Download The effects of maternal helminth and malaria infections on mother

The effects of maternal helminth and malaria
infections on mother-to-child HIV transmission
Maureen Gallaghera, Indu Malhotraa, Peter L. Mungaia,b,
Alex N. Wamachic, John M. Kiokob, John H. Oumad,
Eric Muchirib and Christopher L. Kinga,e
Objective: To investigate the effect of helminth and/or malaria infection on the risk of
HIV infection in pregnant women and its transmission to their offspring.
Design: A retrospective cohort study of pregnant Kenyan women and their offspring
from term, uncomplicated vaginal deliveries (n ¼ 936) with a nested case–control
study.
Methods: We determined the presence of HIV, malaria, schistosomiasis, lymphatic
filariasis, and intestinal helminthes in mothers and tested for HIV antibodies in 12-24
month-old offspring of HIV-positive women. We related these findings to the presence
of cord blood lymphocyte activation and cytokine production in response to helminth
antigens.
Results: HIV-positive women (n ¼ 83, 8.9% of all women tested) were 2-fold more
likely to have peripheral blood and/or placental malaria (P < 0.025) and a 2.1-fold
greater likelihood of lymphatic filariasis infection (P < 0.001) compared to locationand-parity matched HIV-negative women. Women with HIV and malaria tended to
show an increased risk for mother-to-child-transmission (MTCT) of HIV, although this
difference was not significant. MTCT of HIV, however, was significantly higher in
women co-infected with one or more helminthes (48%) verses women without
helminth infections (10%, P < 0.01; adjusted odds ratio, 7.3; 95% confidence interval,
2.4–33.7). This increased risk for MTCT of HIV correlated with cord blood lymphocytes production of interleukin-5/interleukin-13 in response to helminth antigens
(P < 0.001).
Conclusion: Helminth co-infection is associated with increased risk for MTCT of HIV,
possibly by a mechanism in which parasite antigens activates lymphocytes in utero.
Treatment of helminthic infections during pregnancy may reduce the risk of MTCT of
ß 2005 Lippincott Williams & Wilkins
HIV.
AIDS 2005, 19:1849–1855
Keywords: HIV, vertical transmission, malaria, lymphatic
filariasis, schistosomiasis, intestinal helminthes, infants
Introduction
Mother-to-child transmission (MTCT) of HIV occurs in
an estimated 500 000 newborns and infants each year in
sub-Saharan Africa [1]. Pregnant women infected with
HIV are often co-infected with malaria, and various
blood-borne and intestinal helminth infections in subSaharan Africa. These co-infections may increase the risk
From the aCenter for Global Health and Diseases and Center for AIDS Research, Case Western Reserve University, Cleveland, OH,
USA, the bDivision of Vector Borne Diseases, Nairobi, Kenya, the cKenyan Medical Research Institute, Kenya, the dMaseno
University, Maseno, Kenya, and the eDepartment of Veteran’s Affairs Medical Center, Cleveland, OH, USA.
Correspondence to C. L. King, Center for Global Health and Diseases, Case Western Reserve University, 2103 Cornell Rd, WRB
Rm 4132, Cleveland, OH 44106-7286, USA.
Tel: +1 216 368 4817; fax: +1 216 368 4825; e-mail: [email protected]
Received: 11 March 2005; accepted: 6 June 2005.
ISSN 0269-9370 Q 2005 Lippincott Williams & Wilkins
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AIDS 2005, Vol 19 No 16
for MTCT of HIV. Thus the eradication of these coinfections in pregnant women could reduce MTCT of
HIV.
Several observations have implicated malaria as a potential
risk factor for MTCT of HIV. Malaria infections can
increase HIV loads in peripheral blood [2,3] and greater
viral loads enhance the risk for MTCT of HIV [4]. Coinfection with HIVand malaria during pregnancy doubles
the risk that women will have placental malaria [5].
Placental malaria stimulates increased CCR5 expression
on placental macrophages [6], making those macrophages
more susceptible to HIV infection that can potentially
increase viral loads in the placenta [6]. Placental malaria
can also damage the placenta which may facilitate
transplacental passage of HIV to the fetus. Yet the few
epidemiological studies that have examined the association of placental malaria with the risk of MTCT have
produced conflicting results. Some studies show malaria
increases risk for MTCT [7], others do not [8]. Other
studies show a variable effect; low levels of placental
parasitemia actually protect against HIV transmission, and
high placental parasitemia increases the risk for MTCTof
HIV [9].
