SectionSection 1 2 Fetal disease: pathogenesis and principles Chapter Intrauterine growth restriction: placental basis and implications for clinical practice 18.1 John Kingdom, Melissa Walker, Sascha Drewlo, and Sarah Keating

Introduction the peripheral terminal villi creates an organ with a substan- tial surface area of capillary exchange of 12.4 m2 at term [3], Advances in obstetrical ultrasound, combined with ancil- weighing just 1/7th that of the newborn. Diffusional exchange lary magnetic resonance imaging and rapid molecular test- between maternal and fetal is optimized by directing ing of amniotic fluid, have greatly improved our diagnostic maternal blood onto the fetally derived epithelial surface of capabilities when assessing the with suspected intra- the villi, the . The invasive extra villous uterine growth restriction (IUGR). Despite these advances, , termed interstitial extravillous several frustrating issues confront clinicians when man- (EVT), fulfil, this role towards the end of the first trimester, aging suspected IUGR as follows. First, an unacceptably shown elegantly using punch biopsies [4]. An earlier step in high false-positive rate for the diagnosis of IUGR in later placental development is however crucial to the attainment of gestation increases unnecessary interventions (induction of normal placental function – and is commonly misunderstood labor and/or cesarean delivery) and iatrogenic morbidity in by clinicians. It makes no sense to direct oxygenated blood to small-for-gestational-age newborns. As an example, 33.4% the developing human embryo because it is highly susceptible of 650 women recruited to the recently published DIGITAT to oxidative stress and lacks oxidative defence mechanisms (Disproportionate Intrauterine Growth Intervention Trial at [5]. How therefore can it develop? The solution, developed Term) trial had no postnatal evidence of IUGR ( weight more obviously in other species, such as the horse, is to feed <10th percentile) [1]. Second, clinician uncertainty regarding the embryo via transformed uterine epithelial glands. This is cause or prognosis for suspected IUGR may trigger frequent known as histiotrophic nutrition (Figure 18.1.2) [6]. To keep short-term tests of fetal well-being (biophysical profile ultra- maternal blood away from the embryo, a subset of endovas- sounds and non-stress tests) even via hospital admission, in cular EVT therefore have an earlier task, which is to occlude the absence of any objective diagnosis. Third, in the absence uterine epithelial capillaries as the conceptus embeds into of a perinatal and placental pathology service, clinicians have the deciduas [7]. This occlusive process also keeps maternal only proxy markers of disease, reflected by performance in blood, and therefore oxygen, away from the developing pla- labor and short-term neonatal morbidity, to audit their centa [8]. As shown in Figure 18.1.3, this capillary occlusion decision-making. A common solution to improving clin- renders the developing placental villi hypoxic – providing a ical practice in IUGR management may therefore be found stimulus for branching to drive growth of the in a reappraisal of the value of placental pathology to guide definitive placental villi ( frondosum) whereas the maternal-fetal medicine and obstetric practice. This chapter non-occluded area with maternal arterial oxygen tension will will review the pathological basis of placental IUGR that is exhibit vascular regression to form the definitive membranes meaningful to everyday practice, so that “placentology” can (chorion laeve) [10, 11]. This is the mechanism by which the be integrated into obstetric and postpartum care. encasement of a developing embryo by the trophoblastic shell converts to a fetus with a definitive discoid and Key steps in formation of the membranes (reviewed in Burton et al. [12]). definitive placenta The basic structure of the term placenta is familiar to mater- Clinical implication nal-fetal medicine specialists, characterized by maternal By the time of the nuchal translucency ultrasound examin- blood entering the inter-villous space to perfuse the floating ation, the distinction between definitive placenta and mem- villous trees (Figure 18.1.1). Growth and specialization of branes has become obvious (Figure 18.1.4; 12 week placenta).

Fetal Therapy, ed. Mark D. Kilby, Anthony Johnson and Dick Oepkes. Published by Cambridge University Press. © Cambridge University Press 2012.

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Figure 18.1.2 Photomicrograph of the maternal-fetal interface from the same specimen, showing the opening of an endometrial gland (eg) through the cytotrophoblastic shell (cs). The carbohydrate-rich gland secretions, Figure 18.1.1 The mature human placenta in situ is composed of the staining blue, can be seen dispersing in the between the villi tissues between the chorionic plate (CP) and the basal plate (BP). The fetally (v). Cytotrophoblast cell columns contributing to the shell are arrowed. Image vascularized chorionic villous trees project from the chorionic plate into the kindly provided by Professor G. J. Burton, Cambridge. inter-villous space (IVS). This space is perfused by spiral that spray oxygenated maternal blood (red) into the center of villous trees. Maternal blood percolates amongst the outer well-developed peripheral gas- system [15]. EVT only invade 3–4 mm of the distal spiral arte- exchanging villi, losing oxygen and entering the uterine . Oxygenated rioles in normal pregnancy [16], whereas spiral vasodila- fetal blood enters the (UC) (red arrow). BP = basal plate; M = myometrium; CL = chorion laeve; A = ; MZ = marginal zone between tation precedes EVT invasion in normal pregnancy (reviewed placenta and , where maternal blood enters the peripheral in Burton et al. [17], likely part of a generalized systemic vaso- uterine veins; * = cell island, connected to a villous tree. dilatation mediated by up-regulation of endothelial nitric oxide Reproduced, with permission, from Kaufmann and Scheffen [2] synthase activity [18, 19] or hemoxygenase [19]. The anatomical erosion of the distal spiral arteries has an Since small/dysmorphic placentae are commonly found in important role, to produce a funnel that creates a Ventouri severe IUGR deliveries[14] an appreciation of these early effect, whereby high-volume maternal blood flow to the inter- developmental steps is key to understanding the potential of villous space can take place at low pressure thereby protecting placental morphologic imaging as a screening tool for severe the distal fetoplacental vasculature within terminal villi from placental insufficiency in the early second trimester [13]. external compression (Figure 18.1.5) [17]. Pathological changes in the , termed decidual vasculopathy, are predicted to EVT and the uteroplacental circulation alter inter-villous blood flow in several ways (high pressure high The end of the first trimester is characterized by dissolution of velocity flow, unstable flow causing ischemia-reperfusion) that the endovascular EVT plugs and migration of interstitial EVT will disrupt the integrity of the developing villi (see below). through the decidua to transform the proximal myometrial portions of the spiral arteries [4]. In tandem the non-pregnant Development of the placental villi endometrium is transformed into the decidua, a pro-angiogenic At the end of the first trimester, all villi are vascularized and structure populated by cells of the maternal innate immune therefore classed as tertiary villi. The growth zones of these

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Figure 18.1.3 (A) Low power photomicrograph of an 8 week gestational age placenta-in-situ specimen showing regression of the at the superior pole (**) (cystic space is a shrinkage artifact during fixation). The embryo and amnion have been removed, leaving only the attachment of the umbilical cord to the chorionic plate (arrow). Note depth of developing chorionic villi beneath the arrow that will become the definitive placenta. c = cervix. (B) Corresponding diagrammatic representation of the placenta and at 8–9 weeks showing the myometrium (m), decidua (d), definitive placenta (p), extraembryonic coelom (eec), amniotic cavity (ac), and (ys). Maternal blood flow (arrows) starts in the periphery of the developing placenta (chorion frondosum), where trophoblast invasion and plugging of the spiral arteries is least extensive. This onset of blood flow causes locally high levels of oxidative stress and inhibition of a hypoxic drive to angiogenesis within developing villi; the net effect is regression of the villi over the superficial pole of the sac (*) (corresponding to ** in A) and formation of the chorion laeve. Reproduced, with permission, from Jauniaux, et al. [9].

