factors were evaluated as potential confounders. Socioeconomic indicators included educational level (≥ 7 vs. < 7 years) and presence vs. absence of own income. Marital status was dichotomized as married/cohabiting vs. single/divorced/separated/widowed status.
  3. Maternal obstetric history. 
    This included parity (number of prior pregnancies to date) and history of adverse pregnancy outcomes in past pregnancies. For the latter, ever vs. never history of early neonatal mortality and ever vs. never history of spontaneous abortion by the 7th month of gestation were defined.
  4. Delivery factors. 
    These included cesarean section vs. spontaneous vaginal, assisted breach or vacuum extraction delivery, intra-partum nevirapine administration (yes vs. no), vaginal tears (yes vs. no), episiotomy (yes vs. no), full-term vs. pre-term birth, and hospital vs. home/other nonhospital delivery.
  5. Child birth characteristics. 
    These included male vs. female, low (< 2500 g) vs. normal (≥ 2500 g) birth weight, and full-term (≥ 37 weeks) vs. pre-term (< 37 weeks) birth.
  6. Post-delivery factors. 
    These included any vs. no infant early breast-feeding exposure and maternal breast health. In line with the literature [20], a binary variable was defined to distinguish mothers who reported having cracked nipples, bleeding nipples, an abscess or other signs of inflammation or infection on physical examination from those without any of these symptoms, between delivery and their child's 6th week of life.
  7. Seasonality and relevant temporal trends. 
    Because the intensity of exposure to the malaria parasite varies by season, we adjusted for maternal enrolment in the rainy vs. dry seasons in multivariate models.

Statistical analyses

We built a generalized estimating equations model that assumed a binomial distribution with a log link function to estimate the RR and 95% confidence interval (CI) associated with HIV MTCT at 6 weeks, as the outcome, and malaria during pregnancy, as the primary predictor. We adjusted for a wide range of potential confounders in multivariable analyses using a manual backward selection approach. Based on univariate analyses, all covariates whose association with HIV MTCT had a P-value ≤ 0.20 were included in the final multivariable models.

Separate multivariable models were built to investigate the independent associations between early HIV MTCT and (i) clinical MIP diagnoses and (ii) nonspecific fever symptoms during pregnancy. A joint multivariable model with mutual adjustment for MIP and fever symptoms was implemented to evaluate the extent to which any association between MIP and early HIV MTCT was mediated by nonspecific fevers in HIV-positive pregnant women and vice versa. Finally, we evaluated the heterogeneity of the association of maternal MIP diagnosis and early HIV MTCT by levels of the following factors: baseline maternal educational status, baseline maternal immune deficiency, baseline maternal WHO HIV disease stage, child sex and prematurity. If the P-value associated with the interaction was < 0.10, models were re-run (and results provided) within strata of the effect modifier.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Limitations and strengths
  8. Acknowledgements
  9. References

Enrolled in the parent study were 2387 HIV-positive mothers and their HIV-exposed infants. The average gestational age at enrolment was 22 weeks. Of the 2387 mother−child pairs, detailed maternal pregnancy health history and HIV status data at 6 weeks were available for the 2367 pairs who formed the study base for this nested longitudinal study. Eighty-four per cent of mothers breast fed their infants post-delivery. By the infant's 6th week of life, 262 (11.1%) were HIV positive (Table 1). The prevalences of fever symptoms and ever doctor-diagnosed clinical malaria during pregnancy were 16.6% (n = 394) and 15.9% (n = 376), respectively. Clinical malaria was also diagnosed in 54% of women with fever symptoms in pregnancy. Among women with clinical MIP, 1.6, 27.5 and 47.2% of all diagnoses occurred in the first, second and third trimesters, respectively. As many as 30.7% (n = 122) of women were clinically diagnosed with at least two episodes of MIP within the same trimester or across multiple trimesters. The vast majority (96%) of clinical MIP diagnoses were classified as uncomplicated malaria, but a laboratory test to confirm parasitaemia was ordered in 38% of women only. Test results, however, were available for only 19 women, of whom 18 were positive for the malaria parasite (data not shown).

Table 1. Sociodemographic, obstetric history and at-birth description of HIV-infected mothers and their newborns from Dar es Salaam, Tanzania
 OverallChild HIV-positive at 6 weeksChild HIV-negative at 6 WeeksP-value
(n = 262; 11.1%)(n = 2105; 88.9%)
  1. Values are n (%), unless otherwise stated.