Concomitant helminth infections have also been postulated to increase the risk for HIV infections [10]. The
hallmark of persistent helminth infections are expanded
populations of Th2-type lymphocytes [11,12] that are
more susceptible to HIV infection and propagation
[13,14]. Chronic helminth infections can lead to a state of
persistent immune activation [15], with increased
expression of CCR5 and CXCR4 on peripheral blood
CD4 T cells and monocytes [16], thus increasing their
susceptibility to HIV infection. Helminth co-infections
may also increase the risk of MTCT of HIV by releasing antigens intravascularly that can cross the placenta
and stimulate an immune response in the fetus [17].
These chronically activated lymphocytes may increase a
neonate’s susceptibility to HIV infection in utero, perinatally or post-natally (breast-feeding). Urinary schistosomiasis can produce lesions in the cervix or vagina that
may increase viral shedding thereby enhancing the infant’s
risk for HIV infection [18]. The presence of chronic
helminth infections has not been previously examined as
to whether it increases risk of MTCTof HIV. Here we test
the hypotheses that women with chronic intravascular
parasite infections are more likely to be HIV infected
and that HIV-positive, pregnant women co-infected
with malaria or helminthes have an increased risk for
MTCT of HIV in a Kenyan population where urinary
schistosomiasis, lymphatic filariasis, malaria, intestinal
helminthes and HIV are endemic.
Methods
This retrospective cohort study examined the presence of
HIVand parasitic coinfections in 936 Kenyan mother and
infant pairs recruited between 1996 and 2002 at the
Msambweni District Hospital and Vanga Health Center
in Kwale District, Coast Province of Kenya, as part of a
birth cohort study examining schistosomiasis and
lymphatic filariasis. Plasma samples were cryopreserved
at 808C prior to examination. Fresh cord blood
lymphocytes were previously examined for the capacity
to produce interleukin (IL)-2, IL-5, IL-13, and interferon
(IFN)-g to crude soluble antigens prepared from adult
Schistosoma haematobium and Wuchereria bancrofti worms
and W. bancrofti microfilaria as previously described [17].
Plasma was obtained every 6 months until 2 years of age
and annually thereafter from infants as part of the birth
cohort study beginning in 1996. Ethical approval to
conduct this retrospective study was obtained from
Institutional Review Boards at Case Western Reserve
University and the Kenyan Institute for Medical
Research. All samples were collected prior to institution
of a program involving treatment with anti-retroviral
drugs perinatally (HIV testing, counseling, and peripartum anti-retroviral treatment began in the antenatal clinic
at Msambweni District Hospital in June 2002). All
women included in the retrospective cohort had healthy,
term, uncomplicated, vaginal deliveries. The overall
sample ascertainment and study design is shown in Fig. 1.
Healthy pregnant
women n = 936
HIV negative
n = 853
HIV positive
n = 83
Matched
Examine for parasite
co-infection prior to
delivery
No follow-up
n = 40
HIV negative
controls n = 166
Case-control
analysis
HIV positive
n = 83
Offspring tested for HIV at
12 months age, n = 44
Cord blood examined at birth
for infants examined at 12
months, n = 34
Association of
parasite co-infection
with MTCT of HIV
Association of
lymphocyte reactivity
to helminth antigens
with MTCT of HIV
Fig. 1. Diagram of the study design and analysis (in bold).
One HIV-positive woman had twins. Therefore of 43 HIVpositive women, 44 offspring were examined for the presence
of HIV infection during infancy.
Helminths and vertical HIV transmission Gallagher et al.
HIV-ELISA tests were performed on the frozen, stored
samples collected from women at delivery and from their
infants at 12 months and repeated at 18–24 months of
age. A child was considered infected if both samples were
HIV positive by serology. If a sample was unavailable at
18–24 months of age and was found to be serologically
positive at 12 months (n ¼ 2), an HIV serology was
performed on the 6-month sample and a positive test was
scored only if the antibody titer was similar or higher in
the sample collected at age 12 months to exclude the
possibility that HIV antibodies may have persisted from
birth. Testing was conducted anonymously such that the
HIV status of a sample could not be linked to a particular
individual, and only relevant data was extracted from the
database. We measured the presence of anti-HIV antibodies with the Genetic Systems HIV-1 assay (Bio-Rad
Laboratory Virus Division, Redmond, Washington,
USA) that uses a highly purified lysate of the LAV strain
of HIV-1 and recombinant HIV-1 envelope protein gp41.
