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The partner's role in the etiology of preeclampsia
Journal of Reproductive Immunology 57 (2002) 203–215 www.elsevier.com/locate/jreprimm
The partner’s role in the etiology of preeclampsia Gus Dekker * Department of Obstetrics and Gynaecology, Uni6ersity of Adelaide, Head Di6ision of Obstetrics/Gynaecology and Paediatrics, North Western Adelaide Health Ser6ice, Lyell McEwin Hospital, Haydown Road, SA 5112, Elizabeth Vale, SA, Australia Received 5 March 2002; received in revised form 5 April 2002; accepted 9 April 2002
Abstract 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. Recent data strongly indicate an important role for the male partner in the causation of this common pregnancy disorder. The aim of this review is to discuss the relevant literature and to explain how paternal, relational and sexual factors play an important role in the etiology of preeclampsia. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Preeciampsia; Etiology; Immunology; Partner
1. Introduction Preeclampsia, a condition characterised by hypertension, proteinuria and often degrees of intra-uterine growth restriction (IUGR), occurs in 3–5% of pregnancies and is a major cause (15 –20%) of maternal mortality in developed countries and a leading cause of (iathrogenic) preterm birth and small-for-gestational-age infants. Shallow, endovascular cytotrophoblast in* Tel.: +61-8-8182-9306; fax: +61-8-8182-9337. E-mail address: [email protected] (G. Dekker). 0165-0378/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 5 - 0 3 7 8 ( 0 2 ) 0 0 0 3 9 - 6
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vasion in the spiral arteries, inappropriate endothelial cell activation and an exaggerated inflammatory response, involving intravascular leucocytes as well as the clotting and complement systems, are features in the pathogenesis of preeclampsia (Roberts and Redman, 1993; Redman et al., 1999). Redman et al. (1999) demonstrated that even normal pregnancy is characterised by a marked inflammatory response and that the differences between preeclampsia and normal pregnancy are less striking than between the pregnant and the non-pregnant state. A number of hypotheses on the etiology and early pathogenesis of preeclampsia are currently popular: one of the popular hypotheses is the immune/immunogenetic maladaptation hypothesis. According to this hypothesis immune maladaptation may, via an inappropriate decidual release of Th1 cytokines, proteolytic enzymes, and free radical species (Dekker and Sibai, 1998), cause both shallow invasion of spiral arteries by endovascular cytotrophoblast cells and systemic endothelial cell dysfunction. Several explanations for maternal immune disturbances have been proposed, one of which invokes factors of paternal origin. This review will focus on the paternal factor and how it fits within the immune maladaptation hypothesis.
2. The paternal factor and sperm exposure
2.1. Nulliparity 6ersus primipaternity Generally, genuine preeclampsia is thought of as a disease of first pregnancies (Roberts and Redman, 1993). Indeed, a previous normal pregnancy is associated with a markedly lowered incidence of preeclampsia; even a previous abortion provides some protection in this respect (Eras et al., 2000). The protective effect of multiparity, is however lost with change of partner. The term primipaternity was introduced by Robillard et al. (1993) and Robillard et al. (1999) to facilitate exploration of the relationship between severe preeclampsia and changes in paternity patterns among multigravidae. In their first study, Robillard et al. (1993) described that in 61.7% of multiparous women with preeclampsia the father of the current pregnancy was different than that of the former, compared to 16.6% in the control group (PB 0.0001). Therefore these authors suggested that preeclampsia may be a problem of primipaternity rather than primigravidity. This study Robillard et al. (1993) was criticised because preeclampsia in these multiparous women was not defined by the classic combination of pregnancy-induced hypertension plus proteinuria. Tubbergen et al. (1999) repeated this study in a Dutch population of 392 hypertensive multiparous patients, and showed that multiparous women with strictly defined
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preeclampsia and/or HELLP (haemolysis-elevated liver enzymes -low platelets) syndrome had a new partner in 22–25% of cases versus 3.4% in a control group of 182 normotensive multiparous patients. Also Trupin et al. (1996) in a prospective study in 5068 nulliparas and 5800 multiparas, of whom 573 had new partners, found that the preeclampsia incidence in nulliparas (3.2%) and multiparas with changed paternity (3%) is similar, and much higher than the 1.9% incidence in multiparas with no change in partner. Li and Wi (2000) recently published an important study showing that the effect of changing partners depends on the woman’s history of preeclampsia. These investigators studied a cohort of 140 147 Californian women with two consecutive births during 1989–1991. Among women without preeclampsia in the first pregnancy, changing partners resulted in a 30% increase in the risk of preeclampsia in the subsequent pregnancy compared with those who did not change partners (95% CI 1.1–1.6). On the other hand, among women with preeclampsia in the first pregnancy, changing partners resulted in a 30% reduction in the risk of preeclampsia in the subsequent pregnancy (95% CI 0.4–1.2). It is important to note that notwithstanding the study’s large sample size, the actual number of patients with preeclampsia in the obstetric history and a new partner and recurrent preeclampsia was only n= 15.
