Infection

DOI 10.1007/s15010-017-1031-2

REVIEW

Human infectious diseases and risk of preeclampsia: an updated

review of the literature
Malihe Nourollahpour Shiadeh1,2 · Zahra Behboodi Moghadam2 · Ishag Adam3 ·
Vafa Saber5 · Maryam Bagheri2 · Ali Rostami4,5,6 

Received: 24 April 2017 / Accepted: 25 May 2017

© Springer-Verlag Berlin Heidelberg 2017

Abstract  virus, and some parasites especially Plasmodium spp. and

Background  Preeclampsia (PE) is one of the major causes Toxoplasma gondii can be effective in development of PE.
of maternal and perinatal morbidity and mortality, espe- Inflammation responses against infections has major role in
cially in low- and middle-income countries. In recent years, the inducement of PE. The shift of immunological cytokine
a growing body of literatures suggests that infections by profile of Th2 toward Th1 and high levels of pro-inflamma-
bacteria, viruses, and parasites and their related inflamma- tory cytokines (TNF-ɑ, IL-12, IFN-γ, etc.), increase of oxi-
tions play an important role in the pathogenesis of PE. dative stress, increase of anti-angiogenic proteins, increase
Methods We searched PubMed, Google scholar, and of vascular endothelial growth factor receptor 1 (sVEGFR1),
Cochrane databases using the following search words: and complement C5a are the main potential mechanisms
“infection and preeclampsia,” “bacterial infection and related to infections and enhanced development of PE.
preeclampsia,” “viral infection and preeclampsia” and Conclusion Thus, early diagnosis and treatment of bac-
“parasitic infection and preeclampsia.” terial, viral, and parasitic infections could be an effective
Results The literature review revealed that many bacteria strategy to reduce the incidence of PE.
including Helicobacter pylori, Chlamydia pneumonia, and
those are involved in periodontal disease or urinary tract Keywords  Preeclampsia · Infections · Inflammation ·
infections (UTIs) and some viral agents such as Cytomegalo- Cytokine
virus, herpes simplex virus type-2, human immunodeficiency

* Ali Rostami
Introduction
[email protected]; [email protected]
Preeclampsia (PE), a multisystem vascular syndrome, is
1
Department of Reproductive Health, School of Nursing characterized by the gestational onset of hypertension and
and Midwifery, Tehran University of Medical Sciences,
proteinuria and generally occurred after 20 weeks’ of gesta-
Tehran, Iran
2
tion [1]. PE is one of the major causes of maternal and peri-
Department of Midwifery and Reproductive Health, Nursing
natal morbidity and mortality, especially in low- and mid-
and Midwifery School, Mazandaran University of Medical
Sciences, Sari, Iran dle-income countries [2, 3]. It affects approximately 5–8%
3 of all pregnancies around the world [4], and is responsi-
Faculty of Medicine, University of Khartoum, Khartoum,
Sudan ble for almost 350,000 maternal deaths [3, 5], six million
4 perinatal deaths [6], eight million preterm births [7], and
Infectious Diseases and Tropical Medicine Research Center,
Babol University of Medical Sciences, Babol, Iran approximately 20 million low-birth-weight newborns in
5 developing countries [8]. Moreover, it is demonstrated that
Departments of Parasitology and Mycology, School
of Medicine, Shahid Beheshti University of Medical PE is associated with higher risks of chronic noncommuni-
Sciences, Tehran, Iran cable diseases in later life of affected women [9]. Despite
6
Student Research committee, Shahid Beheshti University several researches to identification of the major risk fac-
of Medical Sciences, Tehran, Iran tors and potential mechanisms and much advance in our