A positive sample had to have at least an antigen unit (AU,
optical density of test sample/control) of > 2 which was
repeated twice to confirm positivity. Samples with AU
between 1 and 2 or that showed discordant results in the
repeated ELISA assays were confirmed by Western Blot.
Pregnant women in the study were screened for helminth
and malaria infections in the antenatal clinics and/or at
delivery. Urine samples for detecting schistosomiasis were
not available for 64 women, stools samples were not
collected for 103 women, and plasma samples for
detecting for lymphatic filariasis were missing for 14
individuals. In addition, insufficient or missing intervillous placental blood samples made it not possible to test
for malaria for 109 deliveries. The proportion of missing
samples was equally distributed between HIV-positive
and -negative women (P > 0.2).
To examine for the presence of malaria, thin and thick
blood smears were performed on maternal peripheral
blood and intervillous placental blood; smears were
stained with Geimsa, and 200 high-powered fields with at
least one polymorphonuclear cell were examined for
malaria parasites. The presence of malaria was also assessed
by real-time quantitative PCR which [19] amplifies the
gene encoding the small subunit ribosome of Plasmodium
falciparum using 2.5 ml of DNA prepared from 200 ml of
the red cell pellet obtained after ficoll–hypaque
preparation of peripheral blood mononuclear cells.
DNA was also extracted from 200 ml of whole
intervillous placental blood obtained by careful cannulation of the intervillous space, after clearing away excess
blood. Fresh stool samples were concentrated and
examined for intestinal helminthes by the Kato–Katz
method. The presence of S. haematobium eggs was measured by Nuclopore (Pleasanton, California, USA) polycarbonate filtration of 10 ml of freshly collected urine.
Infection by W. bancrofti or lymphatic filariasis (LF) was
assessed by detection of circulating antigen in plasma
using the Og4C3 mAb assay (Trop Biomed, Townsville,
Australia).
Univariate analysis was performed by chi-square or
Fisher’s exact test (i.e., for cross-tabulations with an
expected value in any cell 5) comparing proportions
for categorical variables among those individuals HIV
positive and negative. Differences in cytokine production
were compared using the Mann–Whitney U test. To
evaluate the independent associations of co-infections and
risk of HIV maternal infection, a conditional logistic
regression analysis was performed using SPSS 11.0 (SPSS
Inc., Chicago, Illinois, USA). Odds ratios (OR) and
confidence intervals (CI) were calculated for infections
with malaria and lymphatic filariasis. We used a logistic
regression model (SPSS, 11.0) to estimate the risk of
MTCT between helminth infected and uninfected HIVinfected women and examined the potential interaction
of malaria. Odds ratios and their respective CI were
calculated for maternal malaria and helminth infection
with respect to MTCT.
Results
Relationship of malaria, lymphatic filariasis,
schistosomiasis and intestinal helminthes to the
presence of HIV infection
To determine whether HIV infected women have more
co-infections with helminthes and malaria, we compared
HIV-positive with HIV-negative women matched
according to date of recruitment, parity, and location.
Out of 936 women screened for anti-HIV antibodies, 83
were identified as positive (8.9%). Each HIV-positive
individual was matched with two controls with respect to
age ( 2 years), parity, residence, level of education
(highest grade completed) and date of enrollment ( 1
month, n ¼ 166, Fig. 1, Table 1). HIV-positive women
were twofold more likely to be infected with malaria.
HIV-positive women were also more likely to be infected
with LF. There was no association between HIV positivity
and infection with schistosomiasis or intestinal helminth
infections, which were predominantly hookworm (91%).
Infection with LF and malaria were independent risk
factors for the presence of HIV infection. The adjusted
OR of HIV infection in pregnant women with malaria
was 2.9 (95% CI, 1.3–6.5; P ¼ 0.007) and for lymphatic
filariasis it was 3.5 (95% CI, 1.9–7.2; P ¼ 0.003).
Addition of co-infection with schistosomiasis or intestinal
helminthes into the model did not alter the observed
association between presence of HIV and co-infection
with LF or malaria in pregnant women.
