Journal of Reproductive Immunology 89 (2011) 126–132

Contents lists available at ScienceDirect

Journal of Reproductive Immunology

journal homepage: www.elsevier.com/locate/jreprimm

Review

The etiology of preeclampsia: the role of the father

Gus Dekker a,b,∗ , Pierre Yves Robillard c , Claire Roberts a
a
Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, South Australia 5005, Australia
b
Lyell McEwin Hospital, Medical School North, University of Adelaide, Elizabeth Vale, South Australia, Australia
c
Department of Obstetrics, Neonatology and Gynaecology, Centre -Hospitalier- Regional Reunion, France

a r t i c l e i n f o a b s t r a c t

Article history: Preeclampsia is often considered as simply a maternal disease with variable degrees of fetal
Received 4 October 2010 involvement. More and more the unique immunogenetic maternal–paternal relationship
Received in revised form
is appreciated, and also the specific ‘genetic conflict’ that is characteristic of haemochorial
29 November 2010
placentation. From that perspective, pre-eclampsia can be seen as a disease of an individual
Accepted 20 December 2010
couple with primarily maternal and fetal manifestations. The maternal and fetal genomes
perform different roles during development. Heritable paternal, rather than maternal,
imprinting of the genome is necessary for normal trophoblast development. Large pop-
Keywords:
Pre-eclampsia ulation studies have estimated that 35% of the variance in susceptibility to preeclampsia
Paternal risk factors is attributable to maternal genetic effects; 20% to fetal genetic effects (with similar con-
tributions of both parents), 13% to the couple effect, less than 1% to the shared sibling
environment and 32% to unmeasured factors. Not one of these large population studies
focussed on the paternal contribution to preeclampsia, which is demonstrated by (1) the
effect of the length of the sexual relationship; (2) the concept of primipaternity versus
primigravidity; and (3) the existence of the so-called ‘dangerous’ father, as demonstrated
in various large population studies. It is currently unknown how the father exerts this effect.
Possible mechanisms include seminal cytokine levels and their effect on maternal immune
deviation, specific paternal HLA characteristics and specific paternal single nucleotide poly-
morphisms (SNPs), in particular in the paternally expressed genes affecting placentation.
Several large cohort studies, including the large international SCOPE consortium, have
identified paternal SNPs with strong associations with preeclampsia.
Crown Copyright © 2011 Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction ically encounter preeclampsia as a maternal disease with

The etiology of preeclampsia is often considered to be
purely maternal, i.e. maternal constitutional factors that
impair maternal cardiovascular/endothelial mechanisms
normally required to cope with the specific pregnancy
demands, being primarily a generalised inflammatory
response and a hyperdynamic circulation. Clinicians typ-
∗ Corresponding author at: Department of Obstetrics & Gynaecology,
Medical School North, Lyell McEwin Hospital, University of Adelaide, Hay-
down Road, Elizabeth Vale, South Australia 5112, Australia.
Tel.: +61 8 81829306; fax: +61 8 81829337.
E-mail address: gustaaf.dekker@adelaide.edu.au (G. Dekker).
variable degrees of fetal involvement, not recognizing that
preeclampsia is actually a couple’s disease with maternal
and fetal manifestations (Dekker and Robillard, 2005). The
unique immunogenetic maternal–paternal relationship is
becoming more and more appreciated, and as such also the
specific ‘genetic conflict’ that is characteristic of haemocho-
rial placentation (Haig, 1993).
The aim of this paper is to provide an overview on how
and to what extent paternal/relational factors play a role in
the causation of preeclampsia. Within the context of a con-
cise review this paper certainly does not pretend to provide
a comprehensive overview of all ‘paternal literature’; our
aim is to provide a review that reflects the broad spectrum

0165-0378/$ – see front matter. Crown Copyright © 2011 Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.jri.2010.12.010
 G. Dekker et al. / Journal of Reproductive Immunology 89 (2011) 126–132
of paternal factors without necessarily going into too much
detail for each paternal risk factor.
The clinical findings of preeclampsia can manifest as
a maternal syndrome (hypertension and proteinuria with
or without other multisystem abnormalities) and/or as
a fetal syndrome (IUGR), reduced amniotic fluid, and
abnormal oxygenation (Redman and Sargent, 2009). The
syndrome “preeclampsia” probably encapsulates more
than one disease process. Thus, near-term preeclamp-
sia without demonstrable fetal involvement is different
from preeclampsia associated with low birth weight and
preterm delivery, and preeclampsia in nulliparous women
may be different from that in women with pre-existing
vascular disease, multifetal gestation, diabetes mellitus, or
previous preeclampsia (Sibai et al., 2005). The two-stage
model of preeclampsia envisages (Redman and Sargent,
2009) that preeclampsia arises in various ways includ-
ing from placental ischaemia–reperfusion injury secondary
to deficient placentation. Whereas some consider abnor-
mal placentation to be the start and invariable cause of
preeclampsia, it is much more likely that it is a com-
pletely separate, but predisposing condition. Some, but
certainly not all, cases of preeclampsia are associated with
poor placentation. Poor placentation defines the first stage,
which would appear to have a different origin; first-stage
decidual immune responses account for risk factors dis-
cussed later in this review like the primipaternity and
possible partner specificity of preeclampsia (Redman and
Sargent, 2009; Sibai et al., 2005). A systemic inflammatory
response represents the second stage. Although normal
pregnancy stimulates a systemic inflammatory response, in
a completely normal woman this is not intense enough to
generate the signs of preeclampsia. To do that requires the
abnormal stimulus from an oxidatively stressed placenta
(“placental preeclampsia”). In a woman with a chronic
systemic inflammatory response associated with condi-
tions, such as chronic hypertension, diabetes, or obesity,
the starting point is abnormal enough that even a nor-
mal placenta can stimulate a systemic response of such an
intensity as to give the signs of preeclampsia (“maternal
preeclampsia”; Redman and Sargent, 2009). In a previous
review, Robillard et al. (2007) stressed that the presence
of these two major subtypes of preeclampsia probably
underlies the many major disagreements in the literature
regarding cause, risk factors and long-term prognosis of
preeclampsia. Although many if not virtually all articles
reviewed in this paper do not specifically define which
subtype of preeclampsia was addressed in their respective
studies, the focus of this paper on paternal risk factors is by
default on that type of preeclampsia that is associated with
defective placentation.