13
 M. N. Shiadeh et al.

knowledge, the PE’s etiology remains elusive. However, it with either a bacterial or viral infection had twofold higher
is hypothesized that PE’s etiology is multifactorial, involv- risk to develop PE compared with women without infection
ing both maternal and placental contributions [10]. (OR 2.1; 95% CI 1.6–2.7).
The maternal infections, especially those that are trans- Several retrospective and prospective studies demon-
missible in utero, are responsible for several incidences of strated potential risk of UTIs by bacteria to induce PE [32–
morbidity and mortality during pregnancy [11]. TORCH 35]. Several pathogenic bacteria are responsible for UTIs
complex, comprise toxoplasmosis, other (syphilis, vari- including Escherichia coli, responsible for 70–80% of all
cella-zoster, parvovirus B19, Hepatitis B), Rubella, Cyto- UTIs in pregnancy; Gram-negative bacteria include Kleb-
megalovirus (CMV), and Herpes infections, hepatitis infec- siella, Enterobacter, Proteus, Pseudomonas, Citrobacter,
tions, human immunodeficiency virus (HIV) are the most and Gram-positive bacteria, for example, group B Strepto-
common transplacentally acquired infections by the fetus cocci [36]. Moreover, other bacteria, including Ureaplasma
[11, 12]. These infections are responsible for several con- parvum, Gardnerella vaginalis, Mycoplasma hominis,
genital anomalies like still birth, abortion, intrauterine fetal lactobacilli, and Chlamydia trachomatis, have also been
deaths, congenital malformations, and other congenital reported to induce UTIs [33, 37–39]. It is demonstrated
failures [11, 13–15]. Zika virus infection is considered as that the early diagnosis and treatment of UTI decreased the
the newest TORCH complex that is associated with several incidence of PE by 64% [40]. Hsu et al. in a retrospective
complications such as intrauterine fetal infection, micro- study on 13,852 pregnant women reported that risk of PE
cephaly, neurological abnormalities, and Guillain–Barré was significantly more (OR 4.2; 95% CI 1.1–5.1) among
syndrome [16–18]. Moreover, coinfection with the above women who developed UTIs during pregnancy [32].
mentioned microorganisms can lead to more adverse effect Conde-Agudelo et al. [22] in a comprehensive meta-anal-
on mother and fetus and also can lead to difficulties in ysis study have shown that that risk of PE was increased in
actual diagnosis [19, 20]. pregnant women with UTIs (OR 1.57; 95% CI 1.45–1.70).
In recent years, a growing body of literatures suggests Periodontal disease (PD) is another most prevalent
that infections by bacteria, viruses, and parasites and their human infection disease that has been reported as potential
related inflammations play an important role in the patho- risk factor for the development of PE. Several genera of
genesis of PE [21, 22]. Several maternal infectious agents bacteria include Treponema, Bacteroides, Porphyromonas,
including HIV, malaria, different bacteria, and periodontal Prevotella, Capnocytophaga, Peptostreptococcus, Fuso-
disease or urinary tract infections (UTIs) have been sug- bacterium, Actinobacillus, Tannerella, and Eikenella, and
gested to increase the risk of PE [21, 22]. This narrative their related species are involved in PD [41]. In a case–
review will discuss the role the infectious agents in develop- control study, Contreras et al. have found that the presence
ment of PE and possible mechanisms related to these infec- of microorganisms related in PDs such as Porphyromonas
tions that are involved in PE. For this purpose, we searched gingivalis (OR 1.8; 95% CI 1.1–2.8), Tannerella forsythia
PubMed, Google scholar, and Cochrane databases using (OR 1.8; 95% CI 1.1–3.0), and Eikenella corrodens (OR
the following search words: “infection and preeclampsia,” 1.8; 95% CI 1.1–2.8) were significantly associated with
“bacterial infection and preeclampsia,” “viral infection and the development of PE in pregnant women [42]. Conde-
preeclampsia,” and “parasitic infection and preeclampsia.” Agudelo et al. in their meta-analysis reported significant
Publications in English language were considered, but we relationship between the presence of PD and the induction
did not impose any study design or geographic limitations. of PE (OR 1.76; 95% CI 1.43–2.18) [22]. Similar finding
Review was conducted on more than 38 potentially relevant (OR 2.79; 95% CI 2.01–3.01) was achieved in a recent
articles published between 2009 and 2017. meta-analysis study by Wei et al. [43]. Two comprehen-
sive studies by Rustveld et al. and Conde-Agudelo et al.
have been published in 2008; we summarized recently
Bacterial infection conducted studies (2009–2016) regarding the association
between UTIs and PD [2, 34, 35, 44–51] with development
In the last three decades, several epidemiological and of PE in Table 1.
casual studies have evaluated the possible relationship Chlamydia pneumonia, Ureaplasma urealyticum, and
between maternal bacterial and viral infections and PE. Helicobacter pylori are other bacterial organisms that were
Many of these studies indicated a positive association reported as potential risk factors for the development of PE
between bacterial and viral infections and PE [23–28]. [52, 53]. Heine et al. using a case–control study demon-
Moreover, intrauterine infections and their resulting inflam- strated that women with elevated titers of IgG to C. pneu-
matory responses are responsible for early preterm births moniae have a threefold increased risk of PE (OR 3.1, 95%
and labor in pregnant women [29–31]. Rustveld et al. [21] CI 1.2–7.9) compared with healthy controls [23]. Although
in a meta-analysis study have demonstrated that women in other studies, no significant correlation was observed