The effect of parasite infection on vertical
HIV transmission
To determine whether the presence of helminth
infections or malaria affected the probability that a
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AIDS 2005, Vol 19 No 16
Table 1. Relationship of parasitic infections with HIV seropositivity among women attending antenatal clinics in Kenya.
Women HIV status
HIV positive (n ¼ 83)
Presence of maternal malariab
Peripheral blood (blood smear)
Peripheral blood (PCR)
Placental intervillous blood (PCR)
Lymphatic filariasisc
Schistosomiasis
Intestinal helminthsd
34
13/82
23/82
24/60
29/80
5/63
24/57
Pa
HIV negative (n ¼ 166)
(41%)
(16%)
(28%)
(40%)
(36%)
(8%)
(42%)
34
11/164
32/161
15/82
22/155
12/122
43/89
(21%)
(7%)
(20%)
(18%)
(14%)
(10%)
(48%)
P < 0.001
P < 0.025
P ¼ 0.2
P < 0.02
P < 0.001
P > 0.2
P > 0.3
a
Chi-square test; significance taken as P < 0.05.
Presence of malaria determined by blood smear and/or PCR in peripheral circulation and/or placental intervillous blood.
c
Presence of lymphatic filariasis assessed by detection of circulating antigen in plasma using the monoclonal antibody Og43C.
d
91% of intestinal helminthes were hookworm; many of these patients were co-infected with Trichuris trichuris.
b
HIV-positive woman would infect their offspring with
HIV perinatally, plasma samples were collected from
infants at 12, 18 and/or 24 months of age and examined
for the presence of HIV antibodies. Of the 83 HIVpositive women initially identified, plasma samples were
available from offspring for 43 women (52%). A total of
44 infant samples (one woman had twins) were examined:
13 HIV positive and the remaining 31 HIV negative
(MTCT rate of 29.5%, Table 2). HIV-positive women
who transmitted HIV infection to their infants were more
likely to be co-infected with malaria; however this
difference was not significant (Table 2). Since primigravid
or secundagravid women are more likely to be infected
with malaria and have placental malaria during gestation
[20], this serves as a surrogate for increased risk for malaria
throughout pregnancy. We found no association with
gravidity and whether an infant became HIV infected or
not. In contrast, HIV-positive women co-infected with
one or more helminthes were more likely to have
children infected with HIVat 1 year of age (Table 2). The
presence of maternal LF infection was most strongly
associated with MTCT, although similar trends were
observed for the other helminth infections. Twenty-three
HIV-infected pregnant women were also infected with
one or more helminth infections and 11 transmitted HIV
to their offspring (48% MTCT transmission). Two of 20
HIV infected women who were not co-infected with
helminth infections transmitted HIV to their offspring
(10% MTCT, P < 0.01 compared to infected women).
Controlling for a potential confounding effect of
concurrent malaria, HIV-positive women with helminth
infections were sevenfold more likely to transmit HIV to
their offspring (Table 2).
Relationship of cord blood cytokine production
to helminth antigens and risk for MTCT of HIV
To investigate whether activation of fetal lymphocytes
in utero by helminth antigens contributes to the observed
association of helminth infection with MTCTof HIV, we
examined helminth antigen-induced cytokine responses
in available cord blood lymphocytes from 34 of 44
newborns (77%) born to HIV-positive mothers. Seventeen of 34 (50%) samples had IL-5, IL-13, IFN-g and/or
IL-2 production in culture supernatants in response to
filarial (n ¼ 13), schistosome (n ¼ 10), or both (n ¼ 6)
antigens based on previously reported criteria [17]. Cord
Table 2. The relationship of maternal malaria or helminth infections among HIV-positive women with vertical transmission of HIV to their
newborns.
