In Utero Imaging of the Placenta: Importance for Diseases of Pregnancy

Article Outline

• Abstract
• 1. Introduction
• 2. Placental development
• 3. Imaging technologies
  • 3.1. Early technologies (for more details and references, see [8])
  • 3.2. Where are we now?
    • 3.2.1. Ultrasound
    • 3.2.2. Magnetic resonance (MR) imaging
    • 3.2.3. Clinical aspects
  • 3.3. Where are we headed?
    • 3.3.1. Ultrasound contrast agents
    • 3.3.2. Magnetic resonance spectroscopy and microscopy
• 4. Conclusions
• References
• Copyright

Abstract 

Maurice Panigel demonstrated by X-rays, almost 40years ago, placental maternal blood jets in non-human primates. Although to researchers the importance of the placenta is evident, in clinical obstetrical imaging, the fetus takes precedence. The placenta is imaged almost as an after thought and mostly to determine its location in the uterus. In animal species, the placenta was imaged with techniques which would be considered too invasive (or too costly for routine use) in humans, many pioneered by Panigel: radioangiography, radioisotopes scintigraphy, thermography, magnetic resonance imaging (MRI) and spectroscopy, positive emission tomography (PET) and single photon emission computed tomography (SPECT). Ultrasound allows for detailed, and, as far as is known, safe analyses of not only placental structure in the human but also its function. Earlier, only 2-dimensional grey-scale was available and more than 20years ago, placental grading was popular. Later, colour imaging and spectral Doppler analysis of blood velocity both in the umbilical artery and within the placenta as well as the uterus and fetal vessels became essential and, more recently, the use of ultrasound contrast agents has been described, albeit not yet in a clinical setting. Three-dimensional ultrasound permits evaluation of the placenta in several planes, more precise depiction of internal vasculature as well as more accurate volume assessment. Several medical disorders of the pregnant woman or her fetus begin or end in the placenta, and ultrasound is the optimal investigation method. Obvious examples include pre-eclampsia and other forms of hypertension in pregnancy, less than optimal fetal growth (i.e. intrauterine growth restriction), triploidy (and its placental manifestation: partial mole), non-immune hydrops as well as several infectious processes. Ultrasound is also particularly suited to evaluate specific placental conditions, such as abnormal placentation (placenta previa and accrete for instance), gestational trophoblastic disease and placental tumors (e.g. chorioangioma).

Keywords: Placenta, Ultrasound, Pregnancy, Fetal–maternal circulation, Pre-eclampsia

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1. Introduction 

The notion of placental circulation dates from Antiquity. At the end of the first century AD, Soranus of Ephesus, in his “Treaty of women illnesses”, described the chorion, amnion and the cord, containing 4 vessels and a urinary channel [1]. At the time and for many years to come, approximately the middle of the 16th century, in fact [2] maternal and fetal circulations were thought to be continuous. Over the ensuing years, arguments continued regarding the purely fetal versus shared origin of the placenta and the timing of the connection between the two systems (see historical perspectives [3], [4]). The question of exactly when is the actual uteroplacental circulation established, posed by Ramsey and Donner [5] is still debated [6], [7].

Many imaging techniques have been used in the last 50years [8], culminating in ultrasound and all its modalities: starting with regular B-mode [9], spectral [10], [11], power, also known as energy or colour angio [12] and colour Doppler [13], 3D/4D [14], [15] and, more recently, ultrasound contrast agents [16]. These have allowed in situ observation of the placenta and have elucidated in part some of the long-standing questions on the aetiology of several gestational conditions, such as pre-eclampsia and intrauterine growth restriction (IUGR). In this review, some facts on placental implantation will be detailed as well as past, present and future imaging modalities and their importance in diagnosing or predicting pregnancy complications. Some of these complications will be discussed, more from the imaging standpoint that in detailed clinical aspects.