13
 Table 1  Studies regarding the associations between increased risk of preeclampsia and urinary tract infections (UTIs) and periodontal disease (PD)
First author/year Country Study design Sample size Odds ratio (95% CI) Main findings References

Urinary tract infections

 Mazor-Dray (2009) Israel Retrospective population-based 199,093 1.8 (1.4–2.2) UTI was associated with increased risk of mild- [44]
study to-moderate PE (OR 1.3; 95% CI 1.1–1.5)
and chronic hypertension (OR 1.5; 95% CI
1.2–1.8)
 Shamsi (2010) Pakistan Case–control Ca: 131 2.0 (1.21–3.49) No significant association was observed [45]
Co: 262 between UTI and PE in adjusted OR
 Minassian (2013) UK Nested case–control Ca: 1533 1.22 (1.03–1.4) UTI was associated with increased risk of PE [34]
Co: 14,236 Moreover Antibiotic prescriptions (OR 1.28;
95% CI 1.14–1.44) was associated with
increased risk of PE
 Bilano (2014) WHO Global Survey Cross-sectional 276,388 1.13 (1–1.2) UTI was associated with increased risk of PE [2]
 Easter (2016) USA Cohort 2607 3.2 (2–5.1) UTI was associated with increased risk of PE [35]
In longitudinal analysis of angiogenic profiles,
the authors observed a significant elevation of
PlGF concentrations during pregnancy among
women who were diagnosed with UTI
Periodontal disease (PD)
 Lohsoonthorn (2009) Thailand Case–control Ca: 150 Severe PE: 0.92 (0.26–3.28) PD was associated with increased risk of PE [46]
Co: 150 Moreover, PD was associated with mild PE:
(OR 0.83; 95% CI 0.43–1.60) and moderate
Human infectious diseases and risk of preeclampsia: an updated review of the literature

PE: (OR 0.77; 95% CI 0.35–1.69)

 Shetty (2010) India Cohort 130 5.78 (2.41–13.89) PD was associated with increased risk of PE [47]
Moreover, PD was associated with PE after
delivery (OR 20.15; 95% CI 4.55–89.29).
 Politano (2011) Brazil Case–control Ca: 58 3.73 (1.32–10.58) PD was associated with increased risk of PE [48]
Co: 58 Increased TNFa mRNA expression was
observed in preeclamptic women
 Moura da Silva Brazil Case–control Ca: 248 8.60 (3.92–18.88) PD was associated with increased risk of PE [49]
(2012) Co: 290
 Taghzouti (2012) Canada Case–control Ca: 92 1.13 (0.59–2.17) PD was associated with increased risk of PE [50]
Co: 245 The percentage of periodontal disease was
18.5% in preeclamptic women and 19.2% in
normotensive women
 Kumar (2013) India Cohort 340 5.16 (1.94–13.71) PD was associated with increased risk of PE [51]

