Placenta
Volume 31, Supplement , Pages S47-S53, March 2010

IFPA Award in Placentology Lecture: Complicated interactions between genes and the environment in placentation, pregnancy outcome and long term health

  • C.T. Roberts

      Affiliations

    • Corresponding Author InformationTel.: +61 8 83033118; fax: +61 8 83034099.

Robinson Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia 5005, Australia

Accepted 4 January 2010. published online 25 January 2010.

Article Outline

Abstract 

Most research on the developmental origins of health and disease has implicated poor nutrition in the fetus, most often conferred by deficiencies in maternal nutrition, as an important causal factor that programmes offspring physiology for adult disease. Emerging evidence implicates interactions between genes and the environment that may help to explain why poor growth before birth is associated with a variety of adult onset diseases that appear in different individuals of the same birthweight. However, it is underappreciated that the placenta, particularly trophoblast invasion, is key to health of both the mother and child in both the short and long term and that the role of the father is more important than perhaps ever expected. Intrauterine growth restriction (IUGR) is but one of a continuum of several pregnancy complications that may be related and that may reflect the long term health of both parents and offspring. These include preeclampsia, pre-term birth and gestational diabetes, as well as IUGR. Polymorphisms in genes that regulate how the placenta invades maternal tissues, differentiates and functions and how the mother adapts to pregnancy have been identified as candidates that confer risk to pregnancy success. Potentially, pregnancy provides a window that gives clues to modifiable risk factors that should be addressed early to ameliorate late adult disease. Placentation and trophoblast invasion and its inhibitors in other species may provide new ideas for understanding what goes wrong in human pregnancy. Placentologists and clinicians may usefully collaborate to identify factors that predict risk for pregnancy complications and poor health later in life.

Keywords: Trophoblast, Pregnancy complications, Preeclampsia, IUGR

 

Back to Article Outline

1. Introduction 

Pregnancy is somewhat of a paradox. Although physiological, it is a prothrombotic, inflammatory, insulin resistant state that places huge demands on the mother's cardiovascular, renal and hepatic functions. Despite this, the global population reflects the overall success of human pregnancy. However, a continuum of complications affect pregnant women, perhaps more commonly than in other species, in which defective placentation, particularly impaired trophoblast invasion, is a predisposing factor. Indeed pregnancy and childbirth could be considered the most dangerous times in a woman's life and how well the placenta grows may be the key to determining just how dangerous they are. A variety of genetic and environmental factors interact to contribute to adverse outcomes that affect the health of both mother and child in the short and long term. Genetic factors may also provide links between health in pregnancy and health of the father.

Back to Article Outline

2. Trophoblast invasion and pregnancy success 

Impaired trophoblast invasion has been implicated in a continuum of complications of pregnancy such as unexplained miscarriage [1], preeclampsia and intrauterine growth restriction (IUGR) [2], placental abruption [3], pre-term labour with intact membranes [4], premature rupture of the membranes [5] and stillbirth [6]. In preeclampsia and some miscarriages, for example, invasion of the spiral arterioles and the maternal decidual stroma is shallow and assumed to result in poor maternal blood flow to the placenta [1]. Recently, blood flow in the uterine spiral arteries when insufficient transformation occurs has been modelled [7]. The poorly remodelled spiral artery fails to undergo the five-fold dilation that occurs in normal pregnancy and consequently blood flow is not slowed (from 1–2 m/sec to 10 cm/sec) as it enters the intervillous space and the fast turbulent flow causes significant damage to the placental villi [7]. The resultant damage may secondarily reduce oxygen and nutrient delivery to the fetus compromising its growth [7]. Furthermore, concomitantly, ischaemia-reperfusion injury may follow inappropriate vasoconstriction of untransformed arteries, increasing oxidative stress and syncytiotrophoblast shedding and then maternal systemic vascular inflammation which are important features of preeclampsia [7], [8].

The placenta in pregnancies afflicted by IUGR has poor villous growth and development with impaired vasculogenesis [9] and a small surface area of syncytiotrophoblast for exchange [10]. Reports on structure of the preeclamptic placenta indicate either no change [9] or poor villous development [11] compared to normal placenta. However, the pregnancies studied by Teasdale et al. were complicated by both preeclampsia and IUGR. This has been resolved by studies designed to distinguish effects of preeclampsia, IUGR and the combination of the two. IUGR appears to associate with more profound changes to placental structure than preeclampsia but the reduced villous volumes observed in preeclamptic placenta in one study are likely to be due to the earlier [12] onset of the disease in cases studied than those in another study that did not find any differences in the preeclamptic placenta compared to those from uncomplicated pregnancies [13]. This may indicate that early onset preeclampsia is indeed a placental disease while that occurring in late pregnancy may be a maternal syndrome only.

The causes of poor trophoblast invasion have been elusive but a number of growth factors and cytokines have been shown to promote trophoblast invasion in vitro and which are localised to extravillous cytotrophoblasts and/or decidua in vivo. The best described are insulin-like growth factor (IGF)-II and heparin binding epidermal growth factor (HB-EGF). IGF-II is thought to stimulate trophoblast invasion in vitro [14], [15] and is abundantly expressed by extravillous cytotrophoblasts at the invasive front [16]. IGF-II is a highly conserved molecule between species and appears to play a role in placentation in a variety of mammalian species [17]. In the mouse, IGF-II is abundantly expressed by the early post-implantation embryo and trophoblasts of the ectoplacental cone, with abundant expression in invading trophoblast giant cells, as well as decidual cells and vasculature suggesting roles in embryogenesis, placentation and decidual development [18]. Furthermore, ablation of the IGF2 gene in mice reduces the number of glycogen cells, the population of trophoblasts that leave the placental junctional zone and invade the decidua in mid-late gestation in the mouse [19].