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2. Placental development 

While a detailed analysis of maternal–fetal communications is well beyond the scope of this article, some details may be helpful in understanding the aetiology of certain pregnancy conditions, their manifestations in the placenta and the contribution of imaging techniques in interpreting changes occurring as a result of these situations. Anomalies on the maternal side, rather than the fetal side are, generally, at the origin of later pathological conditions. The interested reader is referred to a recently published excellent discussion of implantation, trophoblastic invasion and remodelling changes occurring in the uterine spiral arteries [17].

Invasion of the myometrium (maternal tissue) by the trophoblast (fetal origin) has traditionally been described as occurring in two phases: first (up to 12weeks) and early second (12–16weeks) trimesters [18]. More recently, this process has been depicted as progressive rather than biphasic [19], although there does not seem to be absolute certainty regarding one or the other [17]. This trophoblastic invasion transforms the normally coiled uterine spiral arteries into open and straight vessels, causing resistance to fall dramatically in the uterine arteries, as can be demonstrated with spectral Doppler [20]. Abnormal placentation may allow either lower levels of O₂ with resulting villous hypervascularisation, as seen in pre-eclampsia or higher than normal levels with abnormal branching and fetal growth restriction [21], [22]. If, on the contrary, the capillary obliteration is incomplete, excessive entry of maternal blood at a very early stage inside the developing placenta results in oxidative stress and subsequent degeneration of villous tissue [23]. Documentation of blood flow in the intervillous space in cases of first-trimester miscarriage by colour Doppler is useful in the prediction of success or failure of expectant management [24]. Premature and diffuse onset of intervillous blood flow can be detected by grey-scale and colour imaging and confirmed by spectral Doppler. This abnormal blood flow pattern may increase the oxidative stress on the early placental tissue, subsequently impair placental development and is often associated with early pregnancy failure [25]. The continuing invasion (referred to by some as the second invasion phase) may occur as late as 20–24weeks. Spiral arteries are widely open, resulting in a further drop in the impedance in the uterine arteries and a major increase in the end-diastolic velocity, as documented by Doppler velocimetry [20]. Both syncytiotrophoblast and cytotrophoblast growth, development and invasion are regulated by an apoptosis cascade within the villous trophoblast [26]. This cascade is active in the earlier stages of trophoblastic invasion and becomes reactivated several weeks later. Derangement in the cascade (upregulation) and abnormal secondary invasion is thought by most to be the phenomenon at the origin of pre-eclampsia. If severe, it can also be responsible for early miscarriages while, if less severe, it may induce other pathological conditions, such as IUGR [19], [26]. Extravillous trophoblast apoptosis, however, has been found to be reduced in pre-eclampsia [27]. In 75–90% of cases of “placenta-induced” IUGR, uterine artery will demonstrate abnormal Doppler velocimetry [24], [27]. Endothelial dysfunction too is involved in the process of abnormal placentation in pre-eclampsia and IUGR [26], [29]. Abnormal uterine artery Doppler velocimetry is observed in most cases of early onset pre-eclampsia and IUGR, in association with laboratory signs of endothelial dysfunction and less in late-onset pre-eclampsia where such dysfunction is not observed [28].

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3. Imaging technologies 

There is a large variety of techniques for placental imaging, many of them pioneered by Panigel in animal imaging, such as radioisotope scintigraphy, thermography and magnetic resonance imaging with gadolinium [8]. Some early technologies were used in animals with variable degrees of success but less in humans, in some cases because of concerns for safety of the fetus. Presently ultrasound and, to a much lesser extent, magnetic resonance imaging, are the options of choice for imaging of the placenta in health and disease. In the future, the use of ultrasound contrast agents will, undoubtedly, bring further understanding to placental implantation process and physiopathology.

3.1. Early technologies (for more details and references, see [8]) 

These have been used successfully as a placental imaging technique but mostly in animal and laboratory setups because they are far too invasive for human studies: conventional X-rays, particularly angiography, with injection of contrast agents; computer-assisted tomography; radionuclide scintigraphy to localise implantation, study haemodynamics and diagnose placenta previa; thermography; magnetic resonance imaging and its variations, such as microscopic MR, MR angiography, particularly with gadolinium DTPA, MR spectroscopy; and positron emission tomography (PET) which allows analysis of materno-fetal transport and placental blood volume. Some, if not most of these methods (except MR) are contraindicated in the pregnant human and have essentially been replaced by ultrasound.