  2. SD, standard deviation; GA, gestational age; PEPFAR, President's emergency plan for AIDS relief.

Mother's age (years) [mean (SD)]28.5 (4.9)28.8 (4.94)28.6 (4.95)0.5170
Mother's years of education [mean (SD)]7.2 (2.7)7.2 (2.33)7.19 (2.79)0.6195
GA at enrolment (weeks) [mean (SD)]22.2 (5.30)22.2 (5.39)22.1 (5.29)0.7276
Married/cohabiting1996 (85.0)213 (80.7)1783 (85.6)0.1782
Mother has own income809 (34.5)79 (29.9)730 (35.0)0.1001
Post-PEPFAR enrollee1449 (61.2)154 (58.8)1295 (61.5)0.3955
Obstetric history    
Neonatal deaths in prior pregnancies351 (15)60 (22.7)291 (14.0)0.0008
Spontaneous abortions (prior pregnancies)437 (18.5)52 (19.9)385 (18.3)0.5377
Gravidity (including current pregnancy)    
1531 (23.6)56 (21.5)475 (23.0)Ref
2772 (32.9)83 (31.4)689 (33.0)0.9619
3524 (22.3)67 (25.4)457 (21.9)0.2805
≥ 4499 (21.3)55 (20.8)444 (21.3)0.8541
Malaria during pregnancy    
Ever513 (21.6)64 (24.1)450 (25.1)0.3210
Number of malaria episodes    
01855 (78.3)180 (76.0)1537 (78.6)0.0178
1391 (16.5)39 (14.9)352 (16.7) 
2101 (4.3)18 (6.9)83 (3.3) 
≥ 321 (0.9)6 (2.3)15 (0.7) 
Delivery details and infant characteristics    
Mothers who took nevirapine at labour onset711 (30.0)66 (25.2)645 (30.6)0.0703
In-hospital delivery2011 (85.7)214 (81.8)1797 (86.2)0.0241
Vaginal tears351 (15.0)49 (18.6)396 (19.0)0.8632
Female sex1083 (45.7)131 (50.0)952 (45.2)0.1417
Cesarean section275 (11.7)23 (8.7)252 (12.1)0.1076
Full-term birth1774 (75)1578 (75.7)186 (70.5)0.0623
Low birth weight157 (6.7)42 (15.9)115 (5.5)< 0.0001
Infant received nevirapine within 72 h1691 (71.4)170 (64.9)1521 (72.2)0.0132
Breast fed between delivery and 6 weeks1989 (84.0)230 (87.8)1759 (83.5)0.0759
Maternal health; immunological/laboratory details    
Anaemia at enrolment643 (27.2)89 (34.0)554 (26.3)0.0085
Breast pain/inflammation, or cracked or  bleeding nipple by 6 weeks32 (1.4)6 (2.4)26 (1.2)0.1629
CD4 count < 350 cells/uL at enrolment774 (34.0)102 (45.6)672 (32.9)< 0.0001
HIV disease stage > 1 at enrolment383 (16.2)43 (16.4)340 (16.1)0.9116
On antiretrovirals at any time during pregnancy166 (7.1)5 (1.9)161 (7.6)0.0006

Sociodemographic, obstetric and at-birth information for the mother−child pairs is presented in Table 1. Mothers of children who were HIV positive at 6 weeks did not differ from mothers of children who were HIV negative at 6 weeks with respect to age, educational status, gestational age at study enrolment, gravidity or marital status. A greater proportion of mothers whose children were HIV negative at 6 weeks, however, delivered in hospitals and received antiretroviral therapy during pregnancy. Similarly, the proportion of mothers who took nevirapine prophylaxis at the onset of labour and the proportion of infants who received nevirapine prophylaxis within 72 h of birth were higher among infants who were HIV negative at 6 weeks. In addition, a lower percentage of mothers with HIV-negative children at 6 weeks had low-birth-weight infants, a prior history of early neonatal deaths, and CD4 cell counts < 350 cells/uL at enrolment. However, infants whose mothers had multiple episodes of malaria during pregnancy were over-represented among infants who were HIV-infected at 6 weeks (Table 1).

Based on multivariable models (Table 2), the RR of HIV infection at 6 weeks was elevated by 24%, but not statistically different, for infants whose mothers were ever vs. never (95% CI 0.94−1.64) diagnosed with clinical malaria and for infants whose mothers were diagnosed with a single vs. no malaria episodes (RR 1.07; 95% CI 0.77–1.48) during pregnancy. The RR of HIV MTCT, however, rose significantly per malaria episode increment during pregnancy (RR 1.29; 95% CI 1.04–1.58), and infants of HIV-positive women with at least two malaria diagnoses in pregnancy were more than twice as likely as infants of HIV-positive women not diagnosed with MIP to be HIV-infected at 6 weeks (RR 2.12; 95% CI 1.31–3.45). These malaria-associated estimated risks of HIV MTCT were robust to adjustment for variations in infant-related factors, maternal sociodemographic factors, delivery factors, maternal health status in pregnancy, and seasonality. Additional adjustment for potential mediators, including maternal immunological status at enrolment, use vs. non-use of HAART in pregnancy, and maternal WHO HIV disease stage, slightly attenuated but did not materially change the malaria-associated high risk of HIV MTCT (Table 2). Similarly, the adjustment of multivariable models for number of nonspecific fever symptoms reported in pregnancy slightly attenuated but did not ablate the positive association between early HIV MTCT and (i) number of clinical MIP diagnoses in pregnancy (RR 1.25; 95% CI 1.00−1.57) and (ii) multiple vs. no MIP diagnosis (RR 1.92; 95% CI 1.13−3.25).