primitive villi are the immature intermediate villi (IIV) that will produce 10–20 generations of new villi to expand the vil- lous trees via branching angiogenesis. IIV finally convert to their mature forms that exhibit a predominantly non-branch- ing angiogenesis, and in doing so, produce lateral buds that are the gas-exchanging terminal villi (Figure 18.1.6). For detailed review see Kaufmann et al. [22]. The villous trophoblast compartment Placental villi are covered by the fetally derived epithelial layer termed villous trophoblast – this is a distinct lineage under sep- arate transcriptional control from the EVT in mammalian pla- centae [23]. In humans, this layer continuously expands to cover the developing villi through the proliferative actions of the villous that reside beneath the outer multinucleated syncytiotrophoblast (Figure 18.1.7) [24]. Villous cytrophoblasts Figure 18.1.4 Two-dimensional ultrasound image of the placenta and divide asymmetrically, directed by glial cell missing-1 (GCM1) to membranes at 12 weeks’ gestation at the time of the nuchal translucency (NT) examination. The definitive placenta on the posterior wall of the uterus produce a post-mitotic fusion-enabled daughter cell [26] via the (outlined by ++ and XX) is distinct from the chorion laeve on the anterior wall expression of syncytin [27]. The GCM1-negative cell remains for (arrowheads). Black, amniotic fluid; F, fetus; P, placenta. Since the anatomy further rounds of cell division. Trophoblast stem cells (that pro- of the placenta and membranes is established at this stage, morphological assessment can detect placental insufficiency due to “chorion regression” liferate symmetrically in response to fibroblast growth factor 4 syndrome with low maternal serum pregnancy-associated placental protein A [FGF4] and heparin) have been derived from the mouse placenta (PAPP-A) levels [13]. [28]. Thus far they have not been isolated from the human pla- centa, though a subset of villous cytotrophoblasts do respond to FGF4/heparin [29] and the epigenetic regulation of the population of villous trophoblast progenitors is increasingly understood 30].

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Figure 18.1.5 Diagrammatic representation (not to scale) of the effects of conversion on the inflow of maternal blood into the inter-villous space and on lobule architecture predicted by modeling. Funnel dilation of the distal segment in normal pregnancies will reduce the velocity of incoming blood to form a spray (Ventouri effect) that enters the central cavity (CC) at 10 cm/s, where villi are characteristically immature (see Figure 18.1.1). From the CC maternal blood disperses evenly amongst the peripheral specialized gas-exchanging villi over 25–30 seconds allowing adequate time for oxygen exchange. Pressure of maternal blood is indicated by mmHg in blue and drops across the non-dilated segment of the spiral artery. In pathological circumstances where none or minimal spiral artery conversion occurs, maternal blood enters the inter-villous space at speeds of 1–2 m/s. The resultant high momentum is predicted to rupture anchoring villi (indicated by *), compress and damage peripheral villi to form echogenic cystic lesions (ECL) lined by thrombus (brown) [20]. These abnormal physical forces will impair transplacental gas exchange while the retention of smooth muscle cells (SMC) that accompanies decidual vasculopathy will increase the likelihood of ischemia-reperfusion injury to further impair the integrity of the peripheral villi [21]. Reproduced, with permission, from Burton et al. [17].

The population of proliferating villous cytotrophoblasts slowly neat system whereby EVT express the enzyme indoleamine increases as gestation advances, though these cells are dispersed 2,3-dioxygenase (IDO) to deprive them of tryptophan [37]. due to growth of the placental villous trees [24]. These consid- Pathological invasion of the inter-villous space and villi by the erations are important because villous cytotrophoblast depletion maternal immune system is a feature in a subset of IUGR preg- is a central feature of severe IUGR [31, 32]. The outer syncytio- nancies (see below). trophoblast is post-mitotic and specialized, with an outer brush border that expresses several energy-dependent active carrier sys- Gross pathology of the iugr placenta tems. Until recently it was considered a passive structure, translat- Table 18.1.1 (adapted from Walker et al. [33]) summarizes the ing proteins based on mRNAs entering via syncytial fusion [32]. range and frequency of specific gross and histological lesions Recent data now show that the syncytiotrophoblast is capable of in 153 severe IUGR placentae over a 10-year period deliv- de-novo mRNA synthesis [33, 34] which is highly relevant to the ering between 22 and 32 weeks’ gestation in our institution pathogenesis of associated severe preeclampsia (see below). As (Mount Sinai Hospital, Toronto, Canada). Representative the human placenta matures the volume of syncytiotrophoblast gross examples are shown in (Figure 18.1.8). Severe early- increases due to sustained villous cytotrophoblast proliferation onset IUGR was defined by birth weight <10th percentile for and syncytial fusion. Syncytiotrophoblast nuclei in the near-term gestational age and sex, with absent or reversed end-diastolic placenta tend to aggregate in syncytial knots, in part to facilitate flow by umbilical artery Doppler prior to delivery. Coexistent focal thinning of this layer, as vasculo-syncytial membrane lack- severe preeclampsia was present in 45% while perinatal mor- ing nuclei, to maximize diffusional exchange. These senescent tality occurred in 46%. At a gross level, small-for-dates pla- areas can exhibit some features of apoptosis and a small fraction centae were sixfold greater than normal, often accompanied may shed into maternal blood (reviewed in detail in Burton and by features of what we term “chorion regression syndrome” Jones [35]). implying excess formation of membranes (chorion laeve) at the expense of the definitive placenta (chorion frondosum) The maternal immune system [13]. Excess chorion regression in the first trimester was The maternal-fetal interface, or decidua, is rich in cell lineages elegantly observed using transvaginal ultrasound [10] and of the maternal immune system, in particular large granular may explain the clinical association between recurrent first lymphocytes and uterine natural killer (NK) cells. Synergistic trimester bleeding and adverse outcomes, including severe interactions between these cells and EVT likely promote a pro- IUGR [39]. The early developing placenta secretes preg- angiogenic response of the host to pregnancy [15] (reviewed in nancy-associated placental protein A (PAPP-A) into mater- detail in Parham and Guethlein [36]). Other leukocyte lineages nal blood, measured at 11–13 weeks to derive the risk for are specifically excluded from within the placenta, utilizing a Trisomy 21 [40). In the absence of aneuploidy, low PAPP-A

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2300 Figure 18.1.6 Diagramatic representation of a chorionic villous tree from the third trimester

C 2200 human placenta (compare with Figures 18.1.1 and 18.1.6). (A) The villous tree (placentome) is

2100 connected between the chorionic plate (CP) and basal plate (BP) by the anchoring villi. Most villi however float within the inter-villous space as 2000 branches off the anchoring villi (inset). (B) External CP appearancs of developing villi progressing from