3.2. Where are we now? 

Ian Donald is credited with the first publication, in 1958, in the Lancet, on the use of ultrasound in abdominal masses, Since then, its use has burgeoned to a point that virtually every pregnant woman who receives prenatal care will have, at least, 1 (and, often, many more) ultrasound scans. Ultrasound imaging has an excellent record of safety in pregnancy and it has rapidly supplanted all other techniques used to study human pregnancy in general and the placenta in particular. Conventional B-mode ultrasound can give information on the general appearance of the placenta and its location but none on its function [9]. In combination with colour flow imaging, it permits direct visualisation of placental vasculature which can then be interrogated by spectral Doppler to obtain in vivo functional assessment of both uteroplacental and fetoplacental circulations in health and disease with correlation with placental histomorphology [30], [31], [32], [33], [34]. In 1977, the first description of “noninvasive measurement of human fetal circulation using ultrasound…” with continuous Doppler was published [35]. The Doppler principle was applied earlier to placental flow [10] but without the discrimination that Fitzgerald and Drumm brought [35]. Studies of early placental physiology are possible. The question of when does maternal- fetal circulation establishes itself can, thus, be addressed [6], [7], [33]. Some authors maintain that it is present since the earliest stages of gestation [36]. Others uphold that there is no intervillous flow in the first trimester and that actual circulation begins only around 10–12weeks [37]. If earlier connection occurs, this is pathological [23]. It has been reported that the placenta appears hypervascular in pregnancies destined to miscarry [13], [24]. Improving technologies, such as the use of contrast agents (vide infra) may allow better observation of the very early placental circulation, as proposed by Jauniaux in an excellent editorial [38]. Physiopathology of the placenta later in pregnancy is clearer.

Abnormal placental development as expressed by increased ultrasonographic placental thickness [39], [40] and morphologic characteristics and abnormal uterine Doppler velocimetry is associated with subsequent abnormal fetal growth or hypertensive disorders of pregnancy [29], [41]. Blood flow indices (ratio of systolic to diastolic velocity [S/D] or combination thereof, such as resistive [S-D/S] and pulsatility indices [S-D/mean]) diminish as pregnancy progresses, both in the maternal (uterine) and fetal (umbilical artery) circulations, a sign of increased vascularity in the placenta [20], [30], [41]. When certain complications occur, either because of or associated with increased placental resistance, the indices are elevated [31], [42]. Correlation between abnormal indices and placental morphopathology has been documented [31]. As previously described, in normal development, secondary to trophoblastic invasion, resistance is greatly reduced in the uterine and umbilical arteries [17]. Therefore, in general, after 20–22weeks’ gestation, profuse end diastolic velocity should be displayed in spectral Doppler of both circulations. Decreased end-diastolic velocity and presence of an early diastolic notch are signs of increased resistance and predict the onset of pre-eclampsia or IUGR [19], [43], [44]. Prognosis for the fetus is much worse with absent or reverse end-diastolic velocity in the umbilical artery [32], [45], a sign of extremely elevated placental vascular resistance because of vessel obliteration by the disease process [46]. It is interesting to note that placental vascular disease, as determined by Doppler analysis has been associated with a fetal inflammatory response, also expressed by increased cytokine [47]. Because of placental reserves, the signal in the umbilical artery can still be normal, although placental disease is advanced. This is why certain authors recommend analysis of the internal placental vessels, in addition to, or even rather than, the umbilical artery [48], [49]. Intraplacental blood flow determination was more sensitive than umbilical artery blood flow in detecting abnormal umbilical-placental flow impedances as manifested by the presence of IUGR [48]. This takes several forms: colour Doppler, power (also known as energy) Doppler and colour velocity imaging (CVI). While colour Doppler is based on a frequency change, power Doppler is based on an amplitude changes, hence is more sensitive and thus offers better imaging of slow flow but is non-directional. This allows visualisation of details of the villous tree, as soon as the first trimester [50]. Abnormal (decreased) invasion by the trophoblast can be observed [51]. Several conditions have thus been studied, IUGR in particular with correlation between the clinical picture and a reduced number of detectable intraplacental tertiary-stem villi arteries and branches [52]. With CVI, the position of a group of erythrocytes is recorded with an ultrasound beam. A second beam is emitted a few moments later to verify the new position of the cells, thus calculating flow velocities. The two most investigated pregnancy conditions, most particularly with Doppler are pre-eclampsia [28], [34] and IUGR [43], [52]. In IUGR, Doppler permits close follow-up of fetal well-being since there appears to be a sequence of events with changes in different vascular beds associated with worsening health status [53], [54]. Although it has been analyzed much less than the arterial beds, the venous system appears to be very important in predicting acid–base fetal status when arterial Doppler shows elevated resistance [55].