HB-EGF has also been shown to stimulate trophoblast invasion in vitro and is expressed in both villous and extravillous cytotrophoblasts in first trimester human placenta [20]. In addition, receptors for HB-EGF are present in first trimester placenta [20] and HB-EGF is less abundant in both placental villi and basal plate in placentas from preeclamptic pregnancies compared to those from gestational age matched pre-term and small for gestational age pregnancies [21].

A number of factors have been found to inhibit trophoblast invasion, some of which are expressed by extravillous cytotrophoblasts but which are most abundant in the decidua. Transforming growth factor (TGF) β1 is the best described and has been shown to inhibit invasion by reducing urokinase plasminogen activator (uPA), increasing tissue inhibitor of metalloproteases (TIMP)-1 expression and altering the integrin profile on the cell surface [22]. For detailed reviews of molecular mechanisms in trophoblast invasion see Ferretti et al. [23] and Fitzgerald et al. [24].

Back to Article Outline

3. The maternal immune response and pregnancy success 

That pregnancy is an inflammatory state is without question [25]. However, the cause of the excessive inflammatory response in pregnancy complications, particularly preeclampsia, is under intense debate. Normal pregnancy requires the tolerance of foreign (paternal) antigens expressed by the fetus and placenta. Recent research suggests that this may be mediated by immune deviating cytokines inducing appropriate numbers of T regulatory (Treg) cells with immunosuppressive activity. This is described elsewhere in this issue but for a comprehensive review see Guerin et al. [26].

Appropriate levels of immune tolerance in women are thought to be elicited by pre-pregnancy exposure to partner specific antigens delivered at sexual intercourse [27]. Certainly short periods of sexual cohabitation before pregnancy are associated with higher rates of preeclampsia and small for gestational age babies with abnormal uterine artery Doppler at 20 weeks gestation (SGA) which are greatest in pregnancies in which conception occurred on the first sexual encounter (OR 5.75 for PE and OR 8.02 for SGA) [28].

There are those who believe that T cells may not be involved significantly in human pregnancy but that this is more a feature of murine pregnancy. Rather the role of NK cells in interacting with trophoblasts in the decidua and the maternal circulation have been demonstrated in both mice and women. NK cells appear to be involved in spiral arteriole remodelling in early pregnancy and a strong response to trophoblasts may stimulate optimal implantation and placentation [29]. The cytokine profile of NK cells in the decidua in early pregnancy and the maternal circulation later, especially secretion of IFNγ in response to deported syncytiotrophoblast microparticles, may be the pivot point between normal and excessive inflammation [29].

In addition, polymorphisms in the KIR genes which encode NK cell receptors interacting with HLA-C polymorphisms in the fetus (placenta), and obviously of paternal origin, have been associated with preeclampsia [30] and potentially affect molecular interactions between NK cells and invading trophoblasts. Thus the maternal immune response to pregnancy may have great importance in determining the quality of placentation and hence pregnancy success.

Back to Article Outline

4. Health in pregnancy predicts health of the offspring 

The fetal origins, and now developmental origins, of health and disease hypothesis asserts that pre-natal and early postnatal life exposures are critical in determining adult health because they are said to program organ function for life [31]. There is substantial evidence to support this with maternal nutrition a key variable in determining the level of nutrition ultimately transferred to the fetus [31]. Indeed maternal nutrition strongly influences the structural differentiation of the placenta and hence its capacity to transport nutrients to, and eliminate wastes from, the fetal circulation [32]. This is not simply a consequence of low nutrient intake equating to low nutrient transfer. The differentiation of the placenta is altered by maternal undernutrition. In our guinea pig studies in which maternal global nutrition was limited, both the fetus and placenta were growth restricted and placental differentiation was impaired [32] and associated with reductions in circulating IGF-I and -II in the mother [33], [34]. Hence, growth factors that modulate placental development and which are regulated by nutrition may affect the placenta's capacity to transfer the limited substrates available. Indeed, the IGFs, and IGF-I in particular, have been shown by many in vitro studies to promote placental transport and enhance System A amino acid transport [35].

Placental transport capacity in human IUGR has been well studied. IUGR is accompanied by reduced activity of amino acid transporters, particularly Systems A, L, TAUT and Y+ transporters. Alterations in the pattern of expression of nutrient transporters were demonstrated to precede fetal growth restriction. For a comprehensive review of placental nutrient transport see Jones et al. [35].

Abundant evidence suggests that size at birth is an important predictor of adult health. Large cohort studies indicate that the growth restricted infant is at risk of developing a variety of adult onset diseases including cardiovascular disease, hypertension, type 2 diabetes and obesity [36] and that particular patterns of growth of both the placenta and fetus may explain which of these is the more likely outcome [31]. Furthermore, in a large Finnish cohort, size at birth appeared to be a predictor of premature death in men and all cause mortality in women [37]. That the placenta is key to this variation is exemplified by the finding in a Norwegian cohort that a relatively large placental weight to birthweight ratio is associated with death from cardiovascular disease, particularly from stroke [38].

Furthermore, the size and shape of the placenta, which has been suggested to reflect patterns of growth in response to the uterine environment, associate with different adult health outcomes in male and female offspring [39]. Differences in late onset disease risk between men and women suggest sex differences in response to an adverse intrauterine environment which may occur within both the fetus and placenta. These are discussed elsewhere in this issue.

Recently, three-dimensional modelling of placental shape and its vasculature have shown that the variability in shape is associated with differences in the branching structure of the vascular tree [40]. Irregular placentas such as those that are star shaped indicate perturbations in vascular branching, presumably induced by various stressors to which the placenta responds, that are reflected in reduced birth to placental weight ratio, a measure of placental functional efficiency [40].