Ca cases, Co controls, PE preeclampsia, OR odds ratio, CI confidence intervals

13
 M. N. Shiadeh et al.

between C. pneumoniae and PE [54–56], Dadelszen et al. of birth control [70]. In another study, Trogstad et al.
in a prospective cohort study reported that women with reported an increased risk of PE among women who were
early-onset PE had significantly higher levels of IgG to seronegative for, and therefore at the risk of acquiring
Chlamydophila pneumonia compared with normotensive EBV (OR 3.5; 95% CI 1.1–10.6), CMV (OR 1.6; 95%
pregnant women [24]. CI 0.8–3.2), and HSV-2 (OR 1.7; 95% CI 0.7–4.2) infec-
The significant relationship between H. pylori infection tions [71]. Moreover, there are several studies regarding
and PE was described for the first time by Ponzetto et al. the effect of HIV on hypertensive disorders of pregnancy
[57]. They reported that seropositive women for H. pylori [72–76]. Based on data from a comprehensive meta-anal-
had almost threefold higher risk to develop PE [57]. Subse- ysis study [77], however, no evidence was found regard-
quent studies reported also a significantly higher H. pylori ing the relationship between HIV infection and PE (OR
seropositivity rate in preeclamptic women compared with 1.04; 95% CI 0.60–1.79), but significant associations
controls [25, 26, 58–61, 65, 66]. Moreover, recent studies were observed regarding HIV infection with hypertension
described that infection with Cytotoxin-associated antigen (OR 1.46; 95% CI 1.03–2.05) and eclampsia (OR 2.56;
A (CagA)- and Vacuolating cytotoxin A (VacA)-positive 95% CI 0.15–44.11) among pregnant women. Recent
H. pylori-strains is significantly related with PE and, espe- studies (2009–2017) regarding the associations between
cially with “placental PE” [58]. This could be explained viral infections and PE [28, 39, 64, 67, 78–84] are sum-
by the fact that CagA- and VacA-positive H. pylori strains marized in Table 3.
are generally associated to higher levels of inflammatory
mediators compared with negative strains [62]. Recently
conducted studies (2009-2017) regarding the associations Mechanisms for bacterial and viral infections
between C. pneumonia, C. trachomatis, and H. pylori
infections and PE [25, 26, 39, 52, 58–61, 63–66] are sum- Inflammation responses against infections play important
marized in Table 2. roles in the initiation and enhancement of acute uteropla-
cental atherosis or destruction of trophoblast cells, major
risks known to induce PE [68]. Moreover, clinical and epi-
Viral infection demiologic data indicated that acute atherosis is directly
associated with PE [70, 85]. The increase of monocytes
Among the viral pathogens, Cytomegalovirus (CMV), circulation resulting from infections and establishment of
Adeno-Associated Virus-2 (AAV-2), herpes simplex virus macrophage foam cells in the arterial intima could be the
type-2 (HSV2), Epstein-Barr virus (EBV), and human key factors to induce early lesion in atherosclerosis [70,
immunodeficiency virus (HIV) have been more stud- 86–88]. Moreover, several studies have demonstrated that
ied and found to have more likelihood to be effective in inflammatory responses are excessive in preeclamptic preg-
PE. Dadelszen et al. through a nested case–control study nancies compared with normal pregnancies [89–93]. Bacte-
indicated that women with early-onset PE had higher rial and viral infections during pregnancy could stimulate
anti-CMV levels than women with late-onset PE and nor- release of high level of pro-inflammatory cytokines (TNF-ɑ,
motensive women (P < 0.05) [24]. Similar results were IL-12, IFN-γ, etc.) and also increase of oxidative stress and
obtained by Xie et al. in two subsequent studies [28, 67]. endothelial cell dysfunction, all of which could lead to initi-
Moreover, their results showed that women with PE have ation of hypertension disorders including PE [70]. Increased
upregulated TLR-2/-4 mRNA expression, increased levels levels of oxidative stress induced by Chronic or acute infec-
of serum IL-6 and TNF-α, and reduced IL-10 compared tions could impair the production and bioactivity of nitric
with matched normal and nonpregnancy controls [67]. oxide (NO) that can lead to endothelial dysfunction, a cru-
Arechavaleta-Velasco et al. [68] in a molecular study cial event to induce the PE. In agreement with this state-
reported that rates of AAV-2 placental infection were sig- ment, PE-like manifestations were observed in experimental
nificantly higher among women with severe PE compared models by blocking endothelial production of NO [94–97].
with women having normotensive placentas (P = 0.002). In addition to the above mentioned mechanisms, some
In a subsequent study, same team reported that the first- antigenic factors of microorganisms like Cytotoxin-asso-
trimester maternal IgM seropositivity for AAV-2 was 5.6 ciated antigen A (CagA) may be directly related PE [98].
times more prevalent among PE (P  = 0.0004) than in Recent studies showed that anti-CagA antibodies are able
healthy controls [69]. Rustveld et al. have found that sero- to cross-react with antigens (β-actin proteins) of endothelial
conversion for HSV 1/2 or CMV was associated with a cells and cytotrophoblast cells of placenta that can lead to
fivefold increased risk for developing PE (OR 5.4; 95% negative effects on its invasiveness ability [99, 100]. More-
CI 1.0–29.0) after adjusting for education, income, smok- over, it is reported that anti-CagA antibodies are able to
ing, years of cohabitation, medical insurance, and type inhibit the activation of mediator factors that are important