2.2. Sperm exposure The duration of sexual relationship is also an important determining risk factor. Marti and Herrmann (1977) were the first to describe that the number of sexual cohabitation’s preceding pregnancy is about three times higher in normal pregnant women than in preeclamptic women, and concluded that their findings might also provide an explanation for the high incidence of preeclampsia in teenage pregnant girls. Klonoff Cohen et al. (1989) subsequently conducted a case-control study, comparing the contraceptive histories of 110 primiparous women with preeclampsia with 115 pregnant women without preeclampsia. Their data indicated a 2.4-fold increased risk of preeclampsia for users of contraceptives that prevent exposure to sperm. Robillard et al. (1994) were the first to launch a prospective study on the relationship between sperm exposure and preeclampsia; 1011 consecutive women delivering in one obstetric unit were interviewed about paternity and duration of sexual cohabitation before conception. The incidence of pregnancy-induced hypertension was 11.9% among primigravidae, 4.7% among same-paternity multigravidae, and 24.0% among new-paternity multigravidae. For both primigravidae and multigravidae, length of sexual cohabita-
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tion before conception was inversely related to the incidence of pregnancy-induced hypertension (P B0.0001). Taking women cohabiting for more than 12 months as reference, a cohabitation period of 0–4 months was shown to be associated with a typical odds ratio (OR) of 11.6, a period of 5– 8 months with a typical OR of 5.9, and a period of 9–12 months with a typical OR of 4.2. The very high incidence (24.0%) of pregnancy-induced hypertension among new-paternity multiparous women was related to a remarkably short period of sperm exposure preceding conception. More or less in contrast to Robillard’s study, a recent retrospective case-control study (Morcos et al., 2000) in a group of 68 women of mixed parity with pregnancy-induced hypertensive disorders found that for primiparous women a shorter duration of sexual cohabitation was associated with only a small and non-significant reduction in the risk of pregnancy-induced hypertensive disorders. For multiparous women, a greater length of time since ceasing the use barrier contraceptives was associated with a greater risk of pregnancy-induced hypertensive disorders. However, the study of Morcos et al. (2000) has some major problems; (a) a relatively high percentage (20–40% of cases) had a history of a previous abortion, (b) the cases and the controls apparently all had some significant fertility limiting factors. The mean number of months of sexual activity without any birth control was 13.2 and 10.9 months, respectively in the primiparous hypertensive cases and controls, and 49.4 and 27.1 months, respectively in the multiparous hypertensive cases and controls. Koelman et al. (2000) assessed the effects of oral sex and found that, when comparing strictly defined primiparous preeclamptic women with primiparous control women, only 18 out of 41 preeclamptic women (44%) had oral sex with their partner before the index pregnancy versus 36 (82%) out of 44 in the control group (P=0.0003). In addition, 17% out of the 41 preeclamptic patients versus 48% out of the 44 controls patients confirmed that they swallowed the sperm (P=0.003).
2.3. Donated gametes Another circumstance where pregnancy is initiated with no prior exposure to paternal antigens is donor insemination. Need et al. (1983) were the first to report the higher incidence (about two-fold) of preeclampsia in pregnancies after artificial donor insemination. This has since been reported by several investigators Dekker et al. (1998) (review). Hoy et al. (1999) in a large cohort of 1552 donor insemination pregnancies com-
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pared with 7717 normally conceived pregnancies, recently provided solid evidence that donor insemination is definitely a risk factor for preeclampsia. Also, oocyte donation is associated with an increased incidence of preeclampsia. In the largest retrospective analysis (Abdalla et al., 1998) of data from 232 ovum donation pregnancies, it was noted that 23% of all pregnancies were complicated by hypertension. Salha et al. (1999) compared the incidence of preeclampsia in pregnancies conceived after donor insemination versus partner insemination, and also after egg donation and embryo donation. In this study 72 were infertility patients who had conceived as a result of sperm, ovum or embryo donation and the other 72 women were age- and parity matched controls who became pregnant with their own gametes, either spontaneously, or following intra-uterine insemination with their partner’s spermatozoa. The overall incidence of preeclampsia in the donated gametes study group was 18.1 versus 1.4% in the age- and parity-matched controls. The incidence of preeclampsia in pregnancies resulting from donated spermatozoa was 18.2% compared with 0% in the age- and parity-matched partner insemination group. The incidence of preeclampsia resulting from ovum donation was also significantly higher at 16% compared with 3.7% in the age- and parity-matched control group. Four out of the 12 (33.3%) women who conceived with donated embryos developed hypertension compared with none of their age- and parity-matched controls.
2.4. Dangerous partner Recent data also provide evidence for the existence of the so-called ‘dangerous’ father. Lie et al. (1998) recently published data based on the complete Norwegian population (1967–1992; about 60 000 births a year). Lie et al. (1998) identified 363 758 pairs of first and second pregnancies when the two children had the same mother and father; 14 266 pairs of pregnancies when the children had the same mother but different fathers; and 26 152 pairs where the children had the same father but different mothers. One of the major findings of this study was that men who fathered one preeclamptic pregnancy where nearly twice as likely to father a preeclamptic pregnancy in a different woman (1.8; 95% CI 1.2– 2.6; after adjustment for parity), regardless of whether she had already had a preeclamptic pregnancy or not. Thus mothers had a substantially increased risk in their second pregnancy (2.9%) if they became pregnant by a man who had fathered a preeclamptic first pregnancy in another woman. This risk was nearly as high as the average risk amongst first pregnancies.
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3. Potential mechanisms underlying seminal effects Deposition of semen in the female genital tract provokes a cascade of cellular and molecular events that resemble a classic inflammatory response. The critical seminal factor appears to be seminal vesicle derived transforming growth factor b1 (TGFb1). Seminal vesicle-derived TGFb1 is secreted predominantly in a latent form. Seminal plasmin and uterine factors transform the latent form into bioactive TGFb1 (Tremellen et al., 1998). Intra-uterine insemination of TGFb1 in-vivo results in an increase in granulocyte-monocyte colony stimulating factor (GM-CSF) production that is sufficient to initiate an endometrial leukocytosis comparable with that seen following mating (Robertson, 2002). The introduction of TGFb1 into the uterus in combination with paternal ejaculate antigens favours the growth and survival of the semi-allogenic fetus, as evidenced by a significant increase in fetal and placental weight in animal studies, in two ways. Firstly, by initiating a post-mating inflammatory reaction, TGFb1 increases the ability to sample and process paternal antigens contained within the ejaculate. Another important role of TGFb1 and the subsequent post-coital inflammatory response is the initiation of a strong Type 2 immune deviation. The processing of an antigen by APCs in an environment containing TGFb1 is likely to initiate a Th2 phenotype within these responding T-cells (Robertson, 2002). By initiating a Type 2 immune response towards paternal ejaculate antigens, seminal TGFb1 may inhibit the induction of Type 1 responses against the semi-allogenic conceptus that are thought to be associated with poor placental development and fetal. Decidual macrophages, present in an immune-suppressive phenotype from the moment of implantation, may inhibit NK cell lytic activity through their release of molecules such as TGFb, Interleukin-10 (IL-10) and prostaglandin-E2 (PGE2). Under the influence of the local cytokine environment, antigen-presenting cells (APCs) such as macrophages and dendritic cells may take up, process and present ejaculate antigens (sperm, somatic cells, and soluble antigens) to T cells in the draining lymph nodes loss (Tremellen et al., 1998; Robertson, 2002).