Moreover, placental shape is generally oval to round. The circumferential expansion of the placenta is thought to occur as the result of trophoblast invasion of increasing numbers of spiral arterioles in the decidua. It appears from studies on the size, surface area and shape of the term placenta, that this expansion is aberrant in preeclampsia where the placenta is thicker and more oval with greater attenuation of the lesser placental diameter resulting in a reduced surface area of the placental disc [41]. Further debate on this concept implicating placental shape is to be expected.

It should be acknowledged that although there are many advocates of the developmental origins of health and disease hypothesis, it also has its detractors. For early discussion of the validity of the hypothesis and the need for systematic studies to refute it as consistent with good scientific method see Paneth [42] and Paneth and Susser [43]. It may be that the hypothesis does not hold for twins [44]. The hypothesis does not deny the role of lifestyle modifications in adult life that may modulate risk for late onset disease but provides potential mechanisms by which the intrauterine environment can program risk, particularly in animal studies designed to test it.

It is underappreciated that pregnancy complications other than IUGR are also associated with poor health in progeny. Preeclampsia predisposes offspring to stroke in adulthood [45] while babies born pre-term are more likely to be insulin resistant aged 4–10 years irrespective of whether they had been small for gestational age or not [46]. Although it is well known that gestational diabetes is associated with type 2 diabetes in offspring, they are also at increased risk of developing obesity, endothelial dysfunction and hypertension later in life [47].

Back to Article Outline

5. Health in pregnancy predicts health of the parents 

It is becoming increasingly clear that the placenta is an important mediator of maternal health, as well as that of the fetus. The placenta is not merely a conduit for exchange of nutrients, oxygen and wastes between the maternal and fetal circulations. It secretes abundant hormones and growth factors into the maternal circulation that modify maternal adaptation to pregnancy and thereby, placental health, both dependent and independent of trophoblast invasion, in part determines that of the pregnant mother. However, later adult health of the mother may also be a reflection of her health in pregnancy.

Women who suffer preeclampsia are more likely to develop hypertension and ischaemic heart disease in later life than those who did not [48] while the odds of a woman afflicted by preeclampsia later suffering a stroke by age 44 is about 1.6 [49]. Similarly, it is well known that women afflicted by gestational diabetes are more likely to develop type 2 diabetes later.

Of considerable interest is the inverse association between progeny birthweight and all cause mortality in both parents [50], [51]. Increasing birthweight corrected for gestational age reduced risk of premature death from cardiovascular disease, particularly coronary heart disease and stroke, alcohol related disease and cancer, particularly lung cancer in both mothers and fathers [50]. Gestational age of offspring at delivery was similarly associated with all cause mortality in mothers only [50]. These suggest that genetic factors in men and women that affect fetal growth may also predispose to adult onset disease.

Back to Article Outline

6. Heritability of pregnancy complications 

Both men and women who were themselves small for gestational age (SGA) are more likely to parent an SGA infant with the effect stronger in women than men [52]. Women who were themselves SGA at birth also have a higher risk of developing preeclampsia when they become pregnant [53] suggesting genetic links between the two complications. Indeed about one quarter of pregnancies complicated by preeclampsia are also complicated by SGA [54]. Furthermore, women with type 1 diabetes prior to pregnancy are four times more likely to develop preeclampsia than those without diabetes [55]. Since both diseases are characterised by inflammation this is perhaps not surprising. Inflammation also causes both insulin resistance and endothelial dysfunction and all three are characteristic of preeclampsia [25].

Paternal genes are thought to contribute to preeclampsia because the risk of preeclampsia increases in women who become pregnant to men who have previously fathered a preeclamptic pregnancy in another woman [56]. Although women whose half-sisters have suffered preeclampsia have an increased risk of developing preeclampsia themselves when they share the same mother, that risk is higher if they share the same father [56]. Furthermore, both men and women who were the product of a preeclamptic pregnancy are more likely to parent a preeclamptic pregnancy [57].

Back to Article Outline

7. Genetic factors that modulate pregnancy success 

Intense efforts around the world are directed at identifying genetic polymorphisms that associate with pregnancy complications. Most studies focus on the mother and some also on the fetus with the rationale that the fetal genome is identical to that of the placenta. Few have determined paternal genotypes that may confer risk for adverse pregnancy outcomes.

Paternal genes (imprinted genes expressed only from the paternal allele) drive placental invasion and growth and maternal genes (those expressed only from the maternal allele) inhibit it and are said to be in conflict [58]. Maternal genes determine how the mother adapts and responds to pregnancy, how her cardiovascular, renal and hepatic tissues accommodate the increased demands of pregnancy and how her immune system responds to the allogeneic conceptus. Fetal genes have been proposed to affect maternal physiology to adversely affect maternal health [59]. Fetal genes, by implication, are the unique combination of paternal and maternal genes. Hormones, growth factors and cytokines are secreted by the placenta into the maternal circulation and modulate maternal adaptation to pregnancy. Since one copy of each gene is inherited from the father and one from the mother, placental and fetal expression of non-imprinted genes can also be influenced by paternal genotype.

The modulating effect of paternal genotype on maternal and fetal health has been demonstrated in mice in which the male had a human renin transgene while the female had a human angiotensinogen trans gene. In these matings, expression of the human renin transgene was localised to the placenta [60] and shown to be secreted into the maternal circulation where the human angiotensinogen was activated and late pregnancy hypertension, proteinuria and fetal growth restriction ensued [60], [61]. Hence, by contributing one copy of each gene to the placenta, paternal genotype may influence placental development and function, and thereby fetal growth, but also maternal adaptation to pregnancy and hence maternal health (Fig. 1).