A relatively new application of ultrasound is three-dimensional reconstruction (3D) and its expansion, real-time 3D or 4D ultrasound. Combination of 3D with colour and Doppler permit amazing representation of the vascular tree, a method often referred to as 3D power colour angio and described both in normal pregnancies [15] as well as numerous pathologies [14], [15], [56]. Placental volume is easier to estimate with 3D ultrasound [57], [58]. This method has been used in a research setting and may be a potential tool for prediction of chromosomal anomalies, where placental volume is decreased early in gestation [59].

Other placental pathologies can also be investigated by ultrasound, particularly with spectral and colour Doppler, as well as 3D/4D: abnormal placentation-placenta previa, accreta, increta, percreta [60], velamentous insertion of the cord [61], vasa previa, as well as placental tumors [62], for instance.

MR is an adjunct to and, occasionally, a rival of ultrasound in placental imaging [63]. It can demonstrate maternal pelvic structures, localise the site of implantation of the placenta, detect the presence of placenta previa or the different forms of placenta accreta, as well as retroplacental haematomas in placental abruption. More to the point of the present review, MR imaging has been used to assess fetal and placental volumes to evaluate normal and disturbed growth [64]. It can be used by itself or with contrast agents, gadolinium compounds in particular. Even without injection of contrast agent, MR can create an angiography-like image, utilising different techniques, such as maximum intensity projection. With improved resolution (down to 4μm), one can now speak of microscopic MR [65]. Functional changes in the placenta, in normal pregnancies and those affected by pre-eclampsia and/or IUGR have been described from 16 to 36weeks’ gestation [66]. The actual volume of blood moving within different regions of the placenta can be estimated with MR [67]. This perfusion fraction mapping identified differences in function within the normal placenta in vivo and between the placentae of 13 normal and 7 pregnancies with growth-restricted fetuses [67]. Placental perfusion has been measured in mice with dynamic MRI [68]. For now, however, in the vast majority of clinical situations, ultrasound remains, by far, the preferred mode of imaging.

A detailed discussion of all placental pathologies diagnosable by contemporary technologies is well beyond the scope of the present review; however, a brief description may benefit the reader. This will consist only of definition of the condition and criteria for imaging diagnosis, mostly by ultrasound which is the preferred clinical imaging method. Clinical material will not be covered. The interested reader may find this in textbooks and various articles [60], [69].

The following major conditions will be considered: placenta previa, placenta accreta, vasa previa (although not genuinely a placental condition), abruption placenta, placental calcifications, gestational trophoblastic disease, and non-trophoblastic placental tumors.

5.Placental calcifications: Ultrasonically detectable placental changes are correlated with fetal maturity, and the placenta is known to mature and calcify [76]. Significant placental calcifications are rarely seen before 37weeks’ gestation. At 40weeks’ gestation or beyond, about 20% of placentas have extensive calcification (Grannum grade 3). Placental grading was not found useful to predict postmaturity and fetal distress [76]. Nevertheless, recently, McKenna et al. [77] determined the significance of an inappropriately mature calcified placenta on ultrasound examination, and concluded that ultrasound detection of a grade 3 placenta at 36weeks’ gestation might help to identify the “at-risk” pregnancy. It helps to predict subsequent development of gestational hypertension and may help in identifying the growth-restricted baby.