2. The role of the father
The concept of the dangerous partner is certainly not
new. Twenty years ago Astin et al. (1981) published a
paper in The Lancet entitled “Preeclampsia/eclampsia: a
fatal father factor”. It might be difficult for a woman to iden-
tify her ideal partner, but some potential paternal factors
are at least in theory relatively easily recognisable:
127
a. Epidemiological studies suggest that advanced paternal
age is a risk factor with the risk to the mother of devel-
oping preeclampsia almost doubling if she has a partner
aged >45 years (Chen et al., 2006; Harlap et al., 2002). At
the moment, the mechanism by which increased pater-
nal age causes an increase in maternal risk of developing
preeclampsia is still unknown. Increased sperm DNA
damage or perhaps altered sperm exposure are hypothe-
ses that need further exploration.
b. Men with a familial history of early-onset cardiovascu-
lar disease and/or hypertension significantly (odds ratio
>3) increase the risk of preeclampsia in their partners
(Rigó et al., 2006; Dekker personal observation; SCOPE
unpublished data; see also Section 6).
c. Paternal obesity represents an independent risk factor
for pregnancies resulting in small-for – gestational age
infants; to our knowledge no data are yet available with
regard to the risk of; preeclampsia (McCowan et al.,
2010). Paternal obesity might not only reflect the cou-
ple’s lifestyle and dietary choices, but almost certainly
also relates to the specific paternal genetic make-up (see
also Section 6).
Preeclampsia is a human disease. The case report on
‘eclamptic gorillas’ (Baird, 1981) reported on pregnant
gorillas with seizures – which could have been many things
(in particular just straightforward epilepsy), but there was
no support for genuine preeclampsia/eclampsia. Why is
preeclampsia so uniquely a human disease? There are
many hypotheses, but an attractive hypothesis for fur-
ther research would be that women, in contrast to other
mammals cannot identify a ‘suitable match’. Could there
be a specifically human lack of pheromone recognition –
after all pheromones certainly have an association with the
MHC (Scott, 2003). Although most data are by default ani-
mal studies (Grob et al., 1998), there are certainly some
human data suggesting that human partner selection on
an olfactory basis would favour HLA (MHC) heterozygos-
ity (Wedekind and Füri, 1997; see also Section 3), while de
Luca Brunori et al. (2003) have described a statistically sig-
nificant increase in HLA-DR homozygosity and a reduced
antigenic variety in ‘preeclamptic couples’ versus control
couples. However, for practical purposes these potential
feminine recognition strategies might not be very practical
in daily human life.
3. The partner’s HLA and parental ethnic
disconcordance
The invasion of trophoblasts into the decidua and
myometrium appears to be primarily controlled by
immune mechanisms. The syncytiotrophoblast does not
express class I HLA mRNA. While all of the classical class
I HLA antigens are absent apart from HLA-C, the invad-
ing cytotrophoblasts express the non-classical HLA-G and
HLA-E. Initially it was thought that the presence of HLA-G,
being monomorphic, played an important role in the affer-
ent arm of maternal tolerance to the fetus. HLA-G allows
trophoblasts to evade detection as foreign and prevents NK
cell mediated cytotoxicity.
128 G. Dekker et al. / Journal of Reproductive Immunology 89 (2011) 126–132
We now know that HLA-G expressed on the invad-
ing cytotrophoblast plays an even more important role
in the vascular adaptations in the placental bed that
are essential to pregnancy success (Moffett-King, 2002).
Since T-cells were thought to be the unique immune
cells required for adaptive immune responses, the absence
of major T-cell interaction in preeclampsia appeared to
negate the Immune Maladaptation Hypothesis (Dekker and
Sibai, 1998). This concept was radically changed by the
realisation of the major role played by the decidual NK
cells. The predominant population of lymphoid cells in
the decidua consists of NK cells while T and B cells are
rare. NK cells express inhibitory and activatory killer-cell
immunoglobulin-like receptors (KIR) capable of recognis-
ing HLA-class I molecules. Uterine NK cells influence both
trophoblast invasion and the vascular transformation of the
maternal placental bed by producing a series of cytokines
involved in angiogenesis and vascular stability, in particu-
lar VEGF, PlGF and Ang-2 (Lash et al., 2006). Moffett-King
(2002) changed our understanding of the importance of
the HLA-C–NK cell receptor interaction. HLA-C loci are
dimorphic for residues 77–80 and these two HLA-C groups
interact with different NK cell receptors. There is great
diversity of NK KIR haplotypes in humans with variations in
the number of genes, as well as polymorphisms at individ-
ual loci. All women express KIR on decidual NK cells for both
groups of HLA-C alleles and because HLA-C is polymor-
phic, each pregnancy will involve different combinations
of paternally derived fetal HLA-C and maternal KIRs.