HIV-positive infants (n ¼ 13)
Vertical transmission of HIV
Malaria infection in mothers
Overall malaria infection in motherb
Peripheral blood (blood smear)
Peripheral blood (PCR)
Placental intervillous blood (PCR)
Maternal gravid status
1
2
3þ
Helminths
Any helminth infectionc
Lymphatic filariasis
Hookworm
Schistosomiasis
a
HIV-negative infants (n ¼ 31)
Pa
Adjusted OR (95% CI)
13 (42%)
6 (19%)
6 (29%)
12/26 (46%)
P ¼ 0.09
P ¼ 0.56
P ¼ 0.32
P ¼ 0.29
P ¼ 0.43
1.2 (0.3–5.5)
P ¼ 0.008
P ¼ 0.04
P ¼ 0.41
P ¼ 0.51
7.3d (2.4–33.7)
13/44 (29.5%)
9
2
4
8
(69%)
(15%)
(44%)
(61%)
2 (15%)
4 (31%)
7 (54%)
11 (85%)
6 (46%)
5/12 (42%)
2/12 (17%)
3 (12%)
5 (20%)
16 (64%)
12/30 (40%)
4/27 (15%)
9/28 (32%)
2/22 (9%)
One-tailed Fisher’s exact test.
Presence of malaria determined by blood smear and/or RTQ–PCR in maternal peripheral or placenta intervillous blood.
Lymphatic filariasis, schistosomiasis and/or hookworm.
d
P ¼ 0.02. OR, Odds ratio; CI, confidence interval.
b
c
Helminths and vertical HIV transmission Gallagher et al.
susceptibility to HIV if exposed. This explanation is
supported by the observation that HIV infected women
co-infected with LF or other helminths is associated with
sevenfold increased odds for transmitting HIV to their
offspring.
Fig. 2. The relationship of helminth antigen-driven cytokine
production by cord blood lymphocytes with MTCT of HIV.
The presence of HIV was determined by ELISA from plasma
collected from the same infant at 12 months of age. Cytokine
production was measured by ELISA in culture supernatants
from 72-h cord blood lymphocyte cultures (2 106/ml) in
responses to soluble filarial or schistosome adult worm and
larval antigens. Bars indicate geometric mean cytokine
levels SEM. For IL-5 or IL-13, difference is significant at
P < 0.001 by Mann–Whitney U test whereas there was no
significant difference for helminth antigen-driven IFN-g
production.
blood lymphocytes from 9 of 12 (75%) HIV-positive
newborns produced IL-5 and/or IL-13, in response to
helminth antigens, compared with 4 of 22 (18%) newborns who did not become HIV infected (P < 0.01). The
overall amount of helminth antigen-driven IL-5/IL-13
by infants who became infected with HIV was
significantly higher compared to HIV-negative infants
(Fig. 2, P < 0.001). Although infants that became
infected with HIV tended to produce more helminth
Ag-driven IFN-g and/or IL-2 (7 of 12, 58%) compared
to HIV-negative infants (7 of 22, 32%, Fig. 1 right panel)
these differences were not significant.
Discussion
These results show that HIV infected women were more
likely to be co-infected with LF. This association was not
observed with other helminth infections. It is unlikely
that LF-infected women display behaviors that put them
at increased risk of HIV compared to LF-negative
women, e.g., blood transfusions (none of the study
subjects had records of blood transfusions) or increased
sexual activity, since women with HIV were matched for
age, parity, residence, level of education, and date of
recruitment to women without HIV. It is also unlikely
that HIV infection predisposes to LF because most
women acquire LF during childhood and early adolescence before becoming sexually active [21]. A more likely
explanation is that LF infection increases a women’s
Potential mechanisms by which helminth co-infections
may affect cellular susceptibility to HIV infection in
women and newborns include immune activation of
lymphocytes and monocytes [22], expansion of Th2-type
cells [13], differential expression of chemokine receptors
that also serve as co-receptors for viral entry into cells
[23,24] or impaired host immunity to HIV because of
immune modulation generated by helminth infection
[25]. Lymphatic filariasis is a persistent intrasvascular
infection with chronic activation of lymphocytes and
strong skewing toward Th2-type phenotype [11].
Helminth infections have been shown to increase the
density of CCR5 and CXCR4, chemokine co-receptors
for viral entry on surfaces of CD4 T cells and monocytes
[16,26]. It has been shown that peripheral blood
lymphocytes from an LF-infected subjects show increased
susceptibility to HIV infection in vitro compared to the
lymphocytes from the same individual following antifilarial treatment [27]. Why LF differs from other helminth infections in their association with HIV infection
in pregnant women is unclear. Intestinal helminthes may
produce less strong immune activation and Th2 skewing
because of their localization in gut mucosa compared to
tissue dwelling or intravascular parasites such as LF or
schistosomiasis. The sample sizes were also smaller for
evaluation of schistosomiasis and intestinal helminthes
and thus may have insufficient power to observe an
association. Other studies, however, have also failed to
associate schistosomiasis infection with increased probability of HIV infection, higher viral loads, or accelerated
progression of HIV to AIDS [28,29].