3.1. Sperm cell or seminal plasma The exact way by which the female organism is exposed to the paternal HLA message is uncertain. Koelman et al. (2000) demonstrated the presence of soluble class I HLA molecules in seminal plasma representing a potential straightforward way of endometrial exposition. Interestingly, soluble HLA molecules have also been demonstrated to induce apoptosis in human cytotoxic T cells (Zavazava and Kronke, 1996), and induction of apoptosis
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may be mechanism in inducing specific tolerance against HLA molecules of the male partner. According to Clark (1993) the genital tract has unusual T cells with g/d rather than a/b type receptors for antigen, and he suggested that these T cells respond to antigens in the vagina and uterus without the usual requirement for simultaneous binding of these antigens to an HLA-A, -B, -C, or -D type antigen on the APC. Such a mechanims would pave the way to recognition of human trophoblast lacking classical HLA surface antigens (Clark, 1993). Data of Smith et al. (1997) suggest that the protective factor is on the spermatozoa and not in the seminal fluid. Sperm cells do not express HLA. HLA-G is certainly not involved here, since human sperm cells do not have mRNA for HLA-G (Hiby et al., 1999). The induction of alloantibodies by pregnancy indicates that the maternal immune system is confronted with paternal HLA-A and -B antigens of the child. It might well be that the tolerance originally induced by soluble HLA-A and -B antigens or translated sperm mRNA encoding for paternal HLA spreads to epitopes of non-classical HLA antigens expressed on the trophoblast (Yang et al., 1999). A generally accepted phenomenon in inflammation, a pregnancy characteristic (Redman et al., 1999) is an increased expression of classical HLA-antigens. For this reason, immune responses to classical HLA class I molecules can not be excluded in the occurrence of preeclampsia.
4. Evolutionary perspective The observation of an inverse relationship between the duration of sexual cohabitation and the incidence of preeclampsia suggests that long-term sperm exposure may be important for human implantation success. This makes physiological sense since the human female is one of the few mammals exposed to her partner’s semen on multiple occasions prior to conception. From an evolutionary perspective, it can be argued that induction of paternal antigen tolerance through repeated sperm exposure may have reproductive advantages, perhaps by promoting implantation and survival of embryos conceived in long-term relationships where it could be argued that the male parent may be more committed to the well-being of the resultant child. In terms of evolution the relatively high incidence of preeclampsia represents a significant reproductive disadvantage in humans as compared with other mammals. During all human history, in developing countries nowadays and until the 1950s in developed countries, eclampsia accounted for at least 1% of human births (Robillard et al., 2002).
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Many authors think that, because of its high incidence, the disease might hide an adaptive advantage somewhere. This may be true for the increase in blood pressure per se, since the increased maternal systemic blood pressure will increase perfusion pressure (Dadelszen von et al., 2000). However, overall the clinical syndrome preeclampsia-eclampsia means that mankind had to adapt to a tremendous reproductive burden. The major difference between the human embryo and their mammal counterparts is the size of its brain requiring about 60% of total fetal nutritional needs during the extraordinary phase of brain development in the second and third trimester of pregnancy (Martin, 1996). According to Robillard et al. (2002) the large size of the human fetal brain requires the deep endovascular trophoblast invasion that can only occur on the basis of major immunogenetic compromises in terms of maternal-paternal tissue tolerance. Robillard et al. (2002) recently hypothesised that the low fecundability rate and loss of oestrus represent the price mankind had to pay for allowing the large size human brain, the required deep endovascular trophoblast invasion and at the same time an acceptably low incidence of preeclampsia. The human female has a very low fecundability rate, 25% at the age of maximum fecundity. In mathematical models on populations, demographers use a mean interval of 7– 8 months after constitutions of couples (without contraception). Being very fertile in a first pregnancy can be considered to be a disadvantage with respect to the high associated preeclampsia risk. According to Robillard et al. (2002), a fecundability rate of 25% observed in the human species is the best compromise between the preeclampsia risk without threatening fertility for additional pregnancies (multiparity) with the same partner.
4.1. Parental HLA sharing Parental sharing of human leukocyte antigens (HLA) may be associated with adverse pregnancy outcome (Ober, 1998). Although still not well understood, maternal immune tolerance is probably initiated by fetal (paternal) immunologic stimulation. Parental HLA sharing may result in a lack of adequate antigenic stimulation and a failure to establish immune tolerance which could lead to a series of adverse pregnancy outcomes ranging from infertility, recurrent spontaneous abortions, and IUGR. The strongest evidence derives from the association between paternal HLA sharing and recurrent spontaneous abortion. IUGR pregnancies are also associated with a greater-than-expected degree of parental HLA sharing. HLA-incompatible fetuses are known to be at an advantage in human pregnancy (Ober, 1998). Parental HLA sharing has also been hypothesised to be a potential
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underlying mechanism for preeclampsia. However, only a limited number of studies have examined this hypothesis, and results are not consistent. Li and Wi (2000) study was also based on the assumption that women with preeclampsia have a high likelihood of sharing HLA antigens with their partners. In a couple without HLA sharing, a prior successful pregnancy should prove enough protection against the risk of preeclampsia in a future pregnancy fathered by the same partner. Therefore, when a parous women changes partners, the protective effect offered by the previous pregnancies no longer exists; thus her risk of preeclampsia in a pregnancy fathered by a new partner is higher than that of a woman who remains with the same partner. The reported increased risk of preeclampsia associated with changing partners in many other studies may have reflected this phenomenon among women without parental HLA sharing because they comprised the majority of those study populations. On the contrary, if a woman had prior preeclampsia, thus indicating her sharing of HLA antigens with her current partner, her ability to establish the protective immune tolerance would be limited due to lack of immunologic stimulation resulting from HLA sharing. Changing a partner, which likely results in less HLA sharing, would reduce the risk of preeclampsia because of the enhanced immunologic stimulation from the fetus fathered by the new partner. Similar findings were reported by Lie et al. (1998). In this Norwegian study (Lie et al., 1998), the risk to develop preeclampsia was 1.7% among second pregnancies in mothers with a history of a normotensive first pregnancy, who had their second pregnancy with the same partner. Mothers who had preeclampsia in the first pregnancy had a risk of 13.1% if she had her second pregnancy with the same partner. This risk dropped to 11.8% if she changed the partner. An alternative and/or additional explanation for the observed effect of changing partners on the risk of preeclampsia in the subsequent pregnancy would be paternally related factors, genetic or otherwise. In other words, a relatively small percentage of men in the general population may carry a higher risk of fathering a pregnancy with preeclampsia. The Norwegian data (Lie et al., 1998) clearly show the pure impact of the partner, since men who fathered one preeclamptic pregnancy where nearly twice as likely to father a preeclamptic pregnancy in a different woman (1.8; 95% CI 1.2–2.6; after adjustment for parity), regardless of whether she had already had a preeclamptic pregnancy or not. Paternal factors could be thus include the degree of HLA sharing, specific genetic risk factors, and or some sustained male sexual preferences such as having oral sex. Seminal factors such as the level of soluble HLA, TGFb1, and plasmin might well be characteristics completely under genetic control. For example some HLA class I types are associated with low or
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high levels of soluble HLA levels in seminal plasma (Koelman et al., 2000).