A 1900 muscularized stem villus (containing arterioles) into mature intermediate villi (MIV) (characterized by long unbranced capillaries) off which the terminal 1800 villi bud. (C) Vascular arrangement within a villus. Note that gas-exchanging terminal villi are formed 1700 by capillary loops that prolapse laterally off MIV to form sinusoid dilations with minimal overlying syncytiotrophoblast. These thinned areas have 1600 maximal oxygen conductance and are termed “vasculo-syncytial membrane.” 1500 1400 1300 1200 stem villus

BP 1100 1000

B mature inter 900

artery 800 mediate villus arteriole 700

capillary and 600 sinusoid 500 venule ter minal villus 400

vein 300 200 100 0 µ m

is associated with severe IUGR [41] and stillbirth [42], espe- severe IUGR and perinatal death [44]. A recent audit of the cially with co-elevation of alpha-fetoprotein (AFP) at 16 relationship between maximum placental length at 19–22 weeks [43]. A subset of women with low PAPP-A (<0.3 MoM weeks and gross placental pathology at delivery revealed sur- [multiple of the median]) exhibit ultrasound features of prisingly poor correlations with a 25% false-negative rate, chorion regression (small/fat placentae with abnormal tex- due to failure to identify eccentric cords in the narrowest ture and eccentric cords) that is predictive of severe IUGR plane (D. Constantini, M. Walker, N. Miltyan, S. Keating, [13]. Amongst women with bilateral abnormal uterine artery J. Kingdan, unpublished data, 2011). This limitation is easily Doppler at 19–22 weeks, reduced placental length (<10 cm) overcome by the use of orthogonal plane measurements with identified a subset of women with a fourfold greater risk of 3D ultrasound as proposed recently [45]. Three-dimensional

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Table 18.1.1 Categories of placental pathology in 153 consecutive ultrasound is now being evaluated as a screening tool for severe early-onset IUGR pregnancies delivered between 22 and 32 weeks’ gestation at Mount Sinai Hospital, Toronto, Canada. IUGR along with maternal serum biochemistry [46] or uter- ine artery Doppler [47]. Placental morphologic ultrasound Placental pathology % n = 153 remains a research tool under investigation but holds much Placental bed pathology promise given the high rates of gross morphologic abnor- Chronic deciduitis 17.0 malities in the severe IUGR placenta. Decidual vasculopathy 35.9 Retro-placental hemorrhage 5.2 Uteroplacental vascular pathology Gross pathology Placental bed biopsy research in both IUGR pregnancies and Placental weight <10th centile 61.4 in pregnancies with documented abnormal uterine artery Eccentric umbilical cord insertion 40.5 Doppler from severe IUGR pregnancies is extensive; read- 2-vessel corda 5.3 ers are directed to a recent book for in-depth study [48]. In severe IUGR, EVT exhibit reduced EVT invasion, in part due Parenchymal pathology to an excess maternal immune reaction by macrophages [49] Inter-villous thrombosis 7.2 that may promote EVT apoptosis 16]. Lack of EVT invasion Infarction 62.7 may be accompanied by fibrinoid deposits in the spiral artery Chronic villitis 3.9 walls, the accumulation of foam cells, and the persistence of Acute or chronic intervillositis 5.2 muscularized distal segments – all features of what is termed Massive perivillous fibrin deposition 6.5 decidual vasculopathy. This pathology may lead to focal hem- Histopathology orrhage and is a risk factor for abruption [50]. This pathology Distal villous hypoplasia 13.7 is illustrated in (Figure 18.1.9). Advanced villous maturation 56.2 Fetal vascular pathology 17.6 Developmental pathology of the Umbilical cord abnormalities 28.8 placental villi a number of cord vessels documented in 151 cases The net effect of abnormal maternal perfusion of the- pla Adapted from Walker et al. [38]. cental villi is one or more of the following: (1) spiral artery thrombosis: this will result in wedge infarction of villous trees due to hypoxic vasoconstriction of the villous stem arteries, (2) unstable perfusion: this causes ischemia-reperfusion injury, resulting in cyclin-induced arrest of the cytotrophoblast cell

Figure 18.1.7 Normal placental development; extravillous cytotrophoblasts proliferate in anchoring columns to successful invade through the decidua (1) and transform the distal spiral arteries (2). These changes mediate high volume flow at low pressure into the inter-villous space (3). The placental villi are covered by the villous trophoblast compartment (4), comprising cytotrophoblasts that proliferate to generate the outer syncytiotrophoblast in direct contact with maternal blood. This research was originally published in Kingdom and Drewlo [25].

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Figure 18.1.8 Gross pathology of the human placenta in IUGR. (A) Chorion regression with a small placenta and marginally inserted umbilical cord. (B) Infarction based on maternal surface with a hemorrhagic area (arrow). (C) Intervillous thrombus (arrow heads) and infarction (arrows). (D) Extensive subchorionic hemorrhage or Breus’ mole showing the characteristic nodular appearance. (E) Large retroplacental hemorrhage with focal adjacent infarction (seen in the most inferior slice), the pathological correlate of chronic abruption. (F) Massive perivillous fibrinoid deposition. Note the extensive pale lacey appearance which diffusely involves a significant proportion of the parenchyma in this condition.

cycle, impaired syncytial fusion, and the induction of endo- energy-dependent maternal-fetal transfer. The stressed outer plasmic reticulum stress in the syncytiotrophoblast [21]. syncytiotrophoblast increases production of the splice-variant Collectively these changes can accelerate apoptosis [51], vascular endothelial growth factor (VEGF) receptor sFLT-1 trigger focal necrosis [59], and cause a global reduction in [53–55] and produces unique proteins such as serpina that may

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Figure 18.1.9 Histopathological features of the placenta in IUGR and normal controls. (A) Second trimester placenta showing distal villous hypoplasia. Note expansion of maternal space, the presence of very small villi and some very narrow elongated villi (100X). (B) Normal second trimester parenchyma for comparison with (A) (100X). (C) Villus from second trimester IUGR placenta with distal villous hypoplasia showing aponecrosis of the surface trophoblast (400X). (D) Normal second trimester parenchyma for comparison with (C) (400X). (E) Fully transformed decidual spiral arteriole. Note the lack of smooth muscle in the wall (100X). (F) Underremodeled decidual spiral arteriole with multiple cross-sections seen as it travels in and out of the plane of section (arrows). Note the persistent smooth muscle in the vessel wall (100X). (G) Decidual arteriole showing fibrinoid necrosis in the wall (arrow) and the presence of prominent foamy macrophages (atherosis) (arrow heads) (100X). (H) Thrombosis of a decidual arteriole (often observed underlying an area of infarction) (250X).

make useful screening tools to screen for preeclampsia and/or differentiation. Stereology studies of 3D structure show a 40% IUGR [56, 57]. The entry of maternal blood at high pressure reduction in the elaboration of gas-exchanging villi when severe and velocity to the inter-villous space, induces shear stress IUGR is accompanied by early delivery and abnormal umbil- and mechanical damage to the surface of the placental villi ical artery Doppler [3]. Scanning electron microscope images (reviewed in detail in Burton et al. [17]). Furthermore this can of vascular casts of villi, and of the villi themselves, from severe lead to rupturing of anchoring villi (to produce short-fat pla- IUGR pregnancies demonstrate the arrest of angiogenesis that centae filled with maternal blood, rather than normal villi) (S. normally drives growth of the placental villous trees [58]. This Porat, B. Fitzgerald, S. Keating, J. Kingdom, unpublished data, type of pathology is termed distal villous hypoplasia, and com- 2011) These surface defects render the surface of placental villi monly is associated with severe cytotrophoblast depletion, and prone to focal thrombosis [58]. wave-like syncytial knotting [52]. Representative examples of Distinct from changes in placental villi secondary to villous pathology in severe IUGR are shown in (Figure 18.1.10). abnormal uteroplacental perfusion, placental villi from severe The underlying molecular pathology of these events is com- IUGR placentae may display features of abnormal villous plex to unravel from “snapshot” placental samples at delivery