Table 2. Mother-to-child HIV transmission by 6 weeks in relation to clinical malaria diagnosis by a doctor during pregnancy among HIV-positive mothers and their HIV-exposed infants from Dar es Salaam, Tanzania
  Univariate associationAdjusted model 1aAdjusted model 2b
  1. CI, confidence interval; RR, relative risk; n = number of seroconversions by 6 weeks; N = number of mothers within strata of maternal malarial morbidity in pregnancy; n/a, not applicable. Estimates are from a GEE (Generalized Estimating Equation) model modelling seroconversion at 6 weeks as the dependent variable. The model assumed a binomial distribution with a logit link. All adjusted covariates reflect their baseline values.

  2. a

    Model 1: covariates include: (a) maternal factors: presence vs. absence of breast/nipple lesions or inflammation, education, age, marital status, malaria prophylaxis at enrolment (self-reported yes vs. no), mother having own income, gravidity (two, three or at least four vs. one), history of neonatal deaths in previous pregnancies, history of still births in previous pregnancies and haemoglobin < 11 vs. ≥ 11 at study enrolment; (b) delivery factors: cesarean section vs. other form of delivery, presence/absence of vaginal tears or episiotomy, full-term vs. pre-term birth and location of delivery (Muhimbili Hospital vs. other); (c) child factors: male vs. female infant, low birth weight, and ever vs. never breast-fed status, and (d) study-relevant secular trends: pre- vs. post-PEPFAR (President's emergency plan for AIDS relief) birth (child born before or during July 2005 vs. after July 2005) and season of mother's recruitment into study: long and short rains vs. dry season.

  3. b

    Model 2: adjusted for all of the above plus the following potential mediators: maternal antiretroviral status during pregnancy, maternal World Health Organization (WHO) stage at enrolment, maternal immunity during pregna ncy at enrolment, i.e. enrolment CD4 count (< 350 vs. ≥ 350 cells/uL), and intra-partum administration of nevirapine.

Maternal malaria in pregnancyn/NRR (95% CI)RR (95% CI)RR (95% CI)

Never clinical malaria

Ever clinical malaria

53/394

209/1974

1.00

1.27 (0.96−1.68)

1.00

1.24 (0.94−1.64)

1.00

1.25 (0.93−1.63)

Per episode increment in clinical malarian/a1.31 (1.081.61)1.29 (1.041.58)1.29 (1.051.59)
Number of doctor-diagnosed clinical malaria episodes    
0209/19741.001.001.00
1 vs. 038/3321.08 (0.78−1.50)1.07 (0.77−1.48)1.09 (0.80−1.48)
≥ 2 vs. 015/622.27 (1.393.71)2.12 (1.313.45)1.99 (1.203.27)

Nonmalaria predictors of HIV MTCT at 6 weeks are presented in Table 3. The ever vs. never maternal report of fever symptoms was strongly and significantly associated with clinical MIP diagnosis (RR 5.80; 95% CI 4.91−6.93) but not with early HIV MTCT in multivariate models mutually adjusted for clinical MIP diagnosis (RR 1.04; 95% CI 0.87−1.29). However, maternal baseline immune-deficiency status, the presence of nipple lesions/inflammation at or before 6 weeks after birth, and infant low birth weight each predicted elevated risks of HIV MTCT at 6 weeks of life. Conversely, the receipt of HAART at any time during pregnancy, maternal possession of own income, and cohabiting or married status were significant protective risk factors for early HIV MTCT (Table 3). The relationship between clinical MIP and the factors identified above was generally invariant within levels of maternal CD4 count at enrolment, maternal WHO HIV disease stage at enrolment, child sex, and prematurity. However, the relationship between MIP (per episode increment) and HIV MTCT was heterogeneous within strata of maternal education (P-value for interaction term = 0.05). Specifically, each unit increment in maternal malaria episode was associated with a 3.2-fold (95% CI 1.49–6.71) RR of HIV MTCT among mothers with fewer than 7 years of education, whereas the risk of HIV MTCT by 6 weeks was nonsignificantly elevated among mothers with 7 or more years of education (RR 1.2; 95% CI 0.94–1.53).