4.2. Maternal factors It is important to keep in mind that the paternal factor is not the only determinant of preeclampsia. Also Li and Wi (2000) data show that maternal factors are definitely strongly involved. If a paternal factor were the sole determinant of preeclampsia, one would have expected the risk to be similar among women who changed partners (assuming random mating), regardless of their history of preeclampsia. However, after changing partners, the risk of preeclampsia was still much higher amongst women in with a history of preeclampsia (6.4%) than among women without such a history (0.9%) (Li and Wi, 2000). One of the potential mechanisms for this maternal importance could be that a history of preeclampsia is a marker for women who do not respond to fetal (paternal) immune stimulation as strongly as do women without such a history, and thus are less likely, under the same fetal stimulation, to establish the immune tolerance needed for a successful pregnancy. The failure in establishing immune tolerance to protect pregnancy could make women more susceptible to various adverse pregnancy outcomes, including preeclampsia. Poor responses to paternal immune stimulation have been reported among women with recurrent spontaneous abortions. Therefore, a history of preeclampsia may be a marker for identifying those women who have reduced capacity of reproductive immune responses, and thus are at a higher risk of preeclampsia. Other maternal reasons for being inefficient in mounting an immune tolerance response might be a certain sustained maternal sexual preference- e.g. not having oral sex, or having a limited length of sexual cohabitation with new partner before conceiving. The latter phenomenon was demonstrated to be present in Robillard et al.’s (Robillard et al., 1993, 1994) studies in multiparous preeclamptic patients.
5. Summary In summary, the protective effect of sperm exposure, the higher incidence after donor insemination and oocyte donation and the paternal factor strongly support the immune/immunogenetic maladaptation hypothesis. Obviously, the etiology of preeclampsia cannot be completely explained by the immune maladaptation hypothesis. The other side of the equation is the way the maternal cardiovascular system, and more specific
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the endothelium, is coping with the exaggerated inflammatory response. Factors having a significant negative impact on the coping capacity of the endothelium include: (1) age, (2) chronic hypertension, (3) thrombophilic disorders, (4) the homocysteine level, (5) obesity, (6) insulin resistance/hyperinsulinemia, and (7) type I diabetes (Dekker and Sibai, 1998). Apparently a marked degree of ‘benign’ inflammation is characteristic of normal pregnancy. Although the exact mechanisms still have to be elucidated it is tempting to consider that this degree of inflammation is one of the triggering or signalling factors required initiating systemic vasodilatation. Immune maladaptation in preeclampsia may relate to both a shallow placentation and an exaggerated systemic inflammatory response. The exaggerated inflammatory response and its subsequent endothelial cell activation, may be initiated by the fetus in order to trigger a maternal response (increased systemic blood pressure) that is intrinsically beneficial to the fetus. Mother nature is mild, and if you are a young and healthy woman the end results will be good for mother and baby. However, if you happen to have significant underlying risk factor and/or the immune stimulus is just too strong you will develop ‘bad’ preeclampsia associated with a very poor outcome. Potential new approaches to be explored that could effective in preventing preeclampsia include: (1) pharmacological agents and/or dietary supplements to modify the Type 1/Type 2 cytokine balance; (2) radical scavengers; (3) promoting longer sexual relationships as pre-pregnancy advice and/or alternate ways of sperm exposure, and (4) boosting the initial post-coital inflammatory response. Preeclampsia is an extremely complex multifactorial disorder. In the coming years the most significant progress will be made when we finally understand the immunologic/molecular genetic mechanisms involved in the partner-specific post-coital tolerance, the identification of (probably a long list) susceptibility genes, and unravelling the endothelial consequences of insulin resistance and obesity.