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Figure 18.1.10 Villous maldevelopment in IUGR resulting in delivery <32 weeks with abnormal umbilical artery Doppler waveforms. Scanning electron microscope images from the surface of placental villi from early-onset severe preeclampsia. The surface of the placental villi (A, B, C) shows multiple folds (indicated by arrows) into ridges and knots, corresponding to the sections of apoptotic syncytial knots shown in Figure 4D. (A) and (B) show patches of biconcave maternal erythrocytes trapped in patches of fibrin (F) indicating pathological inter-villous thrombosis on the surface of these highly abnormal villi.

because it involves several cell types (trophoblast, mesenchy- are aggregated in excessive fibrin generated in the inter-villous mal and immune cells, endothelium) and is compounded by space. Mutation analysis for genes participating in fibrinoly- chronic hypoxia [59]. Isolation of specific cells types from sis do not differ between unaffected and MPVFD placentae severe IUGR placentae at delivery, e.g., villous cytotrophoblasts, [67]. The disease may begin with patchy syncytiotrophoblast provides useful insights, for example such cells exhibit exagger- necrosis and fibrin deposition, then accelerates as bi-potential ated apoptosis in culture [60], and defective GCM1/syncytin villous cytotrophoblasts [29] switch to an EVT secretory expression [61, 62]. A powerful new concept is the utilization phenotype [68]. of spare first trimester chorionic villus sampling placental villi On the fetal side, vascular pathology and umbilical cord to investigate villous trophoblast function at the likely onset of abnormalities are important contributors to IUGR as shown disease in its preclinical phase [63]. in Table 18.1.1. Fetal thrombotic vasculopathy (FTV) is defined as extensive thrombosis of chorionic plate and stem villous vessels, leading to avascularity of downstream villi [69]. This Thrombotic and hemorrhagic pathology is one of several lesions, descending through the The normal placenta, characterized by high volume stable uter- within villi, that contributes to the pathogenesis of severe oplacental blood flow and healthy placental villi covered by IUGR with abnormal umbilical artery Doppler waveforms fresh syncytiotrophoblast, is capable of “self-anticoagulation” [70]. Hemoconcentration, low cardiac output, and abnor- (reviewed in Kingdom and Drewlow [25]). Conversely, the mal peripheral capillary formation in the distal villi in severe developmentally abnormal placenta, characterized by decid- IUGR all contribute to capillary congestion [31] that impairs ual bed pathology, structurally abnormal villi with defective gas exchange, leading to chronic hypoxia and acidosis [71]. or damaged areas of syncytiotrophoblast is prone to throm- Cord abnormalities, including marginal insertion, or excessive bosis. The most common thrombotic lesion, shown in Table coiling [72, 73] contribute to vascular obstruction. Discordant 18.1.1, is villous infarction. We recently demonstrated that one umbilical arteries, where one is narrow with abnormal umbil- or more developmental abnormalities of the placenta (small ical artery Doppler and at risk of thrombosis, may predispose to placental size, decidual vasculopathy, abnormal development FTV including umbilical artery thrombosis [74]. Thrombosis of placental villi) are sevenfold more common than any mater- of an umbilical artery in early gestation may explain the higher nal thrombophilia in the context of placental infarction [64]. rate of two-vessel cord in IUGR accompanied by “chorion By contrast, hemorrhagic lesions, in particular inter-villous regression” (Table 18.1.1). thrombosis (IVT), is associated with severe IUGR and may carry a worse prognosis [50, 65]. In contrast with infarction, which is rarely imaged by ultrasound, IVTs have a character- Immune injury to the placenta istic appearance that is termed echogenic cystic lesion (ECL) The severe IUGR placenta is, as shown in Table 18.1.1, vulner- [20]. When basally located, they may dissect spiral arteries able to inappropriate invasion by the maternal immune system. and trigger abruption[50]. Chronic abruption may occasion- Plasma cell infiltration of the decidua is a feature of decidual ally be found during the course of fetal monitoring for IUGR vasculopathy. Macrophage infiltration participates in EVT cell and presents as a ultrasonolucent black space between the death by apoptosis [49]. Leukocyte lineage invasion beyond the basal placenta and the myometrium [66]. In extreme IUGR, decidua, to surround or invade the placental villi, may be found progressive layers of hemorrhage under the chorionic plate, in IUGR. Chronic inter-villositis (CIV) refers to large numbers termed Breus’ Mole, may be observed. Typically this is a lethal of macrophages populating the inter-villous space; it confers type of pathology due to disruption of placental perfusion. a 2/3 risk of IUGR and has up to an 80% recurrence risk in The final lesion affecting the inter-villous space/maternal subsequent pregnancies [75]. A less severe form is described as side of placental villi is maternal floor infarction, or massive villitis of unknown etiology (VUE) where lymphocytes and mac- peri-villous fibrin deposition (MPVFD), where placental villi rophages invade the villous stroma in the absence of congenital