Table 3. Nonmalaria predictors of mother-to-child HIV transmission by 6 weeks among HIV-positive mothers and their HIV-exposed infants from Dar es Salaam, Tanzania
 With exposureWithout exposureUnivariate model Adjusted modelb
(n/N)(n/N)RR (95% CI)RR (95% CI)
  1. n = number of seroconversions by 6 weeks; N = number of mother−child pairs with or without given exposure; Hgb, haemoglobin. Estimates are from a GEE (Generalized Estimating Equation) model modelling seroconversion at 6 weeks (randomization) as the dependent variable. The model assumed a binomial distribution with a log link. All adjusted covariates reflect their baseline values. Bold typeface denotes statistically significant results from multivariable adjusted regression models.

  2. a

    Self-reported maternal history of a live-born child dying within 7 days of birth or spontaneous abortion by pregnancy month 7. Current pregnancy is not included.

  3. b

    Multivariate model: adjusted covariates include: (a) maternal factors: education, age, marital status, malaria prophylaxis at enrolment (self-reported yes vs. no), mother having own income, gravidity (two, three or at least four vs. 1), history of neonatal deaths in previous pregnancies, history of still births in previous pregnancies and haemoglobin < 11 vs. ≥ 11 at study enrolment; (b) delivery factors: cesarean section vs. other form of delivery, presence/absence of vaginal tears or episiotomy, full-term vs. pre-term birth and location of delivery (Muhimbili Hospital vs. other); (c) child factors: male vs. female infant and low birth weight; (d) infant breast-feeding status (yes vs. no) and maternal breast/nipple health, and (e) study-relevant secular trends: pre- vs. post-PEPFAR birth (child born before or during July 2005 vs. after July 2005) and season of mother's recruitment into study: long and short rains vs. dry season, as well as the following potential mediators: maternal antiretroviral status during pregnancy, maternal World Health Organization (WHO) stage at enrolment, maternal CD4 count at enrolment (< 350 vs. ≥ 350 cells/uL) and intra-partum administration of nevirapine.

Maternal health indicators    
Maternal CD4 count < 350 cells/μL at enrolment94/607168/17611.83 (1.42, 2.35)1.84 (1.44, 2.36)
Ever vs. never maternal fever during pregnancy53/376209/19921.34 (1.01, 1.78)1.04 (0.78, 1.38)
Maternal anaemia at Enrolment    
Moderate anaemia (Hgb 8.5 to < 11 vs. ≥ 11 g/dL)79/587183/17811.38 (1.00, 3.24)1.25 (0.97, 1.62)
Severe anaemia (Hgb < 8.5 vs. ≥ 11 g/dL)10/56252/23121.77 (1.07, 1.79)1.61(0.93, 2.81)
On antiretrovirals in pregnancy5/166257/22020.30 (0.13, 0.73)0.20 (0.08, 0.50)
Maternal obstetric history in prior pregnancies/deliveries    
≥ 1 vs. 0 early child deathsa/spontaneous abortions96/771166/15971.25 (0.97, 1.61)1.19 (0.92, 1.54)
Breast feeding and maternal breast/nipple health    
Any vs. no breast feeding (birth to 6 weeks of life)230/198932/3791.40 (0.94, 2.10)1.27 (0.85, 1.90)
Any vs. no breast lesions/pain/inflammation, or cracked or bleeding nipple (birth to 6 weeks post-partum)6/32256/23361.69 (0.81, 3.51)1.90 (1.02, 3.55)
Delivery factors/infant characteristics    
Nevirapine prophylaxis given to:    
Both mother at labour onset and baby within 72 h of birth60/644202/17240.66 (0.49, 0.90)0.75 (0.53, 1.08)
Baby only within 72 h of birth110/1047152/13210.74 (0.57, 0.97)0.84 (0.60, 1.17)
Mother at labour onset only5/60257/23080.59 (0.25, 1.40)0.67 (0.29, 1.53)
Cesarean section vs. other type of birth23/275239/20930.74 (0.49, 1.12)0.83 (0.55, 1.25)
Premature birth (< 37 vs. ≥ 37 weeks)49/348213/20201.35 (1.02, 1.81)1.01 (0.75, 1.35)
Female vs. male sex131/1083131/12851.19 (0.94, 1.49)1.13 (0.91, 1.41)
Low (< 2500 g) vs. normal (≥ 2500 g) birth weight40/156222/22122.65 (1.96, 3.57)2.30 (1.71, 3.07)
In hospital vs. home/other location of delivery212/202650/3420.70 (0.50, 0.98)0.99 (0.66, 1.48)
Economic/sociodemographic/temporal factors    
Married/cohabiting vs. single/divorced/widowed/separated222/206040/3080.82 (0.60, 1.13)0.73 (0.54, 1.00)
Has own income vs. no income78/813184/15550.81 (0.63, 1.04)0.76 (0.59, 0.98)
Maternal education (≥ 7 vs. < 7 years)234/204628/3221.32 (0.90, 1.92)1.31(0.91, 1.92)