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Robillard, P.-Y., Dekker, G.A., Hulsey, T., 2002. Evolutionary adaptations to pre-eclampsia/eclampsia in humans; low fecundability rate, loss of oestrus, prohibitions of incest and systematic polyandry. Am. J. Reprod. Immunol. 47, 104 –111. Salha, O., Sharma, V., Dada, T., Nugent, D., Rutherford, A.J., Tomlinson, A.J., Philips, S., Allgar, V., Walker, J.J., 1999. The infuence of donated gametes on the incidence of hypertensive disorders of pregnancy. Hum. Reprod. 14, 2268 –2273. Smith, G.N., Walker, M., Tessier, J.L., Millar, K.G., 1997. Increased incidence of preeclampsia in women conceiving by intrauterine insemination with donor versus partner sperm for the treatment of primary infertility. Am. J. Obstet. Gynecol. 177, 455 – 458. Tremellen, K.P., Seamark, R.F., Robertson, S.A., 1998. Seminal transforming growth factor b1 stimulates granulocyte-macrophage colony-stimulating factor production and inflammatory cell recruitment in the murine uterus. Biol. Reprod. 58, 1217 –1225. Trupin, L.S., Simon, L.P., Eskenazi, B., 1996. Change in paternity: a risk factor for preeclampsia in multiparas. Epidemiology 7, 240 – 244. Tubbergen, P., Lachmeijer, A.M., Althuisius, S.M., Vlak, M.E., van Geijn, H.P., Dekker, G.A., 1999. Change in paternity: a risk factor for preeclampsia in multiparous women? J. Reprod. Immunol. 45, 81 –88. Yang, L., DuTemple, B., Gorczynski, R.M., Levy, G., Zhang, L., 1999. Evidence for epitope spreading and active suppression in skin graft tolerance after donor-specific transfusion. Transplantation 67, 1404 –1410. Zavazava, N., Kronke, M., 1996. sHLA class I molecules induce apoptosis in alloreactive cytotoxic T cells. Nat. Med. 2, 1005 –1011.
The partner’s role in the etiology of preeclampsia Gus Dekker * Department of Obstetrics and Gynaecology, Uni6ersity of Adelaide, Head Di6ision of Obstetrics/Gynaecology and Paediatrics, North Western Adelaide Health Ser6ice, Lyell McEwin Hospital, Haydown Road, SA 5112, Elizabeth Vale, SA, Australia Received 5 March 2002; received in revised form 5 April 2002; accepted 9 April 2002
Abstract 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. Recent data strongly indicate an important role for the male partner in the causation of this common pregnancy disorder. The aim of this review is to discuss the relevant literature and to explain how paternal, relational and sexual factors play an important role in the etiology of preeclampsia. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Preeciampsia; Etiology; Immunology; Partner
1. Introduction Preeclampsia, a condition characterised by hypertension, proteinuria and often degrees of intra-uterine growth restriction (IUGR), occurs in 3–5% of pregnancies and is a major cause (15 –20%) of maternal mortality in developed countries and a leading cause of (iathrogenic) preterm birth and small-for-gestational-age infants. Shallow, endovascular cytotrophoblast in* Tel.: +61-8-8182-9306; fax: +61-8-8182-9337. E-mail address: [email protected] (G. Dekker). 0165-0378/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 5 - 0 3 7 8 ( 0 2 ) 0 0 0 3 9 - 6
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vasion in the spiral arteries, inappropriate endothelial cell activation and an exaggerated inflammatory response, involving intravascular leucocytes as well as the clotting and complement systems, are features in the pathogenesis of preeclampsia (Roberts and Redman, 1993; Redman et al., 1999). Redman et al. (1999) demonstrated that even normal pregnancy is characterised by a marked inflammatory response and that the differences between preeclampsia and normal pregnancy are less striking than between the pregnant and the non-pregnant state. A number of hypotheses on the etiology and early pathogenesis of preeclampsia are currently popular: one of the popular hypotheses is the immune/immunogenetic maladaptation hypothesis. According to this hypothesis immune maladaptation may, via an inappropriate decidual release of Th1 cytokines, proteolytic enzymes, and free radical species (Dekker and Sibai, 1998), cause both shallow invasion of spiral arteries by endovascular cytotrophoblast cells and systemic endothelial cell dysfunction. Several explanations for maternal immune disturbances have been proposed, one of which invokes factors of paternal origin. This review will focus on the paternal factor and how it fits within the immune maladaptation hypothesis.
2. The paternal factor and sperm exposure
2.1. Nulliparity 6ersus primipaternity Generally, genuine preeclampsia is thought of as a disease of first pregnancies (Roberts and Redman, 1993). Indeed, a previous normal pregnancy is associated with a markedly lowered incidence of preeclampsia; even a previous abortion provides some protection in this respect (Eras et al., 2000). The protective effect of multiparity, is however lost with change of partner. The term primipaternity was introduced by Robillard et al. (1993) and Robillard et al. (1999) to facilitate exploration of the relationship between severe preeclampsia and changes in paternity patterns among multigravidae. In their first study, Robillard et al. (1993) described that in 61.7% of multiparous women with preeclampsia the father of the current pregnancy was different than that of the former, compared to 16.6% in the control group (PB 0.0001). Therefore these authors suggested that preeclampsia may be a problem of primipaternity rather than primigravidity. This study Robillard et al. (1993) was criticised because preeclampsia in these multiparous women was not defined by the classic combination of pregnancy-induced hypertension plus proteinuria. Tubbergen et al. (1999) repeated this study in a Dutch population of 392 hypertensive multiparous patients, and showed that multiparous women with strictly defined
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preeclampsia and/or HELLP (haemolysis-elevated liver enzymes -low platelets) syndrome had a new partner in 22–25% of cases versus 3.4% in a control group of 182 normotensive multiparous patients. Also Trupin et al. (1996) in a prospective study in 5068 nulliparas and 5800 multiparas, of whom 573 had new partners, found that the preeclampsia incidence in nulliparas (3.2%) and multiparas with changed paternity (3%) is similar, and much higher than the 1.9% incidence in multiparas with no change in partner. Li and Wi (2000) recently published an important study showing that the effect of changing partners depends on the woman’s history of preeclampsia. These investigators studied a cohort of 140 147 Californian women with two consecutive births during 1989–1991. Among women without preeclampsia in the first pregnancy, changing partners resulted in a 30% increase in the risk of preeclampsia in the subsequent pregnancy compared with those who did not change partners (95% CI 1.1–1.6). On the other hand, among women with preeclampsia in the first pregnancy, changing partners resulted in a 30% reduction in the risk of preeclampsia in the subsequent pregnancy (95% CI 0.4–1.2). It is important to note that notwithstanding the study’s large sample size, the actual number of patients with preeclampsia in the obstetric history and a new partner and recurrent preeclampsia was only n= 15.