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infection [76–78]. VUE may recur in around 1/3 pregnancies chorionic gonadotropin [hCG], and inhibin) windows are dis- [79]. The sonographic appearances of the placenta in recurrent tinct proteins that encapsulate several components of placental CIV or VUE are unknown, but are likely to be associated with function [41] (www.mountsinai.on.ca/care/placenta-clinic). a degree of IUGR and low amniotic fluid. An underestimated PAPP-A is secreted by the early EVT and the syncytiotro- sonographic sign in this context may be Grannum grading [80] phoblast, and in a clinical sense is a marker of the “placental since Grannum grade 3 maturation at 36 weeks conferred a footprint” on the uterine wall. A subset of women with low 40-fold excess risk of IUGR in a recent cohort of 1011 healthy PAPP-A have small dysmorphic placentae that predicts still- non-smokers [81]. birth and severe IUGR [13]. By contrast, both hCG and inhibin are derived from the second trimester where high levels, espe- cially in combination, are associated with severe preeclampsia Implications for clinical practice and IUGR [49]. Elevated AFP is presumed to be fetally derived; high levels are associated with IUGR and stillbirth, especially The placental pathology of IUGR is complex and in combination with low PAPP-A [43]. It was shown that the variable use of dual- [43, 87] or multiply-abnormal analytes have much higher positive predictive values for stillbirth or IUGR justi- A range of underlying mechanisms, including abnormal pri- fying increased ultrasound surveillance [41, 88]. We routinely mary development, maternal inflammation, ischemia-reper- incorporate IPS testing with placental morphology and uterine fusion injury, hemorrhage, and thrombosis, exist to a variable artery Doppler to determine the risk of IUGR in our high-risk degree in most severe IUGR placentae. Therefore no single clinic patients [89]. We accept that there is no basis to offer therapeutic agent is likely to be capable of preventing this dis- such screening in apparently healthy women and are presently ease in at-risk women. Low-dose aspirin, a benign medication, conducting this type of prospective research in nulliparous has a small impact on disease prevention [82] but is clearly not women to include placental pathology in addition to clinical capable of reversing major defects in placental development. outcomes. By contrast, despite a variety of maternal inflammatory mech- anisms operating within the IUGR placenta, there is no evi- dence to support the use of maternal corticosteroids to prevent Placental morphologic screening holds promise as placental disease [75, 83]. a screening tool for IUGR Given the high rate of small placentae in severe IUGR, often IUGR is not exclusively mediated by abnormal accompanied by gross abnormalities that imply “chorion uterine artery Doppler regression,” it is important to agree standards for morpho- logic assessment in the second trimester. To date we have Remarkable few studies focusing on screening or prevention used a simple 2D assessment of maximum length in high-risk of IUGR include assessment of the organ responsible for the clinical practice, based on retrospective data defining a disease, namely the placenta. As such, the potential to actu- cut-off of 10 cm in a 19–23 week window that increased the ally image the placenta real-time, based on an appreciation of risk of severe IUGR and perinatal mortality fourfold [44]. the variety of gross abnormalities that are likely to be visible in We recently audited this method to predict small placentae the second trimester of at-risk pregnancies (Table 18.1.1), has in 95 pregnancies with a surprisingly poor positive value (D. received scant attention. By contrast the application of uterine Costantini, M. Walker, N. Milligan, S. Keating, J. Kingdom, artery Doppler, to screen for uteroplacental vascular insuf- unpublished data, 2011). Eccentric cord was a common find- ficiency, has been extensively studied for over 20 years [84]. ing in the false-negative group; to address this we now meas- Severe IUGR is nevertheless well predicted by abnormal uter- ure the orthogonal length at 90 degrees to the maximum ine artery Doppler alone [85], in part because uteroplacental placental length (as illustrated in Figure 11) in order to more vascular insufficiency segregates with small placental size and reliably diagnose small placentae with chorion regression. abnormal shape [44]. Since transplacental transfer is not flow- The alternative method, debated recently in a iournal editor- limited on the maternal side [86] it makes sense that severe ial [90] is to assess placental morphology off-line from 3D IUGR would be better predicted by placental size than by uter- sweeps [45]. Three-dimensional assessment has the distinct ine artery Doppler; this may be the case for women with very advantage of being able to capture images of the placenta in low PAPP-A levels in the first trimester [12]. any uterine location, then rotating to a standard horizontal plane “off-line” – to overcome the inherent disadvantage of Integrated prenatal screening (IPS) tests for 2D to assess lateral or fundal placentae. Trisomy 21 are valuable biomarkers for severe Despite this weakness of 2D assessment, we remain advo- cates of it as a diagnostic tool since it permits real-time assess- placental insufficiency ment of the parenchymal tissue, especially in thick placentae The maternal serum analytes used to derive the risk of Trisomy [91]. Real-time assessment can distinguish healthy “granular” 21 in the 11–13 week (PAPP-A) and 15–20 week (AFP, human villous tissue from hematoma formation, destructive lesions

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[20], or slow-moving maternal blood amongst poorly formed Table 18.1.2 Placental pathology from the HEPRIN trial villi [92]. Unfortunately the most common parenchymal lesion Standard in IUGR, i.e., infarction (Table 18.1.1), is poorly recognized by carea UFH ultrasound as it remains solid, in comparison with inter-villous Variable (n = 15) (n = 16) p value thrombi [44]. Recently, MRI assessment of the extreme IUGR GROSS PATHOLOGY placenta has demonstrated enhanced prenatal diagnosis of vil- lous pathology, especially infarction [93, 94]. Combining pla- Placental weight <10th 7 (46.7) 4 (25) 1.000 centile cental with brain MRI may have a role in a subset of extreme preterm IUGR pregnancies give the link between placental Accessory lobe 1 (6.7) 1 (6.3) 1.000 infarction and white mater brain injury [95]. Two-vessel cord 3 (20) 0 0.101 Velamentous umbilical 3 (21.4) 1 (6.7) 0.330 The role of heparin for the prevention cord insertionb HISTOPATHOLOGY of severe IUGR Infarction 4 (26.7) 3 (18.8) 0.685 The high rate of placental villous infarction in severe IUGR Inter-villous thrombosis 7 (46.7) 2 (13.3) 0.109 placentae (Table 18.1.1) coupled with an association between Large retro-placental 5 (33.3) 1 (6.3) 0.083 IUGR and maternal thrombophilia, provides the rationale for or sub-chorionic investigating the role of anticoagulants (low-dose aspirin and/ hemorrhage or heparin) for the prevention of disease in at-risk women [25]. a Until recently, no randomized trial evaluating heparin in this Data are presented as n (%) or mean, as appropriate. One placenta was not sampled in the standard care group, b n = 14 standard care, 15 UFH. context had included placental pathology. The HEPRIN pilot UFH = unfractionated heparin. randomized trial allocated 32 high-risk women with multi- Kingdom et al. [96]. parameter placental dysfunction in the second trimester to no treatment or unfractionated heparin 7500 IU twice a day until 34 weeks [96]. The placental pathology is shown in Table vasculopathy, disorders of villous development) provides an 18.1.2. Small-for-dates placentae were common, while the rates explanation for villous infarction. Third, given the empiric of placental infarction were similar. These data are consistent 10% recurrence risk [89, 101], a discussion of the gross abnor- with earlier observational data showing that abnormal early malities is a useful avenue to describe placental ultrasound as placental development strongly predisposes to placental infarc- a test of placental function in a future pregnancy. The recur- tion [64]. IUGR pregnancies are prone to severe preeclampsia rence risk for IUGR may be greater when the index case is that may drive the timing of delivery due to maternal ill-health. male than female [102] while the underlying categories of Heparin appears to reduce the recurrence risk of severe pre- placental pathology differ between the sexes (more maternal eclampsia by reversing the natural anti-angiogenic properties inflammation and chorion regression in males, more placen- of developing placental villi [97]. These actions of heparin are tal infarction in females) [38]. Finally, given the link between independent of its anticoagulant actions and occur despite abnormal placental pathology and longer-term cardiovascu- increasing the maternal circulating levels of sFLT-1 [54, 98]. lar risk [103] a discussion of placental pathology can be used Heparin therefore deserves further study for the prevention of to motivate women to address host’s risks, especially obesity, IUGR and its complications, but in a framework that includes before another pregnancy attempt. clinical and molecular pathological studies. References The utility of placental pathology following 1. Boers KE, Vijgen SM, Bijlenga D, et al. Induction versus IUGR delivery expectant monitoring for intrauterine growth restriction at term: randomised equivalence trial (DIGITAT). BMJ 2010;341:c7087. The delivery of an extreme IUGR infant is a common request 2. Kaufmann P, Scheffen I,. Placental development. In: Polin R, Fox for non-pregnant consultation. Unless the placenta is sent to W, eds. Neonatal and Fetal Medicine:Physiology and Pathology, pathology, apart from a review of maternal co-morbidities, Vol. 1. Orlando, Saunders. 1992; 47–55. the most common test that can be offered is a thrombophilia 3. Jackson MR, Walsh AJ, Morrow RJ, et al. Reduced placental screen to search for antiphospholipid antibody syndrome, villous tree elaboration in small-for-gestational-age pregnancies: compound or homozygous genetic thrombophilia [99]. relationship with umbilical artery Doppler waveforms. Am J Thrombophilia test abnormalities are much less common Obstet Gynecol 1995;172(2 Pt 1):518–25. than are gross and histological abnormalities of the placenta 4. Robson SC, Simpson H, Ball E, Lyall F, Bulmer JN. Punch [64, 65, 100]. The availability of placental pathology has many biopsy of the human placental bed. Am J Obstet Gynecol advantages: first, it is commonly the only available abnor- 2002;187(5):1349–55. mal result to confirm a placental basis for the IUGR. Second, 5. Burton GJ. Oxygen, the Janus gas; its effects on human placental the co-presence of developmental pathology (decidual development and function. J Anat 2009;215(1):27–35.