  • View full-size image.
  • Fig. 1 

    Complex interactions of maternal and paternal genes with lifestyle and dietary factors contribute to pregnancy success. Maternal and paternal genes influence the health of the gametes and early embryo. The unique conceptus genome is a combination of maternal and paternal genes and influences the development of both the fetus and placenta. Placental gene expression affects its invasive and functional capacities and thereby the growth and health of the fetus. Placental secreted factors can also influence the quality of maternal adaptation to pregnancy and hence the health of both mother and baby. The fetus may also signal to the placenta and to the mother to modulate their physiology (teleologically speaking) in attempts to match supply and demand although the evidence for this is newly emerging indicated by the dotted lines. Genes also interact with maternal dietary and lifestyle factors which are potentially modifiable. Particular nutrient deficiencies and use and abuse of social and illicit drugs may interact more severely in association with specific genotypes.

Potentially, particular genotypes that confer risk for SGA also affect parental physical characteristics. Previous research has demonstrated common variants in genes associated with both obesity and type 2 diabetes and with low birthweight [62]. Furthermore, low birthweight increases risk for obesity and the related coronary heart disease, hypertension and type 2 diabetes [36].

A good candidate gene for these effects is the paternally expressed imprinted IGF2 gene. Low circulating IGF-II concentrations have been shown to predict weight gain and obesity in humans in some studies [63]. Furthermore, polymorphisms in the insulin (INS) and IGF-II (IGF2) genes which are adjacent to each other in an imprinting cluster on chromosome 11 have been associated with SGA [62] and with obesity and low circulating IGF-II [64]. INS is associated with placental IGF2 expression [65]. Other genes appear to include those involved in angiogenesis, inflammation, diabetes, obesity and thrombosis.

Placentologists are contributing to this research by identifying genes that when ablated in mice produce a placental phenotype. Quite a number of such genes have been identified and have different effects in different placental cell populations at different times in gestation. Some are embryo lethal but some have more subtle effects on placental differentiation and function. For a detailed review of these see Cross et al. 2003 [66].

Back to Article Outline

8. The interaction of genes and the environment predict outcomes 

Although many functional polymorphisms have been identified in genes relevant to placentation and maternal adaptation to pregnancy, the regulation of gene products by other factors such as nutrition should also be considered in the context of pregnancy (Fig. 1). For example, as discussed earlier, both IGF-I and –II are regulated by nutrition. The effect of undernutrition may be more severe if a functional polymorphism that reduces either circulating or placental IGF-II levels is also present in the mother or fetus. An example of this sort of interaction in which certain exposures need to be present for adverse genotypes in certain genes to have an effect has been established with respect to maternal smoking and polymorphisms in two detoxifying genes, CYP1A1 and GSTT1 [67]. Irrespective of maternal genotype, birthweight was reduced by 377 g in babies of women who smoked during pregnancy [67]. Women who smoked and who also had the CYP1A1 Aa/aa genotype delivered babies who were 520 g lighter while those from women with a GSTT1 null genotype who smoked were 642 g lighter than babies born to women who did not smoke [67]. Smokers who had both polymorphisms delivered babies who were 1250 g lighter than those born to non-smoking mothers. These polymorphisms had no effect on birthweight for non-smokers [67].

It is self evident that maternal malnutrition will compromise fetal growth because of frank nutrient deficiency as demonstrated by high rates of IUGR in developing nations. For example, in India 30% of babies are born with low birthweight [68]. In developed nations undernutrition is only a problem in women with eating disorders and certainly there is evidence of increased risk for low birthweight babies in these women [69]. However, it could be argued that obese women, although overnourished with respect to kilojoules, may be deficient in important micronutrients that may contribute to the increased rate of adverse pregnancy outcomes seen in this increasingly large group of women! Much attention has been given to folate as an important micronutrient in pregnancy to prevent neural tube defects. Folate turnover is increased during pregnancy and the growth of placenta, fetus and maternal tissues increases the requirement for folate in the diet [70]. However, negative effects of folate deficiency on placental function and pregnancy outcome may be exacerbated in women with particular genotypes in genes related to one carbon metabolism [71]. For example, women with polymorphisms in genes involved in folate catabolism such as NAT1 that accelerate this process [70] may benefit from extra folate supplementation to overcome these effects.

Recently, the effect of vitamin D deficiency on placental function and pregnancy outcomes has come to the fore. More than one billion people are deficient in this important secosteroid hormone [72] and deficiency has been associated with preeclampsia [73], gestational diabetes [74] and caesarean section [75]. Vitamin D is synthesised by the placenta and both the activating (CYP27B1) and metabolising (CYP24A1) enzymes, as well as the vitamin D receptor (VDR), are expressed in placenta across gestation [76]. Precise actions of vitamin D at different times in gestation and in different trophoblast populations remain unclear.

Obesity is a well known risk factor for most pregnancy and delivery complications with the exception of pre-term birth in which elevated BMI appears to be protective and where low BMI is a risk factor [77]. This suggests that a certain level of nutrient stores in the mother at conception, perhaps interacting with post conception weight gain, is required to maintain pregnancy. A number of genetic polymorphisms have been associated with BMI that may also independently affect pregnancy outcome. Furthermore, obesity is an inflammatory state and together with the increase in inflammation that is a characteristic of normal pregnancy, being obese may tip the immune balance too far [25].

Other factors such as low socioeconomic status, ethnicity and unknown paternity and short period of sexual cohabitation associate with one or more pregnancy complications. These may reflect poor diet and lifestyle, immune maladaptation to paternal antigens or genetic factors that contribute to poor pregnancy outcomes [54]. Clearly some environmental factors are potentially modifiable and discovery of those that associate with severe effects of genotypes may help to identify women who may most benefit from modifying lifestyle. Furthermore, this may also have longer term positive effects on health in both parents and offspring.