Therefore each pregnancy is associated with a specific
immune interaction involving maternal NK cells inter-
acting with ‘paternal’ HLA. Mothers lacking most or all
activating KIRs (AA genotype) when the fetus has HLA-C
belonging to the HLA-C2 group, are at substantial risk of
preeclampsia (Hiby et al., 2004). An important component
of the Hiby et al. (2004) paper was the finding that dif-
ferent human populations have a reciprocal relationship
between KIR AA frequency and HLA-C2 frequency. Thereby,
this very attractive hypothesis could provide an immuno-
logical explanation for the various studies on parental
ethnic disconcordance or racial dissimilarity as a risk fac-
tor for preeclampsia. Indeed, Alderman et al. (1986), based
on a large Washington cohort, reported an almost dou-
bling of the risk of preeclampsia associated with racial
dissimilarity – in this particular cohort primarily Cau-
casian versus African-American. More recently, Caughey
et al. (2005), although confirming the risk associated with
parental ethnic disconcordance, came to much lower risk
estimates. According to the Hiby hypothesis the incidence
of preeclampsia among couples consisting of Japanese
women and Caucasian men should be higher than that
among couples consisting of Japanese women and Japanese
men. However, Saito et al. (2006) investigated the inci-
dence of preeclampsia among 324 couples consisting of
Japanese women and Caucasian men and found it to be
similar to that in couples consisting of Japanese women
and Japanese men. The authors concluded, therefore, that
their data do not support those of Hiby et al. (2004).
Although HLA-G was initially seen as essentially
monomorphic, more recent data have shown that this
might not be the case (Walpole et al., 2010). Various studies
have now demonstrated that specific paternal (fetal) HLA-
G polymorphisms or deletions (Tan et al., 2008, Larsen et al.,
2010) are risk factors for developing preeclampsia.
4. Sperm exposure
Most, but not all, epidemiological studies demonstrate
that regular sexual intercourse over an extended period
reduces the risk of preeclampsia. Marti and Herrmann
(1977) were the first to suggest that repeated prior expo-
sure to semen from the biological father of the baby reduces
the risk of preeclampsia, followed by the landmark study
of Robillard et al. (1994). Although most subsequent retro-
spective studies concurred with this finding (Dekker and
Robillard, 2007), a 2004 prospective study in women of
mixed parity found no association between duration of
sexual relationship with the biological father and the risk
of preeclampsia (Ness et al., 2004). However, in a recent
large prospective cohort study (Kho et al., 2009), 2507
nulliparous women with singleton pregnancies were inter-
viewed at 15 weeks’ gestation about the duration of their
sexual relationship with the biological father. This study
clearly showed that a short duration of sexual relation-
ship was more common in women with preeclampsia
compared with uncomplicated pregnancies (≤6 months
14.5% versus 6.9%, adjusted odds ratio [adjOR] 1.88, 95% CI
1.05–3.36; ≤3 months 6.9% versus 2.5%, adjOR 2.32, 95% CI
1.03–5.25; first intercourse 1.5% versus 0.5%, adjOR 5.75,
95% CI 1.13–29.3). Although the total number of semen
exposures was lower in women who delivered small-for-
gestational-age (SGA) babies, SGA was not associated with
a shorter duration of the sexual relationship. On post hoc
analysis, the subgroup of mothers with SGA fetuses and
abnormal uterine artery Doppler at 20 weeks was more
likely to have had a short sexual relationship compared
with controls (≤6 months adjOR 2.33, 95% CI 1.09–4.98;
≤3 months adjOR 3.22, 95% CI 1.18–8.79; first intercourse
adjOR 8.02, 95% CI 1.58–40.7). The authors concluded that
compared with uncomplicated pregnancies, a short dura-
tion of sexual relationship is more common in women who
develop preeclampsia and women with abnormal uter-
ine artery Doppler waveforms who deliver a SGA baby.
Interestingly, the results of Kho et al. (2009) indicate that
there is no relation between the length of the sexual rela-
tionship and gestational hypertension. However, a recent
paper from Nigeria by Olayemi et al. (2010) reports a
4% drop in the risk of developing hypertension for every
month increase in sexual cohabitation, but this did not
apply to preeclampsia. It should be noted that this Nige-
rian study also confirmed risk reduction (hazard ratio 0.7;
95% CI 0.55–0.93) associated with same-paternity abor-
tion.
The ‘protective’ effect of a more lengthy sexual rela-
tionship is explained by maternal mucosal tolerance to
paternal antigens (Robertson et al., 2002; Peters et al.,
2004). Deposition of semen in the female genital tract
elicits a cascade of cellular and molecular events that
resembles a classic inflammatory response (Sharkey et al.,
2007). Seminal vesicle-derived transforming growth fac-
tor ␤ (TGF␤) is an important contributing factor. Seminal
fluid TGF␤ is present both as a soluble form at five
 G. Dekker et al. / Journal of Reproductive Immunology 89 (2011) 126–132
times the concentration of that in blood (Nocera and
Chu, 1995), as well as bound to sperm (Chu et al., 1996).