2.2. Sperm exposure The duration of sexual relationship is also an important determining risk factor. Marti and Herrmann (1977) were the first to describe that the number of sexual cohabitation’s preceding pregnancy is about three times higher in normal pregnant women than in preeclamptic women, and concluded that their findings might also provide an explanation for the high incidence of preeclampsia in teenage pregnant girls. Klonoff Cohen et al. (1989) subsequently conducted a case-control study, comparing the contraceptive histories of 110 primiparous women with preeclampsia with 115 pregnant women without preeclampsia. Their data indicated a 2.4-fold increased risk of preeclampsia for users of contraceptives that prevent exposure to sperm. Robillard et al. (1994) were the first to launch a prospective study on the relationship between sperm exposure and preeclampsia; 1011 consecutive women delivering in one obstetric unit were interviewed about paternity and duration of sexual cohabitation before conception. The incidence of pregnancy-induced hypertension was 11.9% among primigravidae, 4.7% among same-paternity multigravidae, and 24.0% among new-paternity multigravidae. For both primigravidae and multigravidae, length of sexual cohabita-
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tion before conception was inversely related to the incidence of pregnancy-induced hypertension (P B0.0001). Taking women cohabiting for more than 12 months as reference, a cohabitation period of 0–4 months was shown to be associated with a typical odds ratio (OR) of 11.6, a period of 5– 8 months with a typical OR of 5.9, and a period of 9–12 months with a typical OR of 4.2. The very high incidence (24.0%) of pregnancy-induced hypertension among new-paternity multiparous women was related to a remarkably short period of sperm exposure preceding conception. More or less in contrast to Robillard’s study, a recent retrospective case-control study (Morcos et al., 2000) in a group of 68 women of mixed parity with pregnancy-induced hypertensive disorders found that for primiparous women a shorter duration of sexual cohabitation was associated with only a small and non-significant reduction in the risk of pregnancy-induced hypertensive disorders. For multiparous women, a greater length of time since ceasing the use barrier contraceptives was associated with a greater risk of pregnancy-induced hypertensive disorders. However, the study of Morcos et al. (2000) has some major problems; (a) a relatively high percentage (20–40% of cases) had a history of a previous abortion, (b) the cases and the controls apparently all had some significant fertility limiting factors. The mean number of months of sexual activity without any birth control was 13.2 and 10.9 months, respectively in the primiparous hypertensive cases and controls, and 49.4 and 27.1 months, respectively in the multiparous hypertensive cases and controls. Koelman et al. (2000) assessed the effects of oral sex and found that, when comparing strictly defined primiparous preeclamptic women with primiparous control women, only 18 out of 41 preeclamptic women (44%) had oral sex with their partner before the index pregnancy versus 36 (82%) out of 44 in the control group (P=0.0003). In addition, 17% out of the 41 preeclamptic patients versus 48% out of the 44 controls patients confirmed that they swallowed the sperm (P=0.003).
2.3. Donated gametes Another circumstance where pregnancy is initiated with no prior exposure to paternal antigens is donor insemination. Need et al. (1983) were the first to report the higher incidence (about two-fold) of preeclampsia in pregnancies after artificial donor insemination. This has since been reported by several investigators Dekker et al. (1998) (review). Hoy et al. (1999) in a large cohort of 1552 donor insemination pregnancies com-
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pared with 7717 normally conceived pregnancies, recently provided solid evidence that donor insemination is definitely a risk factor for preeclampsia. Also, oocyte donation is associated with an increased incidence of preeclampsia. In the largest retrospective analysis (Abdalla et al., 1998) of data from 232 ovum donation pregnancies, it was noted that 23% of all pregnancies were complicated by hypertension. Salha et al. (1999) compared the incidence of preeclampsia in pregnancies conceived after donor insemination versus partner insemination, and also after egg donation and embryo donation. In this study 72 were infertility patients who had conceived as a result of sperm, ovum or embryo donation and the other 72 women were age- and parity matched controls who became pregnant with their own gametes, either spontaneously, or following intra-uterine insemination with their partner’s spermatozoa. The overall incidence of preeclampsia in the donated gametes study group was 18.1 versus 1.4% in the age- and parity-matched controls. The incidence of preeclampsia in pregnancies resulting from donated spermatozoa was 18.2% compared with 0% in the age- and parity-matched partner insemination group. The incidence of preeclampsia resulting from ovum donation was also significantly higher at 16% compared with 3.7% in the age- and parity-matched control group. Four out of the 12 (33.3%) women who conceived with donated embryos developed hypertension compared with none of their age- and parity-matched controls.
2.4. Dangerous partner Recent data also provide evidence for the existence of the so-called ‘dangerous’ father. Lie et al. (1998) recently published data based on the complete Norwegian population (1967–1992; about 60 000 births a year). Lie et al. (1998) identified 363 758 pairs of first and second pregnancies when the two children had the same mother and father; 14 266 pairs of pregnancies when the children had the same mother but different fathers; and 26 152 pairs where the children had the same father but different mothers. One of the major findings of this study was that men who fathered one preeclamptic pregnancy where nearly twice as likely to father a preeclamptic pregnancy in a different woman (1.8; 95% CI 1.2– 2.6; after adjustment for parity), regardless of whether she had already had a preeclamptic pregnancy or not. Thus mothers had a substantially increased risk in their second pregnancy (2.9%) if they became pregnant by a man who had fathered a preeclamptic first pregnancy in another woman. This risk was nearly as high as the average risk amongst first pregnancies.