351

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6. Burton GJ, Watson AL, Hempstock J, Skepper JN, Jauniaux E. 21. Yung HW, Calabrese S, Hynx D, et al. Evidence of placental Uterine glands provide histiotrophic nutrition for the human translation inhibition and endoplasmic reticulum stress in the fetus during the first trimester of pregnancy.J Clin Endocrinol etiology of human intrauterine growth restriction. Am J Pathol Metab 2002;87(6):2954–9. 2008;173(2):451–62. 7. Burton GJ, Jauniaux E, Watson AL. Maternal arterial connections 22. Kaufmann P, Mayhew TM, Charnock-Jones DS. Aspects to the placental intervillous space during the first trimester of of human fetoplacental and angiogenesis. human pregnancy: the Boyd collection revisited. Am J Obstet II. Changes during normal pregnancy. Placenta Gynecol 1999;181(3):718–24. 2004;25(2–3):114–26. 8. Burton GJ, Hempstock J, Jauniaux E. Oxygen, early embryonic 23. Simmons DG, Natale DR, Begay V, et al. Early patterning of the metabolism and free radical-mediated embryopathies. Reprod chorion leads to the trilaminar trophoblast cell structure in the Biomed Online 2003;6(1):84–96. placental labyrinth. Development 2008;135(12):2083–91. 9. Jauniaux E, Cindrora-Davies T, Johns J, et al. Distribution and 24. Simpson RA, Mayhew TM, Barnes PR. From 13 weeks to term, transfer pathyways lf antioxidant molecules inside the first the trophoblast of human placenta grows by the continuous trimester human gestation sac. In: J Clin Endocrinol Metab recruitment of new proliferative units: a study of nuclear number 2004;89(3):1452–9. using the disector. Placenta 1992;13(5):501–12. 10. Jauniaux E, Hempstock J, Greenwold N, Burton GJ. Trophoblastic 25. Kingdom JC, Drewlo S. Is heparin a placental anticoagulant in oxidative stress in relation to temporal and regional differences high-risk pregnancies? Blood 2011;118(18):478–8. in maternal placental blood flow in normal and abnormal early 26. Baczyk D, Drewlo S, Proctor L, et al. Glial cell missing-1 pregnancies. Am J Patho. 2003;162(1):115–25. transcription factor is required for the differentiation of the 11. Kaufmann P, Black S, Huppertz B. Endovascular trophoblast human trophoblast. Cell Death Differ 2009;16(5):719–27. invasion: implications for the pathogenesis of intrauterine 27. Liang CY, Wang LJ, Chen CP, et al. GCM1 regulation of the growth retardation and preeclampsia. Biol Reprod expression of syncytin 2 and its cognate receptor MFSD2A in 2003;69(1):1–7. human placenta. Biol Reprod 2010;83(3):387–95. 12. Burton GJ, Jauniaux E, Charnock-Jones DS. The influence of the 28. Tanaka S, Kunath T, Hadjantonakis AK, Nagy A, Rossant J. intrauterine environment on human placental development. Int J Promotion of trophoblast stem cell proliferation by FGF4. Science Dev Biol 2010;54(2–3):303–12. 1998;282(5396):2072–5. 13. Proctor LK, Toal M, Keating S, et al. Placental size and the 29. Baczyk D, Dunk C, Huppertz B, et al. Bi-potential behaviour prediction of severe early-onset intrauterine growth restriction of cytotrophoblasts in first trimester chorionic villi.Placenta in women with low pregnancy-associated plasma protein-A. 2006;27(4–5):367–74. Ultrasound Obstet Gynecol 2009;34(3):274–82. 30. Hemberger M, Udayashankar R, Tesar P, Moore H, Burton GJ. 14. Nordenvall M, Ullberg U, Laurin J, et al. Placental morphology ELF5-enforced transcriptional networks define an epigenetically in relation to umbilical artery blood velocity waveforms. Eur J regulated trophoblast stem cell compartment in the human Obstet Gynecol Reprod Biol 1991;40(3):179–90. placenta. Hum Mol Genet 2010;19(12):2456–67. 15. Dunk C, Smith S, Hazan A, Whittle W, Jones RL. Promotion 31. Macara L, Kingdom JC, Kaufmann P, et al. Structural analysis of angiogenesis by human endometrial lymphocytes. Immunol of placental terminal villi from growth-restricted pregnancies Invest 2008;37(5):583–610. with abnormal umbilical artery Doppler waveforms. Placenta 1996;17(1):37–48. 16. Kadyrov M, Kingdom JC, Huppertz B. Divergent trophoblast invasion and apoptosis in placental bed spiral arteries from 32. Huppertz B, Frank HG, Kingdom JC, Reister F, Kaufmann pregnancies complicated by maternal anemia and early-onset P. Villous cytotrophoblast regulation of the syncytial preeclampsia/intrauterine growth restriction. Am J Obstet apoptotic cascade in the human placenta. Histochem Cell Biol Gynecol 2006;194(2):557–63. 1998;110(5):495–508. 17. Burton GJ, Woods AW, Jauniaux E, Kingdom JC. Rheological and 33. Ellery PM, Cindrova-Davies T, Jauniaux E, Ferguson-Smith physiological consequences of conversion of the maternal spiral AC, Burton GJ. Evidence for transcriptional activity in arteries for uteroplacental blood flow during human pregnancy. the syncytiotrophoblast of the human placenta. Placenta Placenta 2009;30(6):473–82. 2009;30(4):329–34. 18. Nanaev A, Chwalisz K, Frank HG, et al. Physiological dilation 34. Fogarty NM, Mayhew TM, Ferguson-Smith AC, Burton of uteroplacental arteries in the guinea pig depends on nitric GJ. A quantitative analysis of transcriptionally active oxide synthase activity of extravillous trophoblast. Cell Tissue Res syncytiotrophoblast nuclei across human gestation. J Anat 1995;282(3):407–21. 2011;219(5):601–10. 19. Lyall F, Barber A, Myatt L, Bulmer JN, Robson SC. 35. Burton GJ, Jones CJ. Syncytial knots, sprouts, apoptosis, and Hemeoxygenase expression in human placenta and placental bed trophoblast deportation from the human placenta. Taiwan J implies a role in regulation of trophoblast invasion and placental Obstet Gynecol 2009;48(1):28–37. function. FASEB J 2000;14(1):208–19. 36. Parham P, Guethlein LA. Pregnancy immunogenetics: NK cell 20. Proctor LK, Whittle WL, Keating S, Viero S, Kingdom JC. education in the womb? J Clin Invest 2010;120(11):3801–4. Pathologic basis of echogenic cystic lesions in the human 37. Munn DH, Zhou M, Attwood JT, et al. Prevention of placenta: role of ultrasound-guided wire localization. Placenta allogeneic fetal rejection by tryptophan catabolism. Science 2010;31(12):1111–15. 1998;281(5380):1191–3.