13
Human infectious diseases and risk of preeclampsia: an updated review of the literature

Table 2  Studies regarding the associations between increased risk of preeclampsia and bacteria
Bacteria/first author/year Country Study design Sample size Odds ratio (95% CI) Main findings References

Chlamydia pneumoniae
 Gomez (2009) Canada Case–control Ca: 48 4.1 C. pneumoniae DNA was [63]
Co: 30 identified in trophoblast cells
in 18/78 (23%) placentas.
C. pneumoniae DNA was
detected significantly more
frequently in trophoblast cells
from cases (15/48; 31%) than
controls (3/30; 10%)
 Xie (2010) Canada Case–control Ca: 50 ND gDNA copy numbers of C. [52]
Co: 57 pneumoniae were increased
in women with PE compared
with the normal pregnant
(P < 0.05) and nonpregnant
controls (P < 0.05)
 Mosbah (2015) Egypt Case–control Ca: 90 ND The prevalence of C. pneumonia [59]
Co: 90 was significantly higher in
controls (47.8%) than in cases
(27.8%) (P = 0.006). No asso-
ciation was observed between
C. pneumoniae and PE
Chlamydia trachomatis
 Haggerty (2013) USA Nested case– Ca: 509 1.6 Moreover, C. trachomatis [64]
control Co: 336 (0.7–3.6) infection was associated with
severe PE (OR 1.8; 95% CI
0.6–5.3), and PE resulting in
preterm birth (OR 1.7; 95% CI
0.6–4.9)
 Haggerty (2013) USA Nested case– Ca: 206 7.2 (1.3–39.7) Although C. trachomatis infec- [39]
control Co: 423 tion was uncommon (n = 9,
1.4%), in this general pregnant
population, infected women
were more likely to develop
PE
Helicobacter pylori
 Aksoy (2009) Turkey Case–control Ca: 53 2.86 (1.05–7.82) H. pylori seropositivity was [26]
Co: 30 43/53 (81%) in the PE group,
this was 18/30 (60%) in nor-
mal controls (P = 0.036)
 ÜstÜn (2010) Turkey Case–control Ca: 62 ND H. pylori seropositivity was [25]
Co: 49 14/40 (35%) in the PE group,
this was 4/40 (12.5%) in
normal controls. The results
were statistically significant
(P = 0.03)
 Cardaropoli (2011) Italy Case–control Ca: 90 9.22 (2.83–30.04) A significantly higher percent- [58]
Co: 90 age of H. pylori seropositive
women were found among PE
cases (85.7%) compared with
controls (42.9%, P < 0.001)
Antibodies against CagA
antigen was prevalent only in
PE-pregnant women (81.6%)
relative to controls (22.4%)
(P < 0.001; OR 17.66; 95% CI
5.25–59.49)