TGF␤ elicits strong type 2 and Th3 immune responses
towards antigens present in semen (Robertson et al.,
2002). The antigenic stimulus is likely to be conveyed
by sperm, since the risk of preeclampsia is three times
higher in women conceiving via intracytoplasmic sperm
injection (ICSI) with surgically obtained sperm (from men
with complete azoospermia) than in those with stan-
dard in vitro fertilisation and ICSI using sperm obtained
by masturbation (Wang et al., 2002). Repeated inter-
course with sustained antigen exposure in the appropriate
cytokine environment mediated by TGF␤ is now thought
to be essential in this partner-specific mucosal tolerance
(Robertson et al., 2002). By initiating a type 2 or T regulatory
cell-dominated immune response towards paternal anti-
gens (Robertson et al., 2009), seminal TGF␤ may inhibit the
induction of type 1 responses against the semi-allogeneic
conceptus that are thought to be associated with poor
placental development and restricted fetal growth. Fur-
thermore, T helper type 2 (Th2) and Th3 lymphocytes
interact with both placental trophoblasts and the mater-
nal decidual vasculature to facilitate their remodelling
(Leonard et al., 2006). Impaired spiral arterial remodelling
reduces utero-placental perfusion and thereby predisposes
to preeclampsia and SGA. One of the important novel find-
ings of the aforementioned Kho et al. (2009) study is that
longer sexual relationships also provide partial protection
against SGA associated with abnormal uterine Doppler flow
patterns.
5. Primipaternity
Within the context of this review we will not reiter-
ate our concerns regarding the ‘birth-interval hypothesis’
as opposed to the primipaternity hypothesis, since this
has been the subject of an earlier specific review (Dekker
and Robillard, 2003). However, it should be noted that the
primipaternity hypothesis does not reject the possibility
of a relevant biological effect of long intervals between
births. The key point, however, is that the vast major-
ity of studies examining the effect of paternity change,
including the recent large study from Nigeria (Olayemi
et al., 2010), confirms the increased risk associated with a
change in paternity; an effect in those studies that cannot
be explained by the very modest increase in risk associated
with very long birth intervals (Skjaerven et al., 2002). From
a primary preventative perspective the message is clear-for
the best chance on having an uncomplicated second preg-
nancy, if your first pregnancy was uncomplicated, have it
with the same man.
6. Dangerous paternal genes
Large, mostly Scandinavian, studies have shown that for
preeclampsia the genetic effects account for about 31% of
the variation in the propensity to develop preeclampsia
whereby the environment accounts for 63% (Nilsson et al.,
2004). Although we are all aware of the Mendelian laws, it is
interesting to note that in these large epidemiological stud-
ies ‘men’ appear to be a ‘neglected species’. An exception
129
is the study by Lie et al. (1998). These authors have shown
that men who fathered one preeclamptic pregnancy were
almost twice as likely to father a preeclamptic pregnancy
with a different woman. While Esplin et al. (2001) showed
that if the male partner was born of a pregnancy compli-
cated by preeclampsia, the risk of his partner developing
preeclampsia would more than double. Emerging evidence
dictates that we should no longer neglect the role that the
male partner might play in reproductive success. Indeed,
male fetuses are less likely to survive at all time post-
conception than females, and in particular male fetuses
are more likely to be born preterm (Vatten and Skjaerven,
2004). Some of this biology appears to relate to gender-
specific ways in which the fetus responds to stress (Clifton,
2010).
In addition to the aforementioned strict Mendelian
laws, we also have to consider the potential involvement
impact of imprinted genes, and of genes that could change
part of his physiology relevant to reproduction. A few
examples of these three ‘genetic’ possibilities are:
• Dangerous paternal genes following Mendelian law: within
the context of this review it is not possible to report
in detail on this rapidly evolving field. A few exam-
ples will be highlighted to illustrate the principle. The
aforementioned studies on paternal family history of car-
diovascular disease and hypertension (Rigó et al., 2006)
are nothing less than an epidemiological reflection of
a whole set of susceptibility genes passed through to
the feto-placental unit via the father. Paternal (or fetal
autosomal) genetic thrombophilias have been linked to
a range of adverse pregnancy outcomes ranging from
stillbirth, to intra-uterine growth restriction (IUGR) and
preeclampsia (de Galan-Roosen et al., 2005; Gibson et al.,
2006). Andraweera et al. (2010) published data showing
almost a doubling of the risk associated with paternal
SNPs involving VEGF and PlGF, while Zusterzeel et al.
(2002) showed that the polymorphism in the glutathione
S-transferase P1 gene, a major biotransformation enzyme
in placenta and decidua associated with lower enzyme
detoxification capacity, is associated with preeclampsia
irrespective of whether it was of maternal or paternal
origin. The potential involvement of some other paternal
SNPs will be further discussed (see below).
• Dangerous paternal genes and imprinting: epigenetic
features, i.e. genomic imprinting are almost certainly
involved in the pathogenesis of preeclampsia (Cross,
2003). Direct proof of the role of imprinting was pub-
lished by Oudejans et al. (2004) who confirmed the
susceptibility locus on chromosome 10q22.1, previously
identified by Lachmeijer et al. (2001). Haplotype analysis
showed a parent-of-origin effect: maximal allele sharing
in the affected siblings was found for maternally derived
alleles in all families, but not for the paternally derived
alleles. Single nucleotide polymorphisms in the IGF2
gene, which encodes the paternally expressed insulin-
like growth factor II (IGF-II), an important growth factor
in trophoblast invasion and placental function (Roberts,
2010), are associated with a number of adverse outcomes
of pregnancy.
130 G. Dekker et al. / Journal of Reproductive Immunology 89 (2011) 126–132
• Paternal genes changing aspects of male reproductive phys-
iology: nothing has been published on this aspect of
reproductive physiology as far as we are aware. However,
one would expect paternal SNPs to influence seminal
fluid cytokine patterns and as such adversely affect
the required mucosal immunological adaptive changes
(Robertson et al., 2002) and/or the paternal SNPs might
influence his immune defence capacity to respond appro-
priately to genital tract infections (see below).