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Limitations and strengths
  8. Acknowledgements
  9. References

In this cohort of HIV-positive mothers from Dar es Salaam, Tanzania, enrolled in the study during pregnancy and followed through delivery, 11% of HIV-exposed infants contracted HIV in utero, intra-partum or within the first 6 weeks of life. The 11% HIV MTCT rate observed in this study is 45 to 62% lower than the typically reported 20 to 29% rate of new HIV infections among HIV-positive treatment-naïve pregnant women [21-23] but comparable to the MTCT rates observed in other malaria-endemic African settings where nevirapine prophylaxis was used for prevention of MTCT in the absence of HAART [24, 25]. We found no difference in the risk of HIV MTCT for infants of women with one vs. no malaria episodes in pregnancy and women with and without fever symptoms during pregnancy. However, there was a significant elevation of HIV MTCT risk per malaria episode increment. MIP diagnosis was an independent predictor of HIV MTCT at 6 weeks for infants of mothers with two or more malaria episodes, compared with infants whose mothers were not diagnosed with malaria during the pregnancy. These associations were strongest for infants born to women with fewer than 7 years of education. We found no evidence that the positive relationship between MIP diagnosis and HIV MTCT was mediated by fever symptoms.

We confirm the overall trend of lower HIV MTCT with greater access to HAART in pregnancy [26] and the positive associations between HIV MTCT risk and maternal immune deficiency [20, 27], child low birth weight [28, 29], and the presence of breast inflammation and nipple lesions in breast-feeding HIV-positive women [20, 30, 31]. Similar to prior reports [32, 33], we found protective associations between indicators of superior socioeconomic position and early HIV MTCT [32].

Our finding of a statistically significant positive association between MIP and MTCT is corroborated by findings of a twofold higher risk of HIV MTCT among HIV-positive mothers with MIP in the Rakai District of Uganda [7, 10] and the recently reported sixfold elevated odds of early HIV MTCT for infants of Rwandan HIV-positive women with MIP [11]. Our results are further supported by the finding of a higher risk of MTCT among HIV-positive pregnant women with high-density placental malaria in western Kenya [6] and the recent finding of a MIP associated increased risk of HIV MTCT by Msamanga et al. in a subset of their sample of pregnant HIV-positive women – specifically, those with low viral load [14].

The above notwithstanding, findings from at least three other epidemiological studies either do not support our findings, with respect to the relationship of maternal MIP to HIV MTCT [13, 14], or are in direct conflict with ours [17]. Specifically, our results are not supported by the overall finding of no association reported by Msamanga et al. [14] In addition, our finding of a higher risk of HIV MTCT among pregnant HIV-positive women with malarial morbidity stands in contrast to the findings from a Mozambican cohort of 207 HIV-positive mothers enrolled in a trial of intermittent malaria preventive treatment with two doses of SP vs. a placebo [17].

We note that salient differences between our study and some of the above studies may be partly responsible for these disparate findings. Naniche et al.'s [17] study included fewer subjects than did ours (n = 207 vs. 2367, respectively), involved very few cases of HIV MTCT (n = 19 vs. 262, respectively), and had complete data on malaria and HIV MTCT for fewer mother−child pairs (n = 153 vs. 2367, respectively), all of which contribute to lower statistical power relative to the present study. These limitations make it difficult to determine whether their findings were true effects or the result of random variation with respect to placental malaria rates and their relationship to HIV MTCT. The findings also may be different when the same question is investigated in the context of a larger, adequately powered sample that includes more mother−child pairs and MTCT events. Despite these potential explanations for the differences in results, rigorously designed large studies using gold-standard malaria diagnostic criteria will be necessary to confirm or refute our findings.

According to the most recent UNAIDS (Joint United Nations Programme on HIV/AIDS) report, there has been an overall 24% reduction in MTCT between 2001 and 2009 [34]. This encouraging trend has contributed to the belief that the virtual elimination of MTCT is achievable with the implementation of proven strategies for prevention of HIV transmission [34]. Yet, the 22% prevalence of clinical malarial morbidity in this cohort is comparable to estimates from other investigations among HIV-positive women from the region prior to widespread access to antiretroviral drugs in pregnancy [6, 7, 10, 13]. Of note, the rate of malarial morbidity has been assessed using varied approaches, including clinical diagnoses and rapid diagnostic and malaria parasitaemia tests. All methods suggest that the incidence of malaria has been on the decline in certain regions of Tanzania, particularly in the island of Zanzibar, since 2000 [35]. Nevertheless, a significant malaria burden remains, particularly for noncoastal regions in the Republic of Tanzania. Hence, the results of this study provide an impetus to provide more comprehensive malaria prevention measures.