Back to Article Outline

9. Trophoblast invasion and models to study it 

Since impaired trophoblast invasion and defective placentation are thought to predispose to pregnancy complications, placentologists are making major contributions in this field. Trophoblast invasion occurs to greater and lesser degrees in a variety of mammalian species. Those with haemochorial placentas in which the trophoblast has eroded each maternal cell layer between it and the maternal blood in which it is bathed, include humans and many, but not all, primates, rodents, lagomorphs and some bats. One species of bat not only has a haemochorial discoid placenta but undergoes decidualisation with an influx of granulocytes, even in infertile cycles, and also menstruates [78], [79]. Maternal endothelial cells are thought to play a role in controlling trophoblast invasion in this species.

Mice are often used to study trophoblast invasive behaviour and its regulation while the guinea pig, and not the human as suggested by Robillard et al. [80], arguably has the deepest trophoblast invasion of any mammal. Trophoblasts in the guinea pig invade beyond the uterine wall and out almost to the arcade artery 3–4 cm into the mesometrial adipose tissue. The transformation of the mesometrial arteries in pregnancy in this species is extensive and funnelling of the terminal end of the vessels where they enter the intervillous space is reminiscent of that in humans with concomitant reduction in speed and pressure of maternal blood flow proposed [81]. There are old data that suggest that guinea pigs also suffer pregnancy toxaemia [82] which is associated with obesity and can be experimentally induced by restricting maternal blood flow to the placenta resulting in hypertension and proteinuria [83].

A variety of species have endotheliochorial placentation which occurs when trophoblast invasion extends as far as the maternal endothelium [84]. These include carnivores but interestingly a family of marsupials, the Dasyuridae, also have an endotheliochorial arrangement but instead of a chorioallantoic placenta it is choriovitelline [85]. However, the identity of the molecular mechanisms by which the trophoblast stalls at the maternal endothelium is unknown. There may be deficits in trophoblast capacity or the endothelium perhaps secretes an inhibitor.

In ruminants, binucleate trophoblasts migrate and fuse with the maternal epithelium to form a feto-maternal syncytium and are said to form a synepitheliochorial placental arrangement [84]. Trophoblasts do not invade through the maternal epithelial basement membrane but it is unclear as to the molecular mechanisms that prevent it going any further. Other species, for example the pig, have epitheliochorial placentas in which trophoblasts are completely non-invasive and in which the chorion is in intimate contact with the maternal epithelium with considerable attenuation of the intervening cell layers. In some of these there are regional specialisations where a population of trophoblasts are invasive, for example the trophoblast girdle cells (previously called endometrial cup cells) in the horse placenta [84]. Interestingly the epitheliochorial placenta is considered the most derived form and the haemochorial placenta is more ancestral [84].

Of considerable interest is the fact that the porcine trophoblast, which is non-invasive in the uterus, is capable of invasion in ectopic sites. Both trophoblasts and endometrium express uPA and matrix metalloprotease (MMP)-2 and -9 which are associated with invasion in a variety of species, including human, but also abundantly express TIMP-1, -2 and -3 which inhibit proteolytic activity and likely inhibit invasion [86]. Similarly, there is an increasing prevalence of placenta accreta in women, particularly in those who have had previous caesarean sections (G. Dekker, personal communication). This may be because in the region of the scar, the endometrium has been largely ablated and should the placenta in a subsequent pregnancy attach over this site, deficiency of the inhibitory factors in the endometrium may permit excessive trophoblast invasion. This points to potent anti-invasive factors in the decidua that control the extent of trophoblast invasion.

The study of placental development in non-human mammalian species clearly is of interest to comparative placentologists and animal scientists among others because they teach us about evolution and factors that may help in improving placental efficiency and animal production. However, a detailed examination of molecular mechanisms that inhibit trophoblast invasion in species in which it is limited may provide useful insights for human pregnancy research by identifying potential targets for diagnostics and therapeutics that may be common to human placenta and decidua and aberrant in abnormal pregnancies. Additionally, a variety of in vitro systems with placental villous explants, trophoblast cell lines and trophoblast decidual co-cultures and ex vivo placental perfusion studies described elsewhere in this issue also provide models with which to elucidate molecular mechanisms in various stages of placental development that may be pertinent to pregnancy complications.

Back to Article Outline

10. Conclusion 

Defective placentation, particularly following poor trophoblast invasion, predisposes to a continuum of pregnancy complications in which genetic and environmental factors may interact to determine the timing and severity of disease. These in turn have long term health consequences in both parents and offspring. Of particular interest is the potential role of paternal genes in influencing placental gene expression, invasion and function as well as maternal adaptation to pregnancy and thereby fetal and maternal health. Therefore research in this field has the potential to impact on public health in general. Potentially modifiable risk factors may be identified that impact lifelong health. Although we know there are a variety of genetic and environmental risk factors for pregnancy complications there is no system to date that puts these together into a framework for risk prediction even for preeclampsia which arguably has been the best studied [55]. Highly detailed data collection is required in large cohorts. Selection of factors that confer risk may be provided by knowledge gained by placentologists in collaboration with clinicians. Sophisticated data analyses may then provide an effective diagnostic tool to predict couples at risk. Importantly, they may also provide potential therapeutic targets that could be employed early in gestation in couples at risk to prevent or ameliorate pregnancy complications. These may provide knowledge that can be translated to other late onset diseases that are becoming an increasing burden on health care systems around the world.

Back to Article Outline

Acknowledgements 

The author gratefully acknowledges financial support from the National Health and Medical Research Council, Australia, the Premier's Science and Research Fund, South Australia and the Channel 7 Children's Research Foundation, South Australia for her research.