352

9781107012134c18.1_p341-354.indd 352 7/17/2012 7:27:06 PM Chapter 18.1: IUGR: placental basis and clinical practice

38. Walker MG, Fitzgerald B, Keating S, et al. Sex-specific basis of to impair endothelial VEGF signaling. J Thromb Haemost severe placental dysfunction leading to extreme preterm delivery. 2011;8(12):2486–97. Placenta 2011;33(7)568–71. 55. Tache V, LaCoursiere DY, Saleemuddin A, Parast MM. Placental 39. Saraswat L, Bhattacharya S, Maheshwari A. Maternal and expression of vascular endothelial growth factor receptor-1/ perinatal outcome in women with threatened miscarriage in the soluble vascular endothelial growth factor receptor-1 correlates first trimester: a systematic review.BJOG 2010;117(3):245–57. with severity of clinical preeclampsia and villous hypermaturity. 40. Nicolaides KH. Screening for fetal aneuploidies at 11 to 13 weeks. Hum Pathol 2011;42(9):1283–8. Prenat Diagn 2011;31(1):7–15. 56. Auer J, Camoin L, Guillonneau F, et al. Serum profile in 41. Dugoff L. First- and second-trimester maternal serum markers preeclampsia and intra-uterine growth restriction revealed by for aneuploidy and adverse obstetric outcomes. Obstet Gynecol iTRAQ technology. J Proteomics 2010;73(5):1004–17. 2010;115(5):1052–61. 57. Buhimschi IA, Zhao G, Funai EF, et al. Proteomic profiling 42. Smith GC, Crossley JA, Aitken DA, et al. First-trimester of urine identifies specific fragments of SERPINA1 and placentation and the risk of antepartum stillbirth. JAMA albumin as biomarkers of preeclampsia. Am J Obstet Gynecol 2004;292(18):2249–54. 2008;199(5):551e1–16. 43. Smith GC, Shah I, Crossley JA, et al. Pregnancy-associated 58. Krebs C, Macara LM, Leiser R, et al. Intrauterine growth plasma protein A and alpha-fetoprotein and prediction of adverse restriction with absent end-diastolic flow velocity in the umbilical perinatal outcome. Obstet Gynecol 2006;107(1):161–6. artery is associated with maldevelopment of the placental 44. Toal M, Keating S, Machin G, et al. Determinants of adverse terminal villous tree. Am J Obstet Gynecol 1996;175(6):1534–42. perinatal outcome in high-risk women with abnormal uterine 59. Soleymanlou N, Jurisica I, Nevo O, et al. Molecular evidence artery Doppler images. Am J Obstet Gynecol 2008;198(3):330 of placental hypoxia in preeclampsia. J Clin Endocrinol Metab e1–7. 2005;90(7):4299–308. 45. Schwartz N, Coletta J, Pessel C, et al. Novel 3-dimensional 60. Crocker IP, Cooper S, Ong SC, Baker PN. Differences placental measurements in early pregnancy as predictors in apoptotic susceptibility of cytotrophoblasts and of adverse pregnancy outcomes. J Ultrasound Med in normal pregnancy to those complicated 2010;29(8):1203–12. with preeclampsia and intrauterine growth restriction. Am J 46. Rizzo G, Capponi A, Pietrolucci ME, Capece A, Arduini D. Pathol 2003;162(2):637–43. First-trimester placental volume and vascularization measured 61. Langbein M, Strick R, Strissel PL, et al. Impaired cytotrophoblast by 3-dimensional power Doppler sonography in pregnancies cell-cell fusion is associated with reduced Syncytin and increased with low serum pregnancy-associated plasma protein a levels. J apoptosis in patients with placental dysfunction. Mol Reprod Dev. Ultrasound Med 2009;28(12):1615–22. 2008;75(1):175–83. 47. Yigiter AB, Kavak ZN, Durukan B, et al. Placental volume and 62. Ruebner M, Strissel PL, Langbein M, et al. Impaired cell fusion vascularization flow indices by 3D power Doppler US using and differentiation in placentae from patients with intrauterine VOCAL technique and correlation with IGF-1, free beta-hCG, growth restriction correlate with reduced levels of HERV PAPP-A, and uterine artery Doppler at 11–14 weeks of pregnancy. envelope genes. J Mol Med (Berl) 2010;88(11):1143–56. J Perinat Med 2011;39(2):137–41. 63. Farina A, Zucchini C, De Sanctis P, et al. Gene expression in 48. Pijenborg R, Brosens I, Romero R. Placental Bed Disorders, 1st chorionic villous samples at 11 weeks of gestation in women edn. Cambridge, UK, Cambridge University Press, 2010. who develop pre-eclampsia later in pregnancy: implications for 49. Reister F, Frank HG, Kingdom JC, et al. Macrophage-induced screening. Prenat Diagn 2011;31(2):181–5. apoptosis limits endovascular trophoblast invasion in the uterine 64. Franco C, Walker M, Robertson J, et al. Placental infarction and wall of preeclamptic women. Lab Invest 2001;81(8):1143–52. thrombophilia. Obstet Gynecol 2011;117(4):929–34. 50. Fitzgerald B, Shannon P, Kingdom J, Keating S. Rounded 65. Viero S, Chaddha V, Alkazaleh F, et al. Prognostic value of intraplacental haematomas due to decidual vasculopathy have a placental ultrasound in pregnancies complicated by absent distinctive morphology. J Clin Pathol 2011;64(8):729–32. end-diastolic flow velocity in the umbilical arteries.Placenta 51. Ray JE, Garcia J, Jurisicova A, Caniggia I. Mtd/Bok takes a swing: 2004;25(8–9):735–41. proapoptotic Mtd/Bok regulates trophoblast cell proliferation during human placental development and in preeclampsia. Cell 66. Walker M, Whittle W, Keating S, Kingdom J. Sonographic Death Differ 2010;17(5):846–59. diagnosis of chronic abruption. J Obstet Gynaecol Can 2010;32(11):1056–8. 52. Fitzgerald B, Levytska K, Kingdom J, et al. Villous trophoblast abnormalities in extremely preterm deliveries with elevated 67. Uxa R, Baczyk D, Kingdom JC, et al. Genetic polymorphisms in second trimester maternal serum hCG or inhibin-A. Placenta the fibrinolytic system of with massive perivillous fibrin 2011;32(4):339–45. deposition. Placenta 2010;31(6):499–505. 53. Nevo O, Soleymanlou N, Wu Y, et al. Increased expression of 68. Walker M, Whitte W, Keating S, Kingdom J. Sonographic sFlt-1 in in vivo and in vitro models of human placental hypoxia diagnosis of chronic abruption. JOGC 2010;32(11): is mediated by HIF-1. Am J Physiol Regul Integr Comp Physiol 1056–8. 2006;291(4):R1085–93. 69. Saleemuddin A, Tantbirojn P, Sirois K, et al. Obstetric and 54. Drewlo S, Levytska K, Sobel M, et al. Heparin promotes perinatal complications in placentas with fetal thrombotic soluble VEGF receptor expression in human placental villi vasculopathy. Pediatr Dev Pathol 2010;13(6):459–64.