7. The father as source of infection
Over the past decade, researchers have started to look
for evidence of an infectious process underlying or at
least triggering the inflammatory pathways involved in
preeclampsia (Trogstad et al., 2001; Xie et al., 2010; Conde-
Agudelo et al., 2008). As a post hoc analysis of their
cerebral palsy cohort, Gibson et al. (2008a) checked for pos-
itive PCR for neurotropic viruses using newborn screening
cards of 717 adverse pregnancy cases and 609 controls.
For both term and preterm births, the risk of developing
pregnancy-induced hypertensive disorders was increased
in the presence of DNA from any herpesvirus (OR 5.70, 95
CI 1.85–17.57), and in particular with the presence of CMV
(OR 3.89, 95% CI 1.67–9.06).
Using the same cohort, all adverse pregnancy outcome
babies and controls were also genotyped for Mannose
Binding Lectin (MBL) SNPs (Ozdemir et al., 2010). The
MBL2 pathway of the complement system is activated
when MBL2 recognises and binds to carbohydrates, such
as mannose- and N-acetyl-glucosamine-rich oligosaccha-
rides, present on a wide range of bacteria, viruses, fungi
and parasites (Matsushita et al., 1998; Petersen et al., 2000).
The human MBL2 gene on chromosome 10 has 6 known
polymorphic sites (Mullighan et al., 2000), three within the
promoter region of exon 1, and 3 within exon 1. These pro-
moter and structural polymorphisms are found in various
cis combinations, resulting in haplotypes associated with
high, intermediate and low levels of MBL2 (Madsen et al.,
1995). Seven different haplotypes have been identified in
a range of populations, and in order of decreasing levels of
MBL2 are: HYPA, LYQA, LYPA, LXPA, HYPD, LYQC, and LYPB.
The HYPD, LYQC and LYPB haplotypes are considered defec-
tive haplotypes because they are associated with virtually
undetectable concentrations of MBL2 (Turner and Hamvas,
2000). These so-called deficient MBL2 haplotypes LYPA or
HYPD may be associated with an increased risk of cere-
bral palsy in the presence of exposure to viral infection and
may act as susceptibility factors for cerebral palsy (Gibson
et al., 2008b). The same group also looked at deficient MBL
haplotypes, viral presence and pregnancy outcome; sig-
nificant associations were found between variant MBL2
haplotypes and pregnancy-induced hypertensive disorders
(PIHD) (LYQC <32 weeks (OR 17.89, 95% CI 2.20–139.57)).
Evidence of exposure to infection increased the effect of
these associations (PIHD OR 23.80, 95% CI 1.08–1414.76)
while in the absence of evidence of exposure to infection
demonstrated that no associations were found between
deficient MBL haplotypes and PIHD (Gibson et al., 2010).
Of course the father directly contributes to the fetal MBL
haplotype.
There are several possible pathways by which certain
viruses, and in particular CMV, would lead to adverse preg-
nancy outcome and more specifically preeclampsia:
(1) Human CMV has been shown to impair clinical aspects
of cytotrophoblast function (Fisher et al., 2000) such
as decreased ␣1␤1 integrin expression and decreased
trophoblast invasion, and interestingly also decreased
HLA-G expression.
(2) CMV can persist in a latent phase in endothelial cells
and may therefore cause chronic endothelial cell dys-
function (Jarvis and Nelson, 2002).
But what about the potential link between the father
and viral presence versus adverse pregnancy outcome?
The connection might well be explained by the fact that
the male urogenital tract is a major reservoir for CMV
(Dejucq and Jégou, 2001) with various studies showing
CMV to be present in semen in 5–10% of men (Bezold
et al., 2007; Kapranos et al., 2003). A chronic CMV pres-
ence in the male genital tract could, at least in theory,
easily change the cytokine levels in seminal fluid and as
such adversely affect the aforementioned partner-specific
mucosal tolerance (Robertson et al., 2002). As mentioned
earlier, the male’s genotype could further influence his
response towards the presence of infection, adding another
layer of complexity. In our opinion this opens a whole new
area of exciting research, all aimed at unravelling the com-
plex genotype–phenotype interaction between a women
and her male partner.
References
Alderman, B.W., Sperling, R.S., Daling, J.R., 1986. An epidemiological study
of the immunogenetic aetiology of preeclampsia. Br. Med. J. (Clin. Res.
Ed.) 292, 372–374.
Andraweera, P., Thompson, S., Zhang, V., Nowak, R., Dekker, G., Roberts, C.,
2010. Maternal, paternal and fetal single nucleotide polymorphisms in
vascular endothelial growth factor family genes associate with preg-
nancy complications. Am. J. Obstet. Gynecol. 201, S13 (SMFM abstract
220).
Astin, M., Scott, J.R., Worley, R.J., 1981. Preeclampsia/eclampsia: a fatal
father factor. Lancet 5 (2), 533.
Baird Jr., J.N., 1981. Eclampsia in a lowland gorilla. Am. J. Obstet. Gynecol.
141, 345–346.
Bezold, G., Politch, J.A., Kiviat, N.B., Kuypers, J.M., Wolff, H., Anderson,
D.J., 2007. Prevalence of sexually transmissible pathogens in semen
from asymptomatic male infertility patients with and without leuko-
cytospermia. Fertil. Steril. 87, 1087–1097.
Caughey, A.B., Stotland, N.E., Washington, A.E., Escobar, G.J., 2005. Mater-
nal ethnicity, paternal ethnicity, and parental ethnic discordance:
predictors of preeclampsia. Obstet. Gynecol. 106, 156–161.