One circumstance where helminth infections may affect
susceptibility to HIV infection is by vertical transmission
of HIV in utero, peri-partum or post-partum as has been
suggested in the current study. We postulate some of the
same mechanisms that may enhance adults’ susceptibility
to HIV may also operate in the fetus, newborns and
infants. The fetus is exposed to soluble parasite antigens
resulting in immune activation in utero and strong skewing
to a Th2-type cytokine responses [15,17]. We found that
newborns whose cord blood cells generated a predominantly Th2-type cytokine response to helminth antigens
were at the greatest risk for infection. Consistent with
these observations are previous reports showing that activated lymphocytes with a Th2-type phenotype in other
species or in vitro (e.g. schistosome infections in rhesus
macques) are more susceptible to HIV infection [13,15,
30–33]. Peripheral blood lymphocytes from individuals
with LF and/or schistosomiasis produce more IL-10
[12,34,35], especially in the fetus [36]. Interleukin-10, in
turn, stimulates increased CCR5 expression by fetal
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monocytes [37,38], which is typically low in cord blood
[39], and may thus increase the fetus or newborn’s
susceptibility to HIV infection.
populations can be reduced in areas where integrated
control programs are implemented.
Co-infections with malaria were more common among
HIV-positive pregnant women as compared to HIVnegative women, and this is similar to findings noted in
previous reports [5,40]. Presumably this results from
impaired cellular and humoral immunity, particularly in
the placenta [40]. There was trend that malaria coinfection increased vertical transmission of HIV to their
newborns, although this difference was not significant
which might be due to the small sample size. This
contrasts with some studies that show malaria as a risk
factor for MTCTof HIV [7,9], although other studies do
not support this finding [8].
Acknowledgements
There are several weaknesses in the study. We did not
report HIV viral load, an important variable in MTCT
transmission. This was a retrospective study using stored
frozen samples where partial RNA degradation may have
resulted in unreliable viral load measurements. It is
unlikely that co-infection with helminths increased
MTCT via a mechanism of increased viral load because
helminth co-infections appear not to affect HIV viral
loads [28,29,41]. Also co-infections with malaria, which
have been shown to affect viral loads [2], was not
significantly associated with increased MTCT of HIV in
the current study. Additional variables that could also
increase the risk for vertical HIV transmission at delivery
(such as episiotomy, perineal tears, prolonged rupture of
membranes and presence of other sexually transmitted
diseases) were not consistently recorded for this retrospective cohort. However these variables are unlikely to
bias the results for several reasons. First, only women with
term pregnancies and uncomplicated deliveries were
selected for the study, i.e., women with prolonged
rupture of membranes were excluded. Second, we
recorded these variables in a more recent cohort and
found no association between helminth or malaria
infections in pregnant women and the presence of
perineal tears, episiotomies or sexually transmitted
diseases. Sexually transmitted diseases occurred in
< 7% of study subjects. Finally we determined HIV
infection in infants by serology and not by detection of
viral nucleic acid. It is unlikely that anti-HIV antibodies
from mothers persist in the infant at 12–18 months of age
and most infants were evaluated twice. We were also
unable to distinguish whether HIV transmission occurred
in utero, peri-partum, or post-partum (breast-feeding).
In summary this study indicates that in pregnant women,
co-infection with helminths increases the chance that
offspring will be infected with HIV. Recently, mass drug
treatment for LF and intestinal helminth, and impending
mass control programs for schistosomiasis has been started
on the Kenyan Coast. This may provide an opportunity to
assess whether the rate of HIV spread in high risk
We appreciate the technical help of Adams Omollo and
Kephar Otieno and Elton K. Mzungu, and Grace Watutu
for data entry. We are grateful for the maternity nurses and
especially the Kenyan women who attended the antenatal
clinics and agreed to participate in this study.
Sponsorhip: Supported, in part, by United States
Public Health Service grants AI36219 and AI33061
by National Institute of Allergy and Infectious Disease
and Department of Veteran’s Affairs Research
Service.
Note: MG and IM contributed equally to the study.
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