13
 M. N. Shiadeh et al.

Table 2  continued
Bacteria/first author/year Country Study design Sample size Odds ratio (95% CI) Main findings References
 Mosbah (2015) Egypt Case–control Ca: 90 ND Seroprevalence of H. pylori [59]
Co: 90 among cases suffering from
PE 49/90 (54.4%) was
significantly more than that
in controls 19/90 (21.1%)
(P = 0.0001)
 Rădulescu (2016) Romany Case–control Ca: 63 ND No difference in H. pylori IgG [60]
Co: 61 seropositivity was demon-
strated between the case
(12.28) and control (11.44)
groups. No association was
observed between H. pylori
and PE (P = 0.471)
 Di Simone (2017) Italy Case–control Ca: 93 2.72 (1.51–4.92) Preeclamptic women showed [61]
Co: 87 higher seroprevalence of H.
pylori infection (57.0%) com-
pared with controls (33.3%)
(P < 0.001). The seropositiv-
ity for CagA- positive strains
of H. pylori was 45.2% in
preeclamptic women vs 13.7%
in controls (P < 0.001)
 Hollander (2017) Netherland Cohort 6348 1.51 (1.03–2.25) H. pylori positivity was found [65]
in 2915 (46%) women, of
whom 1023 (35%) also were
CagA- positive. H. pylori was
associated with increased risk
of PE
 Elkhouly (2016) Egypt Case–control Ca: 50 ND A significantly higher percent- [66]
Co: 50 age of H. pylori stool antigen
(HPSA)-positive women were
found among PE cases com-
plicated by intrauterine growth
restriction (76%) compared
with healthy pregnancies
(32%) (P < 0.0001)

Ca cases, Co controls, PE preeclampsia, OR odds ratio, CI confidence intervals

during trophoblast proliferation, such as ERK and Nuclear invasion to the placenta and inhibit the implantation and
Factor-kB [99]. cell division [101]. Toxoplasmosis is one of the most prev-
alent infection disease with worldwide distribution [102].
It is the cause of many adverse complications in immu-
Parasitic infections nocompromised patients and pregnant women [103, 104].
Todros et al. [105] in a cohort study indicated that preg-
Among the parasite diseases, infections with protozoa nant women treated with spiramycin have shown lower
such as Plasmodium spp., Toxoplasma gondii, Tricho- pregnancy-induced hypertension (OR 0.092; 95% CI
monas vaginalis, and Trypanosoma cruzi could be poten- 0.021–0.399) compared with women who did not take any
tial risk factors for PE, mainly regarding vertical transmis- antibiotic during pregnancy. Although in a recently con-
sion, placental infection, and the host immune response to ducted study in Mexico, it was reported that chronic toxo-
them. Infection with these protozoa during the pregnancy plasmosis is not associated with hypertensive disorders in
could result to low birth weight, still birth, spontane- pregnant women [106].
ous abortion, growth restriction, intrauterine fetal death, Although, there is any study indicating the role of T.
and fetal abnormalities [101]. There are no study explor- vaginalis in PE, but secretion of galectin family (galec-
ing role of the trypanosomiasis in development of PE, tin-1 and galectin-3) by cervical and vaginal epithe-
although some evidences are available regarding parasite lial cells upon T. vaginalis infection could be possible