353

9781107012134c18.1_p341-354.indd 353 7/17/2012 7:27:06 PM Section 2: Fetal disease: pathogenesis and principles

70. Salafia CM, Pezzullo JC, Minior VK, Divon MY. Placental 87. Alkazaleh F, Chaddha V, Viero S, et al. Second-trimester pathology of absent and reversed end-diastolic flow in prediction of severe placental complications in women with growth-restricted . Obstet Gynecol 1997;90(5):830–6. combined elevations in alpha-fetoprotein and human chorionic 71. Pardi G, Cetin I, Marconi AM, et al. Diagnostic value of blood gonadotrophin. Am J Obstet Gynecol 2006;194(3):821–7. sampling in fetuses with growth retardation. N Engl J Med 88. Huang T, Hoffman B, Meschino W, Kingdom J, Okun N. 1993;328(10):692–6. Prediction of adverse pregnancy outcomes by combinations 72. Redline RW. Placental pathology: a systematic approach with of first and second trimester biochemistry markers used in the clinical correlations. Placenta 2008;29 Suppl A:S86–91. routine prenatal screening of Down syndrome. Prenat Diagn 2010;30(5):471–7. 73. Cox P, Marton T. Pathological assessment of intrauterine growth restriction. Best Pract Res Clin Obstet Gynaecol 89. Toal M, Chan C, Fallah S, et al. Usefulness of a placental 2009;23(6):751–64. profile in high-risk pregnancies.Am J Obstet Gynecol 2007;196(4):363e1–7. 74. Klaritsch P, Haeusler M, Karpf E, Schlembach D, Lang U. Spontaneous intrauterine umbilical artery thrombosis leading to 90. Campbell S. Is placental size a good predictor of severe fetal growth restriction. Placenta 2008;29(4):374–7. obstetric complications? Ultrasound Obstet Gynecol 2009;34(3):247–8. 75. Contro E, deSouza R, Bhide A. Chronic intervillositis of the placenta: a systematic review. Placenta 2010;31(12):1106–10. 91. Sepulveda W, Aviles G, Carstens E, Corral E, Perez N. Prenatal diagnosis of solid placental masses: the value of color flow 76. Boog G. Chronic villitis of unknown etiology. Eur J Obstet imaging. Ultrasound Obstet Gynecol 2000;16(6):554–8. Gynecol Reprod Biol 2008;136(1):9–15. 92. Jauniaux E, Moscoso G, Campbell S, et al. Correlation of 77. Katzman PJ, Murphy SP, Oble DA. Immunohistochemical ultrasound and pathologic findings of placental anomalies in analysis reveals an influx of regulatory T cells and focal pregnancies with elevated maternal serum alpha-fetoprotein. trophoblastic STAT-1 phosphorylation in chronic villitis of Eur J Obstet Gynecol Reprod Biol 1990;37(3):219–30. unknown etiology. Pediatr Dev Pathol 2011;14(4):284–93. 93. Messerschmidt A, Baschat A, Linduska N, et al. Magnetic 78. Tang Z, Abrahams VM, Mor G, Guller S. Placental Hofbauer resonance imaging of the placenta identifies placental vascular cells and complications of pregnancy. Ann N Y Acad Sci abnormalities independently of Doppler ultrasound. Ultrasound 2011;1221:103–8. Obstet Gynecol 2011;37(6):717–22. 79. Feeley L, Mooney EE. Villitis of unknown aetiology: correlation 94. Bonel HM, Stolz B, Diedrichsen L, et al. Diffusion-weighted MR of recurrence with clinical outcome. J Obstet Gynaecol imaging of the placenta in fetuses with placental insufficiency. 2010;30(5):476–9. Radiology 2010;257(3):810–19. 80. Walker MG, Hindmarsh PC, Geary M, Kingdom JC. Sonographic 95. Burke CJ, Tannenberg AE, Payton DJ. Ischaemic cerebral injury, maturation of the placenta at 30 to 34 weeks is not associated with intrauterine growth retardation, and placental infarction. Dev second trimester markers of placental insufficiency in low-risk Med Child Neurol 1997;39(11):726–30. pregnancies. J Obstet Gynaecol Can 2010;32(12):1134–9. 96. Kingdom JC, Walker M, Proctor LK, et al. Unfractionated 81. Cooley SM, Donnelly JC, Walsh T, et al. The impact of heparin for second trimester placental insufficiency: a pilot ultrasonographic placental architecture on antenatal course, randomized trial. J Thromb Haemost 2011;9(8):1483–92. labor and delivery in a low-risk primigravid population. J Matern Fetal Neonatal Med 2011;24(3):493–7. 97. Sobel ML, Kingdom J, Drewlo S. Angiogenic response of placental villi to heparin. Obstet Gynecol 2011;117(6):1375–83. 82. Bujold E, Roberge S, Lacasse Y, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in 98. Sela S, Natanson-Yaron S, Zcharia E, et al. Local retention early pregnancy: a meta-analysis. Obstet Gynecol 2010;116(2 Pt versus systemic release of soluble VEGF receptor-1 are mediated 1):402–14. by heparin-binding and regulated by heparanase. Circ Res 2011;108(9):1063–70. 83. Laskin CA, Bombardier C, Hannah ME, et al. Prednisone and aspirin in women with autoantibodies and unexplained recurrent 99. Preston FE, Rosendaal FR, Walker ID, et al. Increased fetal loss. N Engl J Med 1997;337(3):148–53. fetal loss in women with heritable thrombophilia. Lancet 1996;348(9032):913–16. 84. Bewley S, Cooper D, Campbell S. Doppler investigation of uteroplacental blood flow resistance in the second trimester: 100. Mousa HA, Alfirevic Z. Do placental lesions reflect a screening study for pre-eclampsia and intrauterine growth thrombophilia state in women with adverse pregnancy retardation. Br J Obstet Gynaecol 1991;98(9):871–9. outcome? Hum Reprod 2000;15(8):1830–3. 85. Yu CK, Smith GC, Papageorghiou AT, Cacho AM, Nicolaides 101. Farine D, Ryan G, Kelly EN, et al. Absent end-diastolic flow KH. An integrated model for the prediction of preeclampsia velocity waveforms in the umbilical artery – the subsequent using maternal factors and uterine artery Doppler velocimetry pregnancy. Am J Obstet Gynecol 1993;168(2):637–40. in unselected low-risk women. Am J Obstet Gynecol 102. Murji A, Proctor LK, Paterson A, et al. Male sex bias in placental 2005;193(2):429–36. dysfunction. Am J Med Genet 2012;158A(4):779–83. 86. Pardi G, Cetin I, Marconi AM, et al. Venous drainage of 103. Staff AC, Dechend R, Pijnenborg R. Learning from the placenta: the human uterus: respiratory gas studies in normal and acute atherosis and vascular remodeling in preeclampsia-novel fetal growth-retarded pregnancies. Am J Obstet Gynecol aspects for atherosclerosis and future cardiovascular health. 1992;166(2):699–706. Hypertension 2010;56(6):1026–34.

354

9781107012134c18.1_p341-354.indd 354 7/17/2012 7:27:07 PM