A recent review article suggested that coinfections, including malaria, tuberculosis and herpes simplex virus type 2, in high HIV-prevalence areas could be important, persistent drivers of HIV transmission [18] in the HAART era. The results reported herein, and the recently reported elevated risk of postnatal HIV infection for breast-feeding infants of HIV-positive women with malaria compared with those without malaria, provide empirical evidence in support of this position [36]. That the association between MIP diagnosis and HIV infection at birth was slightly attenuated but still statistically significant after controlling for nonspecific fever symptoms suggests that the observed relationship may reflect malaria-parasite-induced immune suppression and HIV viral load amplification. Malarial morbidity is associated with lower immune fitness in HIV-positive persons [8, 9, 37]. The ubiquity of malarial morbidity among pregnant women in SSA may directly counteract the health benefits of increased HAART access for pregnant HIV-positive women and thus has real potential to limit the effectiveness of prevention of MTCT programmes in this population. Our results suggest that maternal malarial morbidity in pregnancy is likely to remain an important independent risk factor for HIV MTCT in malaria-endemic regions of SSA, even when multiple confounders, including maternal immunological status, nonspecific fever symptoms, and the expected beneficial impact of maternal access to HAART during pregnancy, are accounted for.

Limitations and strengths

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Limitations and strengths
  8. Acknowledgements
  9. References

The most important limitation of this study is the use of a clinically defined malaria diagnosis as a surrogate for malarial morbidity. This may have resulted in over-diagnosis of malaria in this study. The extent of over-diagnosis of malaria is unclear, as our cumulative 16.6% prevalence of clinical MIP is lower than the 20.4% clinical malaria prevalence reported among pregnant women from Moshi, Tanzania [38], the 23% prevalence found among pregnant HIV-positive women from Uganda [39], and the 21% malaria prevalence among pregnant HIV-positive women from Rwanda, where more rigorous diagnostic criteria were employed [40]. We acknowledge this limitation of our data and stress the utility of rapid diagnostic assays that are increasingly available at reasonable cost to facilitate accurate diagnosis of malaria, whenever possible, even in the most resource-limited settings. This limitation notwithstanding, our study represents the largest prospective investigation of whether newborns of HIV-infected pregnant women with diagnosed MIP are at elevated risk of HIV infection within 6 weeks of birth in an area of high malaria endemicity, with control for an extensive array of relevant confounders − including number of fever symptoms in pregnancy, maternal HAART use in pregnancy and baseline immunological status, maternal and child nevirapine prophylaxis, and differences in sociodemographic and child-related characteristics.

Our results suggest that malarial morbidity in pregnant HIV-positive women might be an independent risk factor for HIV MTCT in SSA. Our finding that the association between MIP diagnosis and HIV MTCT was not explained by fever symptoms suggests that MIP in HIV-positive women may elevate the incidence of HIV infection in co-endemic regions independent of nonspecific fever symptoms. Hence, the risk of HIV transmission may remain elevated in HIV-positive women in spite of the increasing HAART availability and improved coverage of prevention of MTCT services. Attainment of the expressed goal of zero MTCT by 2015, as noted in the most recent UNAIDS report in malaria and HIV co-endemic settings, will be enhanced by understanding the contribution of malaria and other coinfections to HIV transmission and by ramping up control efforts to mitigate such risks. Given the limitations described above, further studies on this subject, with more rigorous malaria definitions, are warranted to further elucidate the relationship of laboratory-confirmed malarial morbidity in pregnancy and MTCT.

In the light of the grave health risks associated with MIP, the special vulnerability of HIV-positive women to malaria, and its potential contribution to elevated risk of HIV MTCT, we believe that large-scale adoption and consistent implementation of malaria prevention measures, including universal access to insecticide-treated bed nets, among HIV-positive pregnant women are warranted. An additional prevention strategy that might improve patient compliance with malaria prevention measures is large-scale dissemination of information regarding the possible malaria-associated higher risk of HIV MTCT. Further, all HIV-positive adults may benefit from active, rather than passive, clinical assessment for malaria and its treatment when indicated as part of routine health care as asymptomatic malaria parasitaemia is likely to be common among HIV-positive adults.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Limitations and strengths
  8. Acknowledgements
  9. References

We thank the study participants from Dar es Salaam, Tanzania for making this study possible. We are grateful to the field staff for their diligence and energy: Rehema Mtonga, Illuminata Ballonzi, Godwin Njiro, Frank Killa, Emily Dantzer, Elizabeth Long and Jenna Golan. AEE acknowledges, with thanks, salary support during this investigation from the Harvard School of Public Health Yerby Post-doctoral Fellowship programme. The opinions and statements in this article are those of the authors and may not reflect official UNICEF policies.