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3. Potential mechanisms underlying seminal effects Deposition of semen in the female genital tract provokes a cascade of cellular and molecular events that resemble a classic inflammatory response. The critical seminal factor appears to be seminal vesicle derived transforming growth factor b1 (TGFb1). Seminal vesicle-derived TGFb1 is secreted predominantly in a latent form. Seminal plasmin and uterine factors transform the latent form into bioactive TGFb1 (Tremellen et al., 1998). Intra-uterine insemination of TGFb1 in-vivo results in an increase in granulocyte-monocyte colony stimulating factor (GM-CSF) production that is sufficient to initiate an endometrial leukocytosis comparable with that seen following mating (Robertson, 2002). The introduction of TGFb1 into the uterus in combination with paternal ejaculate antigens favours the growth and survival of the semi-allogenic fetus, as evidenced by a significant increase in fetal and placental weight in animal studies, in two ways. Firstly, by initiating a post-mating inflammatory reaction, TGFb1 increases the ability to sample and process paternal antigens contained within the ejaculate. Another important role of TGFb1 and the subsequent post-coital inflammatory response is the initiation of a strong Type 2 immune deviation. The processing of an antigen by APCs in an environment containing TGFb1 is likely to initiate a Th2 phenotype within these responding T-cells (Robertson, 2002). By initiating a Type 2 immune response towards paternal ejaculate antigens, seminal TGFb1 may inhibit the induction of Type 1 responses against the semi-allogenic conceptus that are thought to be associated with poor placental development and fetal. Decidual macrophages, present in an immune-suppressive phenotype from the moment of implantation, may inhibit NK cell lytic activity through their release of molecules such as TGFb, Interleukin-10 (IL-10) and prostaglandin-E2 (PGE2). Under the influence of the local cytokine environment, antigen-presenting cells (APCs) such as macrophages and dendritic cells may take up, process and present ejaculate antigens (sperm, somatic cells, and soluble antigens) to T cells in the draining lymph nodes loss (Tremellen et al., 1998; Robertson, 2002).
3.1. Sperm cell or seminal plasma The exact way by which the female organism is exposed to the paternal HLA message is uncertain. Koelman et al. (2000) demonstrated the presence of soluble class I HLA molecules in seminal plasma representing a potential straightforward way of endometrial exposition. Interestingly, soluble HLA molecules have also been demonstrated to induce apoptosis in human cytotoxic T cells (Zavazava and Kronke, 1996), and induction of apoptosis
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may be mechanism in inducing specific tolerance against HLA molecules of the male partner. According to Clark (1993) the genital tract has unusual T cells with g/d rather than a/b type receptors for antigen, and he suggested that these T cells respond to antigens in the vagina and uterus without the usual requirement for simultaneous binding of these antigens to an HLA-A, -B, -C, or -D type antigen on the APC. Such a mechanims would pave the way to recognition of human trophoblast lacking classical HLA surface antigens (Clark, 1993). Data of Smith et al. (1997) suggest that the protective factor is on the spermatozoa and not in the seminal fluid. Sperm cells do not express HLA. HLA-G is certainly not involved here, since human sperm cells do not have mRNA for HLA-G (Hiby et al., 1999). The induction of alloantibodies by pregnancy indicates that the maternal immune system is confronted with paternal HLA-A and -B antigens of the child. It might well be that the tolerance originally induced by soluble HLA-A and -B antigens or translated sperm mRNA encoding for paternal HLA spreads to epitopes of non-classical HLA antigens expressed on the trophoblast (Yang et al., 1999). A generally accepted phenomenon in inflammation, a pregnancy characteristic (Redman et al., 1999) is an increased expression of classical HLA-antigens. For this reason, immune responses to classical HLA class I molecules can not be excluded in the occurrence of preeclampsia.
4. Evolutionary perspective The observation of an inverse relationship between the duration of sexual cohabitation and the incidence of preeclampsia suggests that long-term sperm exposure may be important for human implantation success. This makes physiological sense since the human female is one of the few mammals exposed to her partner’s semen on multiple occasions prior to conception. From an evolutionary perspective, it can be argued that induction of paternal antigen tolerance through repeated sperm exposure may have reproductive advantages, perhaps by promoting implantation and survival of embryos conceived in long-term relationships where it could be argued that the male parent may be more committed to the well-being of the resultant child. In terms of evolution the relatively high incidence of preeclampsia represents a significant reproductive disadvantage in humans as compared with other mammals. During all human history, in developing countries nowadays and until the 1950s in developed countries, eclampsia accounted for at least 1% of human births (Robillard et al., 2002).
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Many authors think that, because of its high incidence, the disease might hide an adaptive advantage somewhere. This may be true for the increase in blood pressure per se, since the increased maternal systemic blood pressure will increase perfusion pressure (Dadelszen von et al., 2000). However, overall the clinical syndrome preeclampsia-eclampsia means that mankind had to adapt to a tremendous reproductive burden. The major difference between the human embryo and their mammal counterparts is the size of its brain requiring about 60% of total fetal nutritional needs during the extraordinary phase of brain development in the second and third trimester of pregnancy (Martin, 1996). According to Robillard et al. (2002) the large size of the human fetal brain requires the deep endovascular trophoblast invasion that can only occur on the basis of major immunogenetic compromises in terms of maternal-paternal tissue tolerance. Robillard et al. (2002) recently hypothesised that the low fecundability rate and loss of oestrus represent the price mankind had to pay for allowing the large size human brain, the required deep endovascular trophoblast invasion and at the same time an acceptably low incidence of preeclampsia. The human female has a very low fecundability rate, 25% at the age of maximum fecundity. In mathematical models on populations, demographers use a mean interval of 7– 8 months after constitutions of couples (without contraception). Being very fertile in a first pregnancy can be considered to be a disadvantage with respect to the high associated preeclampsia risk. According to Robillard et al. (2002), a fecundability rate of 25% observed in the human species is the best compromise between the preeclampsia risk without threatening fertility for additional pregnancies (multiparity) with the same partner.