Back to Article Outline

Conflicts of interest 

The authors do not have any potential or actual personal, political, or financial interest in the material, information, or techniques described in this paper.

Back to Article Outline

References 

  1. Khong TY, Liddell HS, Robertson WB. Defective haemochorial placentation as a cause of miscarriage: a preliminary study. Br J Obstet Gynaecol. 1987;94:649–655
  2. Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol. 1986;93:1049–1059
  3. Dommisse J, Tiltman AJ. Placental bed biopsies in placental abruption. Br J Obstet Gynaecol. 1992;99:651–654
  4. Kim YM, Bujold E, Chaiworapongsa T, Gomez R, Yoon BH, Thaler HT, et al. Failure of physiologic transformation of the spiral arteries in patients with preterm labor and intact membranes. Am J Obstet Gynecol. 2003;189:1063–1069
  5. Kim YM, Chaiworapongsa T, Gomez R, Bujold E, Yoon BH, Rotmensch S, et al. Failure of physiologic transformation of the spiral arteries in the placental bed in preterm premature rupture of membranes. Am J Obstet Gynecol. 2002;187:1137–1142
  6. Smith GC, Crossley JA, Aitken DA, Pell JP, Cameron AD, Connor JM, et al. First-trimester placentation and the risk of antepartum stillbirth. JAMA. 2004;292:2249–2254
  7. Burton GJ, Woods AW, Jauniaux E, Kingdom JC. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta. 2009;30:473–482
  8. Redman CWG, Sargent IL. Pre-eclampsia, the placenta and the maternal systemic inflammatory response – a review. Placenta. 2003;24:S21–S27
  9. Mayhew TM, Wijesekara J, Baker PN, Ong SS. Morphometric evidence that villous development and fetoplacental angiogenesis are compromised by intrauterine growth restriction but not by pre-eclampsia. Placenta. 2004;25:829–833
  10. Teasdale F, Jean-Jacques G. Intrauterine growth retardation: morphometry of the microvillous membrane of the human placenta. Placenta. 1988;9:47–55
  11. Teasdale F. Histomorphometry of the human placenta in maternal preeclampsia. Am J Obstet Gynecol. 1985;152:25–31
  12. Egbor M, Ansari T, Morris N, Green CJ, Sibbons PD. Pre-eclampsia and fetal growth restriction: how morphometrically different is the placenta?. Placenta. 2006;27:727–734
  13. Mayhew TM, Ohadike C, Baker PN, Crocker IP, Mitchell C, Ong SS. Stereological investigation of placental morphology in pregnancies complicated by pre-eclampsia with and without intrauterine growth restriction. Placenta. 2003;24:219–226
  14. Irving JA, Lala PK. Functional role of cell surface integrins on human trophoblast cell migration: regulation by TGF beta, IGF-II and IGFBP-1. Exp Cell Res. 1995;217:419–427
  15. Hamilton GS, Lysiak JJ, Han VK, Lala PK. Autocrine-paracrine regulation of human trophoblast invasiveness by insulin-like growth factor (IGF)-II and IGF-binding protein (IGFBP)-1. Exp Cell Res. 1998;244:147–156
  16. Han VK, Bassett N, Walton J, Challis JR. The expression of insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) genes in the human placenta and membranes: evidence for IGF-IGFBP interactions at the feto-maternal interface. J Clin Endocrinol Metab. 1996;81:2680–2693
  17. Han VK, Carter AM. Spatial and temporal patterns of expression of messenger RNA for insulin-like growth factors and their binding proteins in the placenta of man and laboratory animals. Placenta. 2000;21:289–305
  18. Pringle KG, Roberts CT. New light on early post-implantation pregnancy in the mouse: roles for insulin-like growth factor-II (IGF-II)?. Placenta. 2007;28:286–297
  19. Lopez MF, Dikkes P, Zurakowski D, Villa-Komaroff L. Insulin-like growth factor II affects the appearance and glycogen content of glycogen cells in the murine placenta. Endocrinology. 1996;137:2100–2108
  20. Leach RE, Kilburn B, Wang J, Liu Z, Romero R, Armant DR. Heparin-binding EGF-like growth factor regulates human extravillous cytotrophoblast development during conversion to the invasive phenotype. Dev Biol. 2004;266:223–237
  21. Leach RE, Romero R, Kim YM, Chaiworapongsa T, Kilburn B, Das SK, et al. Pre-eclampsia and expression of heparin-binding EGF-like growth factor. The Lancet. 2002;360:1215–1219
  22. Irving JA, Lysiak JJ, Graham CH, Hearn S, Han VK, Lala PK. Characteristics of trophoblast cells migrating from first trimester chorionic villus explants and propagated in culture. Placenta. 1995;16:413–433
  23. Ferretti C, Bruni L, Dangles-Marie V, Pecking AP, Bellet D. Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts. Hum Reprod Update. 2007;13:121–141
  24. Fitzgerald JS, Busch S, Wengenmayer T, Foerster K, de la Motte T, Poehlmann TG, et al. Signal transduction in trophoblast invasion. Chem Immunol Allergy. 2005;88:181–199
  25. Redman CW, Sargent IL. Pre-eclampsia, the placenta and the maternal systemic inflammatory response – a review. Placenta. 2003;24(Suppl. A):S21–S27
  26. Guerin LR, Prins JR, Robertson SA. Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment?. Hum Reprod Update. 2009;15:517–535