Chen, X.K., Wen, S.W., Smith, G., Leader, A., Sutandar, M., Yang, Q., Walker,
M., 2006. Maternal age, paternal age and new-onset hypertension in
late pregnancy. Hypertens. Pregnancy 25, 217–227.
Clifton, V.L., 2010. Review: sex and the human placenta: mediating differ-
ential strategies of fetal growth and survival. Placenta 31, S33–S39.
Chu, T.M., Nocera, M.A., Flanders, K.C., Kawinski, E., 1996. Localization of
seminal plasma transforming growth factor-beta1 on human sperma-
tozoa: an immunocytochemical study. Fertil. Steril. 66, 327–330.
Conde-Agudelo, A., Villar, J., Lindheimer, M., 2008. Maternal infection
and risk of preeclampsia: systematic review and metaanalysis. Am.
J. Obstet. Gynecol. 198, 7–22.
Cross, J.C., 2003. The genetics of preeclampsia: a feto-placental or maternal
problem? Clin. Genet. 64, 96–103.
de Galan-Roosen, A.E., Kuijpers, J.C., Rosendaal, F.R., Steegers, E.A., van
Beers, W.A., Ponjee, G.A., Merkus, H.M., 2005. Maternal and pater-
nal thrombophilia: risk factors for perinatal mortality. Br. J. Obstet.
Gynaecol. 112, 306–311.
 G. Dekker et al. / Journal of Reproductive Immunology 89 (2011) 126–132
Dejucq, N., Jégou, B., 2001. Viruses in the mammalian male genital tract
and their effects on the reproductive system. Microbiol. Mol. Biol. Rev.
65, 208–231.
Dekker, G., Robillard, P.Y., 2003. The birth interval hypothesis – does it
really indicate the end of the primipaternity hypothesis? J. Reprod.
Immunol. 59, 245–251.
Dekker, G.A., Robillard, P.Y., 2005. Preeclampsia: a couple’s disease
with maternal and fetal manifestations. Curr. Pharm. Des. 11, 699–
710.
Dekker, G., Robillard, P.Y., 2007. Preeclampsia: is the immune maladapta-
tion hypothesis still standing? An epidemiological update. J. Reprod.
Immunol. 76, 8–16.
Dekker, G.A., Sibai, B.M., 1998. Etiology and pathogenesis of preeclamp-
sia: current concepts. Am. J. Obstet. Gynecol. 179, 1359–
1375.
de Luca Brunori, I., Battini, L., Simonelli, M., Brunori, E., Valentino, V.,
Curcio, M., Mariotti, M.L., Lapi, S., Genazzani, A.R., 2003. HLA-DR in
couples associated with preeclampsia: background and updating by
DNA sequencing. J. Reprod. Immunol. 59, 235–243.
Esplin, M.S., Fausett, M.B., Fraser, A., et al., 2001. Paternal and maternal
components of the predisposition to preeclampsia. N. Engl. J. Med.
344, 867–872.
Fisher, S., Genbacev, O., Maidji, E., Pereira, L., 2000. Human
cytomegalovirus infection of placental cytotrophoblasts in vitro
and in utero: implications for transmission and pathogenesis. J. Virol.
74, 6808–6820.
Gibson, C.S., MacLennan, A.H., Janssen, N.G., Kist, W.J., Hague, W.M.,
Haan, E.A., Goldwater, P.N., Priest, K., Dekker, G.A., South Australian
Cerebral Palsy Research Group, 2006. Associations between fetal
inherited thrombophilia and adverse pregnancy outcomes. Am. J.
Obstet. Gynecol. 194 (947), e1–e10.
Gibson, C.S., Goldwater, P.N., MacLennan, A.H., Haan, E.A., Priest, K.,
Dekker, G.A., 2008a. Fetal exposure to herpesviruses may be asso-
ciated with pregnancy-induced hypertensive disorders and preterm
birth in a Caucasian population. BJOG 115, 492–500.
Gibson, C.S., MacLennan, A.H., Goldwater, P.N., Haan, E.A., Priest, K.,
Dekker, G.A., 2008b. Mannose-binding lectin haplotypes may be asso-
ciated with cerebral palsy only after perinatal viral exposure. Am. J.
Obstet. Gynecol. 198 (509.), e1-509.e8.
Gibson, C.S., MacLennan, A.H., Haan, E.A., Priest, K., Dekker, G.A., Writ-
ing for the South Australian Cerebral Palsy Research Group, 2010.
Fetal MBL2 haplotypes combined with viral exposure are associated
with adverse pregnancy outcomes. J. Matern. Fetal Neonatal Med.,
doi:10.3109/14767058.2010.531324.
Grob, B., Knapp, L.A., Martin, R.D., Anzenberger, G., 1998. The major
histocompatibility complex and mate choice: inbreeding avoidance
and selection of good genes. Exp. Clin. Immunogenet. 15, 119–
129.
Haig, D., 1993. Genetic conflicts in human pregnancy. Q. Rev. Biol. 68,
495–532.
Harlap, S., Paltiel, O., Deutsch, L., Knaanie, A., Masalha, S., Tiram, E., Caplan,
L.S., Malaspina, D., Friedlander, Y., 2002. Paternal age and preeclamp-
sia. Epidemiology 13, 660–667.
Hiby, S.E., Walker, J.J., O’Shaughnessy, K.M., et al., 2004. Combinations of
maternal KIR and fetal HLA-C genes influence the risk of preeclampsia
and reproductive success. J. Exp. Med. 200, 957–965.
Jarvis, M.A., Nelson, J.A., 2002. Human cytomegalovirus persistence and
latency in endothelial cells and macrophages. Curr. Opin. Microbiol.