13
 Table 3  Studies regarding the associations between the increased risk of preeclampsia and viral infections
Virus/first author/year Country Study design Sample size Odds ratio (95% CI) Main findings Ref

Cytomegalovirus (CMV)
 Xie (2010) USA Case–control Ca: 78 ND CMV seropositivity was associated with increased [28]
Co: 109 risk of PE
Women with PE had increased CMV IgG sero-
positivity compared with nIUGR (P < 0.01) and
normal pregnancy controls (P < 0.01); (RR 2.0;
95% CI 1.6–2.5)
 Strand (2012) Norway Nested case–control Ca: 1500 0.89 (0.74–1.05)  CMV seropositivity was not associated with PE [78]
Co: 1000 (P = 0.17)
 Xie (2014) USA Case–control Ca: 30 ND  CMV seropositivity was associated with [67]
10 EOPE-HELLPs (<34 weeks) and 20 LOPE increased risk of PE
(≥34 weeks)  EOPE-HELLPs had significantly increased
Co: 80 CMV IgG seropositivity, upregulated TLR-2/-4
mRNA expression, increased serum IL-6 and
TNF-a, and reduced IL-10 compared
 Haggerty (2013) USA Nested case–control Ca: 509 ND CMV seropositivity in cases and controls (1.7%) [64]
Co: 336 and (1.4%), respectively; (RR 0.9; 95% CI
0.2–3.2)
CMV seropositivity was not associated with PE
 Haggerty (2013) USA Nested case–control Ca: 206 ND CMV seropositivity in cases (2.2%) was lower [39]
Co: 423 than controls (3.3%); (RR 0.7; 95% CI 0.2–2.4)
CMV seropositivity was not associated with PE
Herpes simplex virus (HSV)
 Haggerty (2013) USA Nested case–control Ca: 509 ND HSV seropositivity in cases and controls was [64]
Human infectious diseases and risk of preeclampsia: an updated review of the literature

Co: 336 (2.4%) and (4%), respectively; (RR 0.5; 95% CI

0.2–1.2)
HSV seropositivity was not associated with PE
 Haggerty (2013) USA Nested case–control Ca: 206 ND HSV seropositivity in cases and controls was [39]
Co: 423 (1.1%) and (1%), respectively; (RR 0.5; 95% CI
0.2–1.2)
CMV seropositivity was not associated with PE
Human immunodeficiency virus (HIV)
 Haeri (2009) USA Retrospective cohort HIV positive: 151 ND PE occurred in HIV+ (6%) and in HIV− (12%) [79]
HIV negative: 302 HIV was not associated with PE
 Boyajian (2012) Canada Retrospective cohort HIV positive: 91 0.59 (0.11–3.08) HIV was not associated with PE [80]
HIV negative: 237
 Kalumba (2013) South Africa Case–control Ca: 492 0.62 (0.47–0.82) Among 492 cases of PE, 130 (26.4%) were HIV [81]
Co: 500 infected. In the control group, 183/500 (36.6%)
were HIV infected
HIV was not associated with PE

13
 M. N. Shiadeh et al.

mechanism to induce PE, as these galectins modulate

[82]

[83]

[84]
Ref the inflammatory responses [107]. Than et al. [108] have

1.26–3.28), and late-onset PE (OR 2.64; 95% CI

demonstrated that placental expression of galectin-1 was
were recorded in the HIV positive group than in