Conflicts of interest: The authors do not have commercial (e.g. pharmaceutical stock ownership or consultancy) or other associations that pose a conflict of interest in the collection, analysis, presentation and interpretation of these data.

Funding: This work was supported by the National Institute of Child Health and Human Development, grant number R01HD043688. CD was supported in part by K24 HD058795. The funder of this study had no role in the design, data collection, analysis, interpretation or writing of this report.

Authorship: The corresponding author had full access to all the data in the study and the final responsibility for the decision to submit for publication.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Limitations and strengths
  8. Acknowledgements
  9. References
  • 1
    Horvath T, Madi BC, Iuppa IM, Kennedy GE, Rutherford G, Read JS. Interventions for preventing late postnatal mother-to-child transmission of HIV. Cochrane Database Syst Rev 2009; 1: CD006734.
  • 2
    Mmiro FA, Aizire J, Mwatha AK et al. Predictors of early and late mother-to-child transmission of HIV in a breastfeeding population: HIV Network for Prevention Trials 012 experience, Kampala, Uganda. J Acquir Immune Defic Syndr 2009; 52: 3239.
  • 3
    Read JS. Preventing mother to child transmission of HIV: the role of caesarean section. Sex Transm Infect 2000; 76: 231232.
  • 4
    Spensley A, Sripipatana T, Turner AN, Hoblitzelle C, Robinson J, Wilfert C. Preventing mother-to-child transmission of HIV in resource-limited settings: the Elizabeth Glaser Pediatric AIDS Foundation experience. Am J Public Health 2009; 99: 631637.
  • 5
    Abu-Raddad LJ, Patnaik P, Kublin JG. Dual infection with HIV and malaria fuels the spread of both diseases in sub-Saharan Africa. Science (New York, NY) 2006; 314: 16031606.
  • 6
    Ayisi JG, van Eijk AM, Newman RD et al. Maternal malaria and perinatal HIV transmission, western Kenya. Emerg Infect Dis 2004; 10: 643652.
  • 7
    Brahmbhatt H, Sullivan D, Kigozi G et al. Association of HIV and malaria with mother-to-child transmission, birth outcomes, and child mortality. J Acquir Immune Defic Syndr 2008; 47: 472476.
  • 8
    Mwapasa V, Rogerson SJ, Molyneux ME et al. The effect of Plasmodium falciparum malaria on peripheral and placental HIV-1 RNA concentrations in pregnant Malawian women. AIDS 2004; 18: 10511059.
  • 9
    Tkachuk AN, Moormann AM, Poore JA et al. Malaria enhances expression of CC chemokine receptor 5 on placental macrophages. J Infect Dis 2001; 183: 967972.
  • 10
    Brahmbhatt H, Kigozi G, Wabwire-Mangen F et al. The effects of placental malaria on mother-to-child HIV transmission in Rakai, Uganda. AIDS 2003; 17: 25392541.
  • 11
    Bulterys PL, Chao A, Dalai SC et al. Placental malaria and mother-to-child transmission of human immunodeficiency virus-1 in rural Rwanda. Am J Trop Med Hyg 2011; 85: 202206.
  • 12
    Gallagher M, Malhotra I, Mungai PL et al. The effects of maternal helminth and malaria infections on mother-to-child HIV transmission. AIDS 2005; 19: 18491855.
  • 13
    Inion I, Mwanyumba F, Gaillard P et al. Placental malaria and perinatal transmission of human immunodeficiency virus type 1. J Infect Dis 2003; 188: 16751678.
  • 14
    Kupka R, Msamanga GI, Aboud S, Manji KP, Duggan C, Fawzi WW. Patterns and predictors of CD4 T-cell counts among children born to HIV-infected women in Tanzania. J Trop Pediatr 2009; 55: 290296.
  • 15
    Msamanga GI, Taha TE, Young AM et al. Placental malaria and mother-to-child transmission of human immunodeficiency virus-1. Am J Trop Med Hyg 2009; 80: 508515.
  • 16
    Naniche D, Lahuerta M, Bardaji A et al. Mother-to-child transmission of HIV-1: association with malaria prevention, anaemia and placental malaria. HIV Med 2008; 9: 757764.
  • 17
    Naniche D, Lahuerta M, Bardaji A et al. Mother-to-child transmission of HIV-1: association with malaria prevention, anaemia and placental malaria. HIV Med 2008; 9: 757764.
  • 18
    Barnabas RV, Webb EL, Weiss HA, Wasserheit JN. The role of co-infections in HIV epidemic trajectory and positive prevention: a systematic review and meta-analysis. AIDS 2011; 25: 15591573.