5, 403–407.
Kapranos, N., Petrakou, E., Anastasiadou, C., Kotronias, D., 2003. Detection
of herpes simplex virus, cytomegalovirus, and Epstein–Barr virus in
the semen of men attending an infertility clinic. Fertil. Steril. 79 (Suppl.
3), 1566–1570.
Kho, E.M., McCowan, L.M., North, R.A., Roberts, C.T., Chan, E., Black, M.A.,
Taylor, R.S., Dekker, G.A., SCOPE Consortium, 2009. Duration of sexual
relationship and its effect on preeclampsia and small for gestational
age perinatal outcome. J. Reprod. Immunol. 82, 66–73.
Lachmeijer, A.M., Arngrimsson, R., Bastiaans, E.J., Frigge, M.L., Pals, G.,
Sigurdardottir, S., Stefansson, H., Palsson, B., Nicolae, D., Kong, A.,
Aarnoudse, J.G., Gulcher, J.R., Dekker, G.A., ten Kate, L.P., Stefansson,
K., 2001. A genome-wide scan for preeclampsia in the Netherlands.
Eur. J. Hum. Genet. 9, 758–764.
Larsen, M.H., Hylenius, S., Andersen, A.M., Hviid, T.V., 2010. The 3 -
untranslated region of the HLA-G gene in relation to preeclampsia:
revisited. Tissue Antigens 75, 253–261.
Lash, G.E., Schiessl, B., Kirkley, M., Innes, B.A., Cooper, A., Searle, R.F., Rob-
son, S.C., Bulmer, J.N., 2006. Expression of angiogenic growth factors
by uterine natural killer cells during early pregnancy. J. Leukoc. Biol.
80, 572–580.
131
Leonard, S., Murrant, C., Tayade, C., van den Heuvel, M., Watering, R., Croy,
B.A., 2006. Mechanisms regulating immune cell contributions to spiral
artery modification – facts and hypotheses – a review. Placenta 27 S,
40–46.
Lie, R.T., Rasmussen, S., Brunborg, H., Gjessing, H.K., Lie-Nielsen, E., Irgens,
L.M., 1998. Fetal and maternal contributions to risk of preeclampsia:
a population based study. Br. Med. J. 316, 1343–1347.
Madsen, H.O., Garred, P., Thiel, S., Kurtzhals, J.A., Lamm, L.U., Ryder,
L.P., Svejgaard, A., 1995. Interplay between promoter and structural
gene variants control basal serum level of mannan-binding protein. J.
Immunol. 155, 3013–3020.
Marti, J.J., Herrmann, U., 1977. Immunogestosis: a new etiologic concept of
“essential” EPH gestosis, with special consideration of the primigravid
patient: preliminary report of a clinical study. Am. J. Obstet. Gynecol.
128, 489–493.
Matsushita, M., Hijikata, M., Ohta, Y., Iwata, K., Matsumoto, M., Nakao,
K., Kanai, K., Yoshida, N., Baba, K., Mishiro, S., 1998. Hepatitis C virus
infection and mutations of mannose-binding lectin gene MBL. Arch.
Virol 143, 645–651.
McCowan, L., North, R., Kho, E.M., Black, M., Chan, E., Dekker, G., Poston,
L., Taylor, R., Claire, R., 2010. Paternal contribution to small for ges-
tational age babies: a multicentre prospective study. Obesity (Silver
Spring), doi:10.1038/oby.2010.279.
Moffett-King, A., 2002. Natural killer cells and pregnancy. Nat. Rev.
Immunol. 2, 656–663.
Mullighan, C.G., Marshall, S.E., Welsh, K.I., 2000. Mannose binding lectin
polymorphisms are associated with early age of disease onset and
autoimmunity in common variable immunodeficiency. Scand. J.
Immunol. 51, 111–122.
Ness, R.B., Markovic, N., Harger, G., Day, R., 2004. Barrier methods, length of
preconception intercourse, and preeclampsia. Hypertens Pregnancy
23, 227–235.
Nilsson, E., Salonen Ros, H., Cnattingius, S., Lichtenstein, P., 2004. The
importance of genetic and environmental effects for preeclampsia and
gestational hypertension: a family study. BJOG 111, 200–206.
Nocera, M., Chu, T.M., 1995. Characterization of latent transforming
growth factor-beta from human seminal plasma. Am. J. Reprod.
Immunol. 33, 282–291.
Olayemi, O., Strobino, D., Aimakhu, C., Adedapo, K., Kehinde, A., Odukogbe,
A.T., Salako, B., 2010. Influence of duration of sexual cohabitation on
the risk of hypertension in nulliparous parturients in Ibadan: a cohort
study. Aust. N. Z. J. Obstet. Gynaecol. 50, 40–44.
Oudejans, C.B., Mulders, J., Lachmeijer, A.M., Van Dijk, M., Konst, A.A.,
Westerman, B.A., Van Wijk, I.J., Leegwater, P.A., Kato, H.D., Matsuda,
T., Wake, N., Dekker, G.A., Pals, G., Ten Kate, L.P., Blankenstein, M.A.,
2004. The parent-of-origin effect of 10q22 in preeclamptic females
coincides with two regions clustered for genes with down-regulated
expression in androgenetic placentas. Mol. Hum. Reprod. 10, 589–
598.
Ozdemir, O., Dinleyici, E.C., Tekin, N., Colak, O., Aksit, M.A., 2010. Low-
mannose-binding lectin levels in susceptibility to neonatal sepsis
in preterm neonates with fetal inflammatory response syndrome. J.