  27. Robertson SA, Bromfield JJ, Tremellen KP. Seminal ‘priming’ for protection from pre-eclampsia – a unifying hypothesis. J Reprod Immunol. 2003;59:253–265
  28. Kho EM, McCowan LME, North RA, Roberts CT, Chan E, Black MA, et al. Duration of sexual relationship and its effect on preeclampsia and small for gestational age perinatal outcome. J Reprod Immunol. 2009;82:66–73
  29. Sargent IL, Borzychowski AM, Redman CWG. NK cells and human pregnancy – an inflammatory view. Trends Immunol. 2006;27:399–404
  30. Hiby SE, Walker JJ, O'Shaughnessy KM, Redman CWG, Carrington M, Trowsdale J, et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med. 2004;200:957–965
  31. Barker DJP, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS. Fetal nutrition and cardiovascular disease in adult life. Lancet. 1993;341:938–941
  32. Roberts CT, Sohlstrom A, Kind KL, Earl RA, Khong TY, Robinson JS, et al. Maternal food restriction reduces the exchange surface area and increases the barrier thickness of the placenta in the guinea-pig. Placenta. 2001;22:177–185
  33. Roberts CT, Sohlstrom A, Kind KL, Grant PA, Earl RA, Robinson JS, et al. Altered placental structure induced by maternal food restriction in guinea pigs: a role for circulating IGF-II and IGFBP-2 in the mother?. Placenta. 2001;22:S77–S82
  34. Roberts CT, Kind KL, Earl RA, Grant PA, Robinson JS, Sohlstrom A, et al. Circulating insulin-like growth factor (IGF)-I and IGF binding proteins -1 and -3 and placental development in the guinea-pig. Placenta. 2002;23:763–770
  35. Jones HN, Powell TL, Jansson T. Regulation of placental nutrient transport – a review. Placenta. 2007;28:763–774
  36. Barker DJ. The developmental origins of adult disease. J Am Coll Nutr. 2004;23:588S–595S
  37. Kajantie E, Osmond C, Barker DJ, Forsen T, Phillips DI, Eriksson JG. Size at birth as a predictor of mortality in adulthood: a follow-up of 350 000 person-years. Int J Epidemiol. 2005;34:655–663
  38. Risnes KR, Romundstad PR, Nilsen TIL, Eskild A, Vatten LJ. Placental weight relative to birth weight and long-term cardiovascular mortality: findings from a cohort of 31,307 men and women. Am J Epidemiol. 2009;170:622–631
  39. Eriksson JG, Kajantie E, Osmond C, Thornburg K, Barker DJ. Boys live dangerously in the womb. Am J Hum Biol. 2009;
  40. Yampolsky M, Salafia CM, Shlakhter O, Haas D, Eucker B, Thorp J. Modeling the variability of shapes of a human placenta. Placenta. 2008;29:790–797
  41. Kajantie E, Thornburg K, Eriksson JG, Osmond L, Barker DJ. In preeclampsia, the placenta grows slowly along its minor axis. Int J Dev Biol. 2009;
  42. Paneth N. The impressionable fetus? Fetal life and adult health. Am J Public Health. 1994;84:1372–1374
  43. Paneth N, Susser M. Early origin of coronary heart disease (The “Barker hypothesis”): hypotheses, no matter how intriguing, need rigorous attempts at refutation. BMJ. 1995;310:411–412
  44. Williams S, Poulton R. Twins and maternal smoking: ordeals for the fetal origins hypothesis? A cohort study. BMJ. 1999;318:897–900
  45. Kajantie E, Eriksson JG, Osmond C, Thornburg K, Barker DJP. Pre-eclampsia is associated with increased risk of stroke in the adult offspring: the helsinki birth cohort study. Stroke. 2009;40:1176–1180
  46. Hofman PL, Regan F, Jackson WE, Jefferies C, Knight DB, Robinson EM, et al. Premature birth and later insulin resistance. N Engl J Med. 2004;351:2179–2186
  47. Simeoni U, Barker DJ. Offspring of diabetic pregnancy: long-term outcomes. Semin Fetal Neonatal Med. 2009;14:119–124
  48. Bellamy L, Casas J-P, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ. 2007;335:974
  49. Brown DW, Dueker N, Jamieson DJ, Cole JW, Wozniak MA, Stern BJ, et al. Preeclampsia and the risk of ischemic stroke among young women: results from the stroke prevention in young women study. Stroke. 2006;37:1055–1059
  50. Davey Smith G, Sterne J, Tynelius P, Lawlor DA, Rasmussen F. Birth weight of offspring and subsequent cardiovascular mortality of the parents. Epidemiology. 2005;16:563–569
  51. Davey Smith G, Hypponen E, Power C, Lawlor DA. Offspring birth weight and parental mortality: prospective observational study and meta-analysis. Am J Epidemiol. 2007;166:160–169
  52. Jaquet D, Swaminathan S, Alexander GR, Czernichow P, Collin D, Salihu HM, et al. Significant paternal contribution to the risk of small for gestational age. BJOG: Int J Obstetrics Gynaecol. 2005;112:153–159
  53. Zetterstrom K, Lindeberg S, Haglund B, Magnuson A, Hanson U. Being born small for gestational age increases the risk of severe pre-eclampsia. BJOG: Int J Obstetrics Gynaecol. 2007;114:319–324
  54. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. The Lancet. 2005;365:785–799
  55. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ. 2005;330:565
  56. Lie RT, Rasmussen S, Brunborg H, Gjessing HK, Lie-Nielsen E, Irgens LM. Fetal and maternal contributions to risk of pre-eclampsia: population based study. BMJ. 1998;316:1343–1347