  • 19
    Tangpukdee N, Duangdee C, Wilairatana P, Krudsood S. Malaria diagnosis: a brief review. Korean J Parasitol 2009; 47: 93102.
  • 20
    Fawzi W, Msamanga G, Spiegelman D et al. Transmission of HIV-1 through breastfeeding among women in Dar es Salaam, Tanzania. J Acquir Immune Defic Syndr 2002; 31: 331338.
  • 21
    Bertolli J, St Louis ME, Simonds RJ et al. Estimating the timing of mother-to-child transmission of human immunodeficiency virus in a breast-feeding population in Kinshasa, Zaire. J Infect Dis 1996; 174: 722726.
  • 22
    Bulterys M, Chao A, Dushimimana A et al. Multiple sexual partners and mother-to-child transmission of HIV-1. AIDS 1993; 7: 16391645.
  • 23
    Wabwire-Mangen F, Gray RH, Mmiro FA et al. Placental membrane inflammation and risks of maternal-to-child transmission of HIV-1 in Uganda. J Acquir Immune Defic Syndr 1999; 22: 379385.
  • 24
    Ayouba A, Tene G, Cunin P et al. Low rate of mother-to-child transmission of HIV-1 after nevirapine intervention in a pilot public health program in Yaounde, Cameroon. J Acquir Immune Defic Syndr 2003; 34: 274280.
  • 25
    Guay LA, Musoke P, Fleming T et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999; 354: 795802.
  • 26
    Hoffman RM, Black V, Technau K et al. Effects of highly active antiretroviral therapy duration and regimen on risk for mother-to-child transmission of HIV in Johannesburg, South Africa. J Acquir Immune Defic Syndr 2010; 54: 3541.
  • 27
    Tournoud M, Ecochard R, Kuhn L, Coutsoudis A. Diversity of risk of mother-to-child HIV-1 transmission according to feeding practices, CD4 cell count, and haemoglobin concentration in a South African cohort. Trop Med Int Health 2008; 13: 310318.
  • 28
    Charurat M, Datong P, Matawal B, Ajene A, Blattner W, Abimiku A. Timing and determinants of mother-to-child transmission of HIV in Nigeria. Int J Gynaecol Obstet 2009; 106: 813.
  • 29
    Van Dyke RB. Mother-to-child transmission of HIV-1 in the era prior to the availability of combination antiretroviral therapy: the role of drugs of abuse. Life Sci 2011; 88: 922925.
  • 30
    Kantarci S, Koulinska IN, Aboud S, Fawzi WW, Villamor E. Subclinical mastitis, cell-associated HIV-1 shedding in breast milk, and breast-feeding transmission of HIV-1. J Acquir Immune Defic Syndr 2007; 46: 651654.
  • 31
    Semba RD, Kumwenda N, Hoover DR et al. Human immunodeficiency virus load in breast milk, mastitis, and mother-to-child transmission of human immunodeficiency virus type 1. J Infect Dis 1999; 180: 9398.
  • 32
    Adejuyigbe EA, Fasubaa OB, Onayade AA. Sociodemographic characteristics of HIV-positive mother-child pairs in Ile-Ife, Nigeria. AIDS Care 2004; 16: 275282.
  • 33
    Vieira AC, Miranda AE, Vargas PR, Maciel EL. HIV prevalence in pregnant women and vertical transmission in according to socioeconomic status, Southeastern Brazil. Rev Saude Publica 2011; 45: 644651.
  • 34
    UNAIDS. Global report: UNAIDS report on the global AIDS epidemic 2010., Joint United Nations Programme on HIV/AIDS, 2010: 20.
  • 35
    WHO. World Malaria Report 2010. Geneva, WHO, 2011.
  • 36
    Ezeamama AE, Duggan C, Spiegelman D et al. Malarial Morbidity and Postnatal HIV Infection in Breastfeeding HIV-exposed Infants. Int J Trop Dis Health 2014; 4: 1830.
  • 37
    Barnabas RV, Webb EL, Weiss HA, Wasserheit JN. The role of coinfections in HIV epidemic trajectory and positive prevention: a systematic review and meta-analysis. AIDS 2011; 25: 15591573.
  • 38
    Ogundipe O, Hoyo C, Ostbye T et al. Factors associated with prenatal folic acid and iron supplementation among 21,889 pregnant women in Northern Tanzania: a cross-sectional hospital-based study. BMC Public Health 2012; 12: 481.
  • 39
    De Beaudrap P, Turyakira E, White LJ et al. Impact of malaria during pregnancy on pregnancy outcomes in a Ugandan prospective cohort with intensive malaria screening and prompt treatment. Malar J 2013; 12: 139.
  • 40
    Ivan E, Crowther NJ, Rucogoza AT et al. Malaria and helminthic co-infection among HIV-positive pregnant women: prevalence and effects of antiretroviral therapy. Acta Trop 2012; 124: 179184.