Matern. Fetal Neonatal Med. Early Online, 1–5.
Peters, B., Whittall, T., Babaahmady, K., Gray, K., Vaughan, R., Lehner, T.,
2004. Effect of heterosexual intercourse on mucosal alloimmunisation
and resistance to HIV-1 infection. Lancet 363, 518–524.
Petersen, S.V., Thiel, S., Jensen, L., Vorup-Jensen, T., Koch, C., Jensenius, J.C.,
2000. Control of the classical and the MBL pathway of complement
activation. Mol. Immunol. 37, 803–811.
Redman, C.W., Sargent, I.L., 2009. Placental stress and preeclampsia: a
revised view. Placenta 30, S38–42.
Rigó Jr., J., Boze, T., Derzsy, Z., Derzbach, L., Treszl, A., Lázár, L., Sobel, G.,
Vásárhelyi, B., 2006. Family history of early-onset cardiovascular dis-
orders is associated with a higher risk of severe preeclampsia. Eur. J.
Obstet. Gynecol. Reprod. Biol. 128, 148–151.
Roberts, C.T., 2010. IFPA award in placentology lecture: complicated
interactions between genes and the environment in placentation,
pregnancy outcome and long term health. Placenta 31 (Suppl.),
S47–53.
Robertson, S.A., Ingman, W.V., O’Leary, S., Sharkey, D.J., Tremellen, K.P.,
2002. Transforming growth factor beta – a mediator of immune devi-
ation in seminal plasma. J. Reprod. Immunol. 57, 109–128.
Robertson, S.A., Guerin, L.R., Bromfield, J.J., Branson, K.M., Ahlström, A.C.,
Care, A.S., 2009. Seminal fluid drives expansion of the CD4 + CD25+ T
regulatory cell pool and induces tolerance to paternal alloantigens in
mice. Biol. Reprod. 80, 1036–1045.
Robillard, P.Y., Hulsey, T.C., Perianin, J., Janky, E., Miri, E.H., Papiernik, E.,
1994. Association of pregnancy induced hypertension with duration
of sexual cohabitation before conception. Lancet 344, 973–975.
132 G. Dekker et al. / Journal of Reproductive Immunology 89 (2011) 126–132
Robillard, P.Y., Dekker, G., Chaouat, G., Hulsey, T.C., 2007. Etiology of
preeclampsia: maternal vascular predisposition and couple disease
– mutual exclusion or complementarity? J. Reprod. Immunol. 76, 1–7.
Saito, S., Takeda, Y., Sakai, M., Nakabayahi, M., Hayakawa, S., 2006. The inci-
dence of preeclampsia among couples consisting of Japanese women
and Caucasian men. J. Reprod. Immunol. 70, 93–98.
Scott, K., 2003. Sex and the MHC. Dev. Cell 4, 290–291.
Sharkey, D.J., Macpherson, A.M., Tremellen, K.P., Robertson, S.A., 2007.
Seminal plasma differentially regulates inflammatory cytokine gene
expression in human cervical and vaginal epithelial cells. Mol. Hum.
Reprod. 13, 491–501.
Sibai, B., Dekker, G., Kupferminc, M., 2005. Preeclampsia. Lancet 365,
785–799.
Skjaerven, R., Wilcox, A.J., Lie, R.T., 2002. The interval between pregnancies
and the risk of preeclampsia. N. Engl. J. Med. 346, 33–38.
Tan, C.Y., Ho, J.F., Chong, Y.S., Loganath, A., Chan, Y.H., Ravichandran, J.,
Lee, C.G., Chong, S.S., 2008. Paternal contribution of HLA-G*0106 sig-
nificantly increases risk for preeclampsia in multigravid pregnancies.
Mol. Hum. Reprod. 14, 317–324.
Trogstad, L.I., Eskild, A., Bruu, A.L., Jeansson, S., Jenum, P.A., 2001. Is
preeclampsia an infectious disease? Acta Obstet. Gynecol. Scand. 80,
1036–1038.
Turner, M.W., Hamvas, R.M., 2000. Mannose-binding lectin: structure,
function, genetics and disease associations. Rev. Immunogenet. 2,
305–322.
Vatten, L.J., Skjaerven, R., 2004. Offspring sex and pregnancy outcome by
length of gestation. Early Hum. Dev. 76, 47–54.
Walpole, N.G., Kjer-Nielsen, L., Kostenko, L., McCluskey, J., Brooks, A.G.,
Rossjohn, J., Clements, C.S., 2010. The structure and stability of the
monomorphic HLA-G are influenced by the nature of the bound pep-
tide. J. Mol. Biol. 397, 467–480.
Wang, J.X., Knottnerus, A.M., Schuit, G., Norman, R.J., Chan, A., Dekker, G.A.,
2002. Surgically obtained sperm, and risk of gestational hypertension
and preeclampsia. Lancet 359, 673–674.
Wedekind, C., Füri, S., 1997. Body odour preferences in men and women:
do they aim for specific MHC combinations or simply heterozygosity?
Proc. Biol. Sci. 264, 1471–1479.
Xie, F., Hu, Y., Magee, L.A., Money, D.M., Patrick, D.M., Krajden, M., Thomas,
E., von Dadelszen, P., 2010. An association between cytomegalovirus
infection and preeclampsia: a case–control study and data synthesis.
Acta Obstet. Gynecol. Scand. 89, 1162–1167.
Zusterzeel, P.L., te Morsche, R., Raijmakers, M.T., Roes, E.M., Peters, W.H.,
Steegers, E.A., 2002. Paternal contribution to the risk for preeclampsia.
J. Med. Genet. 39, 44–45.