  57. Esplin MS, Fausett MB, Fraser A, Kerber R, Mineau G, Carrillo J, et al. Paternal and maternal components of the predisposition to preeclampsia. New Engl J Med. 2001;344:867–872
  58. Haig D. Altercation of generations: genetic conflicts of pregnancy. Am J Reprod Immunol. 1996;35:226–232
  59. Petry CJ, Ong KK, Dunger DB. Does the fetal genotype affect maternal physiology during pregnancy?. Trends Mol Med. 2007;13:414–421
  60. Takimoto-Ohnishi E, Saito T, Ishida J, Ohnishi J, Sugiyama F, Yagami K-I, et al. Differential roles of renin and angiotensinogen in the feto-maternal interface in the development of complications of pregnancy. Mol Endocrinol. 2005;19:1361–1372
  61. Takimoto E, Ishida J, Sugiyama F, Horiguchi H, Murakami K, Fukamizu A. Hypertension induced in pregnant mice by placental renin and maternal angiotensinogen. Science. 1996;274:995–998
  62. Adkins RM, Krushkal J, Klauser CK, Magann EF, Morrison JC, Somes G. Association between small for gestational age and paternally inherited 5′ insulin haplotypes. Int J Obes. 2007;32:372–380
  63. Sandhu MS, Gibson JM, Heald AH, Dunger DB, Wareham NJ. Low circulating IGF-II concentrations predict weight gain and obesity in humans. Diabetes. 2003;52:1403–1408
  64. O'Dell SD, Miller GJ, Cooper JA, Hindmarsh PC, Pringle PJ, Ford H, et al. Apal polymorphism in insulin-like growth factor II (IGF2) gene and weight in middle-aged males. Int J Obes Relat Metab Disord. 1997;21:822–825
  65. Paquette J, Giannoukakis N, Polychronakos C, Vafiadis P, Deal C. The INS 5′ variable number of tandem repeats is associated with IGF2 expression in humans. J Biol Chem. 1998;273:14158–14164
  66. Cross JC, Baczyk D, Dobric N, Hemberger M, Hughes M, Simmons DG, et al. Genes, development and evolution of the placenta. Placenta. 2003;24:123–130
  67. Wang X, Zuckerman B, Pearson C, Kaufman G, Chen C, Wang G, et al. Maternal cigarette smoking, metabolic gene polymorphism, and infant birth weight. JAMA. 2002;287:195–202
  68. Agnihotri B, Antonisamy B, Priya G, Fall CH, Raghupathy P. Trends in human birth weight across two successive generations. Indian J Pediatr. 2008;75:111–117
  69. Conti J, Abraham S, Taylor A. Eating behavior and pregnancy outcome. J Psychosomatic Res. 1998;44:465–477
  70. Suh JR, Herbig AK, Stover PJ. New perspectives on folate catabolism. Annu Rev Nutr. 2001;21:255–282
  71. Furness DLF, Fenech MF, Khong YT, Romero R, Dekker GA. One-carbon metabolism enzyme polymorphisms and uteroplacental insufficiency. Am J Obstet Gynecol. 2008;199:276.e1–276.e8
  72. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–281
  73. Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM. Maternal vitamin D deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab. 2007;92:3517–3522
  74. Zhang C, Qiu C, Hu FB, David RM, van Dam RM, Bralley A, et al. Maternal plasma 25-hydroxyvitamin D concentrations and the risk for gestational diabetes mellitus. PLoS ONE. 2008;3:e3753
  75. Merewood A, Mehta SD, Chen TC, Bauchner H, Holick MF. Association between vitamin D deficiency and primary cesarean section. J Clin Endocrinol Metab. 2009;94:940–945
  76. Zehnder D, Evans KN, Kilby MD, Bulmer JN, Innes BA, Stewart PM, et al. The ontogeny of 25-hydroxyvitamin D(3) 1alpha-hydroxylase expression in human placenta and decidua. Am J Pathol. 2002;161:105–114
  77. Zhong Y, Cahill AG, Macones GA, Zhu F, Odibo AO. The association between prepregnancy maternal body mass index and preterm delivery. Am J Perinatol. 2009;
  78. Rasweiler JJ. Development of the discoidal hemochorial placenta in the black mastiff bat, molossus ater: evidence for a role of maternal endothelial cells in the control of trophoblastic growth. Am J Anat. 1991;191:185–207
  79. Rasweiler JJ. Spontaneous decidual reactions and menstruation in the black mastiff bat, molossus ater. Am J Anat. 1991;191:1–22
  80. Robillard P-Y, Hulsey TC, Dekker GA, Chaouat G. Preeclampsia and human reproduction: an essay of a long term reflection. J Reprod Immunol. 2003;59:93–100
  81. Egund N, Carter AM. Uterine and placental circulation in the guinea-pig: an angiographic study. J Reprod Fertil. 1974;40:401–410
  82. Seidl DC, Hughes HC, Bertolet R, Lang CM. True pregnancy toxemia (preeclampsia) in the guinea pig (Cavia porcellus). Lab Anim Sci. 1979;29:472–478
  83. Golden JG, Hughes HC, Lang CM. Experimental toxemia in the pregnant guinea pig (Cavia porcellus). Lab Anim Sci. 1980;30:174–179
  84. Carter A, Enders A. Comparative aspects of trophoblast development and placentation. Reprod Biol Endocrinol. 2004;2:46
  85. Roberts CT, Breed WG. Embryonic-maternal cell interactions at implantation in the fat-tailed dunnart, a dasyurid marsupial. Anat Rec. 1994;240:59–76
  86. Menino AR, Hogan A, Schultz GA, Novak S, Dixon W, Foxcroft GH. Expression of proteinases and proteinase inhibitors during embryo-uterine contact in the pig. Dev Genet. 1997;21:68–74

PII: S0143-4004(10)00002-0

doi:10.1016/j.placenta.2010.01.001

Placenta
Volume 31, Supplement , Pages S47-S53, March 2010

Article Tools

* Image Usage & Resolution