Moreover, significantly fewer cases of gestational

hypertension were recorded in the HIV positive

patients (3/126) and in 14 of 140 HIV-negative

group compared with the HIV negative group
significantly higher in patients with severe PE than in nor-
Significantly fewer cases of PE n = 35 (3.2%)

with severe feature of PE (OR 2.03; 95% CI

PE was diagnosed in 2.38% of HIV-positive

patients (10%), with a relative risk of 0.24

Moreover, HIV was significantly associated

mal controls, and these increases may represent a fetal

HIV was significantly associated with PE

the HIV negative group, n = 57 (4.9%)

response to an exaggerated systemic maternal inflam-

mation. Moreover, T. vaginalis lipophosphoglycan moti-

HIV was not associated with PE

(OR 0.53; 95% CI 0.30–0.94) vates species-specific inflammatory response and selec-
tive chemokine (IL-8 and macrophage inflammatory
protein-3ɑ) upregulation by human cervical and vaginal
epithelial cells [107, 109].
Malaria especially induced by P. falciparum has
Odds ratio (95% CI) Main findings

been the most-described parasitic mechanism to cause

1.82–3.85)
PE. Annually, 125 million pregnant women are at risk
of malarial infection in malarious areas, and the excess
risk of infection varies with gravidity [110, 111].
There are several epidemiological overlaps between
malaria infection and PE [112]. Both malaria and PE
0.65 (0.42–0.99)

2.68 (1.96–3.64)

have markedly higher risk in young and primigravidae

women and also similar seasonal distribution [112–
116]. In addition, some observational studies reported
ND

placental malaria as a potential risk factor for develop-

ing increased maternal hypertension and related disor-
ders, including PE [117–121]. Sartelet et al. [117] in
1996 reported that placental malaria was significantly
related with PE in Senegalian pregnant women (OR
3.0; 95% CI 1.3–6.9). Muehlenbachs et al. in Tanzania
indicated that malaria was associated with the increased
risk of hypertension in young (18–20 years old) first-
time mothers (OR 3.1; 95% CI 1.1–9.0) [115]. In a
HIV negative: 84,272
HIV negative: 1173
HIV positive: 1093

recent case–control study in Sudan, placental malaria

HIV positive: 453

(OR 2.3; 95% CI 1.0–5.2) was significantly associated

Ca cases, Co controls, PE preeclampsia, OR odds ratio, CI confidence intervals
Sample size

with PE [120].
Co: 140
Ca: 126

There are several evidences to multiple mechanisms

contributing to PE associated with malaria in pregnant
women including anemia, alternation in immunologi-
cal milieu, and increase of anti-angiogenic proteins that
Retrospective cohort

contribute to the pathogenesis of PE such as sFlt-1 and

South Africa Prospective cohort

endoglin [115, 116, 122, 123]. Moreover, Muehlenbachs

Case–control
Study design

et al. [115] reported that soluble vascular endothelial

growth factor receptor 1 (sVEGFR1), a preeclampsia bio-
study

marker, was significantly increased in first-time mothers

with both malaria infection and hypertension. Comple-
ment C5a, which plays an important role in induction of
Virus/first author/year Country

inflammation and initiation of acquired immune response,

Italy

Italy

is another factor that is elevated in malarial infection and

has significant role in the induction of PE [122, 124–126].
The shift of immunological cytokine profile of Th2, typi-
Table 3  continued

cal immune profile associated with pregnancy, to Th1

 Sansone (2016)
 Landi (2014)

includes TNF-ɑ, IL-12, and IFN-γ. immune profile more

 Hall (2014)

suited to parasite killing is another important possible

mechanism by malarial infection to induce preeclampsia
[15, 127] [110, 111].

13
Human infectious diseases and risk of preeclampsia: an updated review of the literature

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Funding  There are no funding sources for this paper.
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Compliance with ethical standards 
van den Kerkhof JHCT, Reusken CB, Hahné SJM. Zika virus
infection in 18 travellers returning from Surinam and the
Conflict of interest  The authors declare that there are no conflicts of Dominican Republic, The Netherlands, November 2015–
interest regarding the publication of this paper. March 2016. Infection. 2016;44:797–802.
17. Nourollahpour Shiadeh M, Rostami A, Danesh M, Sajedi AA.
Zika virus as new emerging global health threat for pregnancy
Ethical approval  This study received the approval from the Shahid
and child birth. J Matern Fetal Neonatal Med. 2017;30:562.
Beheshti University of Medical Science Ethical Committee.
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