4.1. Parental HLA sharing Parental sharing of human leukocyte antigens (HLA) may be associated with adverse pregnancy outcome (Ober, 1998). Although still not well understood, maternal immune tolerance is probably initiated by fetal (paternal) immunologic stimulation. Parental HLA sharing may result in a lack of adequate antigenic stimulation and a failure to establish immune tolerance which could lead to a series of adverse pregnancy outcomes ranging from infertility, recurrent spontaneous abortions, and IUGR. The strongest evidence derives from the association between paternal HLA sharing and recurrent spontaneous abortion. IUGR pregnancies are also associated with a greater-than-expected degree of parental HLA sharing. HLA-incompatible fetuses are known to be at an advantage in human pregnancy (Ober, 1998). Parental HLA sharing has also been hypothesised to be a potential
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underlying mechanism for preeclampsia. However, only a limited number of studies have examined this hypothesis, and results are not consistent. Li and Wi (2000) study was also based on the assumption that women with preeclampsia have a high likelihood of sharing HLA antigens with their partners. In a couple without HLA sharing, a prior successful pregnancy should prove enough protection against the risk of preeclampsia in a future pregnancy fathered by the same partner. Therefore, when a parous women changes partners, the protective effect offered by the previous pregnancies no longer exists; thus her risk of preeclampsia in a pregnancy fathered by a new partner is higher than that of a woman who remains with the same partner. The reported increased risk of preeclampsia associated with changing partners in many other studies may have reflected this phenomenon among women without parental HLA sharing because they comprised the majority of those study populations. On the contrary, if a woman had prior preeclampsia, thus indicating her sharing of HLA antigens with her current partner, her ability to establish the protective immune tolerance would be limited due to lack of immunologic stimulation resulting from HLA sharing. Changing a partner, which likely results in less HLA sharing, would reduce the risk of preeclampsia because of the enhanced immunologic stimulation from the fetus fathered by the new partner. Similar findings were reported by Lie et al. (1998). In this Norwegian study (Lie et al., 1998), the risk to develop preeclampsia was 1.7% among second pregnancies in mothers with a history of a normotensive first pregnancy, who had their second pregnancy with the same partner. Mothers who had preeclampsia in the first pregnancy had a risk of 13.1% if she had her second pregnancy with the same partner. This risk dropped to 11.8% if she changed the partner. An alternative and/or additional explanation for the observed effect of changing partners on the risk of preeclampsia in the subsequent pregnancy would be paternally related factors, genetic or otherwise. In other words, a relatively small percentage of men in the general population may carry a higher risk of fathering a pregnancy with preeclampsia. The Norwegian data (Lie et al., 1998) clearly show the pure impact of the partner, since men who fathered one preeclamptic pregnancy where nearly twice as likely to father a preeclamptic pregnancy in a different woman (1.8; 95% CI 1.2–2.6; after adjustment for parity), regardless of whether she had already had a preeclamptic pregnancy or not. Paternal factors could be thus include the degree of HLA sharing, specific genetic risk factors, and or some sustained male sexual preferences such as having oral sex. Seminal factors such as the level of soluble HLA, TGFb1, and plasmin might well be characteristics completely under genetic control. For example some HLA class I types are associated with low or
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high levels of soluble HLA levels in seminal plasma (Koelman et al., 2000).
4.2. Maternal factors It is important to keep in mind that the paternal factor is not the only determinant of preeclampsia. Also Li and Wi (2000) data show that maternal factors are definitely strongly involved. If a paternal factor were the sole determinant of preeclampsia, one would have expected the risk to be similar among women who changed partners (assuming random mating), regardless of their history of preeclampsia. However, after changing partners, the risk of preeclampsia was still much higher amongst women in with a history of preeclampsia (6.4%) than among women without such a history (0.9%) (Li and Wi, 2000). One of the potential mechanisms for this maternal importance could be that a history of preeclampsia is a marker for women who do not respond to fetal (paternal) immune stimulation as strongly as do women without such a history, and thus are less likely, under the same fetal stimulation, to establish the immune tolerance needed for a successful pregnancy. The failure in establishing immune tolerance to protect pregnancy could make women more susceptible to various adverse pregnancy outcomes, including preeclampsia. Poor responses to paternal immune stimulation have been reported among women with recurrent spontaneous abortions. Therefore, a history of preeclampsia may be a marker for identifying those women who have reduced capacity of reproductive immune responses, and thus are at a higher risk of preeclampsia. Other maternal reasons for being inefficient in mounting an immune tolerance response might be a certain sustained maternal sexual preference- e.g. not having oral sex, or having a limited length of sexual cohabitation with new partner before conceiving. The latter phenomenon was demonstrated to be present in Robillard et al.’s (Robillard et al., 1993, 1994) studies in multiparous preeclamptic patients.
5. Summary In summary, the protective effect of sperm exposure, the higher incidence after donor insemination and oocyte donation and the paternal factor strongly support the immune/immunogenetic maladaptation hypothesis. Obviously, the etiology of preeclampsia cannot be completely explained by the immune maladaptation hypothesis. The other side of the equation is the way the maternal cardiovascular system, and more specific
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the endothelium, is coping with the exaggerated inflammatory response. Factors having a significant negative impact on the coping capacity of the endothelium include: (1) age, (2) chronic hypertension, (3) thrombophilic disorders, (4) the homocysteine level, (5) obesity, (6) insulin resistance/hyperinsulinemia, and (7) type I diabetes (Dekker and Sibai, 1998). Apparently a marked degree of ‘benign’ inflammation is characteristic of normal pregnancy. Although the exact mechanisms still have to be elucidated it is tempting to consider that this degree of inflammation is one of the triggering or signalling factors required initiating systemic vasodilatation. Immune maladaptation in preeclampsia may relate to both a shallow placentation and an exaggerated systemic inflammatory response. The exaggerated inflammatory response and its subsequent endothelial cell activation, may be initiated by the fetus in order to trigger a maternal response (increased systemic blood pressure) that is intrinsically beneficial to the fetus. Mother nature is mild, and if you are a young and healthy woman the end results will be good for mother and baby. However, if you happen to have significant underlying risk factor and/or the immune stimulus is just too strong you will develop ‘bad’ preeclampsia associated with a very poor outcome. Potential new approaches to be explored that could effective in preventing preeclampsia include: (1) pharmacological agents and/or dietary supplements to modify the Type 1/Type 2 cytokine balance; (2) radical scavengers; (3) promoting longer sexual relationships as pre-pregnancy advice and/or alternate ways of sperm exposure, and (4) boosting the initial post-coital inflammatory response. Preeclampsia is an extremely complex multifactorial disorder. In the coming years the most significant progress will be made when we finally understand the immunologic/molecular genetic mechanisms involved in the partner-specific post-coital tolerance, the identification of (probably a long list) susceptibility genes, and unravelling the endothelial consequences of insulin resistance and obesity.
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