In addition, in several conditions the placenta will appear thick or oedematous, for instance in fetal hydrops (whether immune or non-immune), and, particularly, in several infections such as syphilis and cytomegalovirus [81].

3.3. Where are we headed? 

Ultrasound and, to a lesser degree, MR will continue to be the major imaging techniques utilised in placental physiology and fetal development. Some new modalities are experimented with and will further enhance imaging: ultrasound contrast agents and several expansions of MR imaging.

Ultrasound is based on the pulse-echo principle: the incident beam hits reflectors, echoes are produce and return to be captured and processed. More reflectors in the tissue should create more echoes and bring additional information, particularly for areas which, naturally, do not contain a large quantity of reflectors, such as cavities or small blood vessels. This forms the basis of the use of ultrasound contrast agents. These can be solid particles in suspension, liquid droplets in emulsion, gas bubbles, encapsulated or not. Colour enhancement of placental blood flow has been described in pregnant macaque monkeys with the use of Levovist [82] and Albunex [83]. With Levovist injections, researchers were able to show changes in flow in small vessels in a fetal sheep model during hypoxic episodes [84]. Intervillous flow could be demonstrated y ultrasound with injection of contrast agent in third-trimester rhesus monkeys [85] and baboons [82], [86]. In perfused human placenta experiments, improvement in grey-scale imaging was obtained, and spectral Doppler studies with the use of UCM (Albunex or iodipamide ethyl ester) demonstrated increase in the echogenicity of the placenta, when injected in the fetal side and a major increase in the Doppler signal which was very weak before the injection [87]. Furthermore, changes induced by injection of vasoactive substances to the model, either U46619, a thromboxane agonist or the vasodilator nitroglycerine, were easily observed [87]. Other contrast agents have also been useful for enhancement of ultrasound imaging in placental perfusion experiments [88]. The technique has been described in the human, without any evident harmful side effects to the mother or the fetus [89]. In particular, the agent SH U 508A (Levovist; Shering, Berlin, Germany) was used in cases of twin pregnancy to confirm interfetal transfusion in monochorionic twins in pregnancies with twin–twin transfusion syndrome, because of the high risk associated with such connection. The agent was injected, under ultrasound guidance, into the intrahepatic portion of the umbilical vein of one fetus and allowed detection of the agent in the second twin, if the direct connection existed. Surprisingly, imaging of the placental angioarchitecture was not improved with injection of the contrast agent [90]. A further technological advance is the use of nanomolecular agents. While previously mentioned agents are in the range of several microns (microbubbles), nanomolecular agents are in the nanometre range and are used in an attempt to image processes at the cellular or molecular levels. Many techniques can be adapted, such as radionuclide (PET) and optical imaging, MRI, CT and ultrasound. While they are too small to be resolved by ultrasound, one can attach to them monoclonal antibodies, ligands, peptides etc. This confers high specificity, allowing active targeted imaging. They have already been used in several clinical situations [91] and may have potential applications in obstetrics and gynaecology, such as analysis of early maternal–fetal communications, uterine vascularisation, placental blood flow and its control, as well as studies of the placental barrier [16].

These are existing applications of MR, not yet in extensive use. MR spectroscopy analyses the energy levels of several elements (ATP for instance) to help characterise metabolic processes and disturbances thereof. It has been used in animals and in dually perfused human term placentae and may, in the future, be used in functional analysis of the placenta in fetal disorders, particularly IUGR, although reconstruction time is still too long for efficient clinical use [92]. Equally important, MR microscopy with improving resolution is already capable of examining tissues in vivo at the cellular level, including the placenta [93] and will most likely play an increasing role in the future.

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4. Conclusions 

Several serious pathological conditions of pregnancy originate in abnormal placentation, particularly faulty trophoblastic invasion: pre-eclampsia and some forms of IUGR for instance. Although both these conditions seem to result from a similar placental pathology, and both have endothelial dysfunction, pre-eclampsia is associated with signs of inflammation (elevated cytokines) and abnormal maternal metabolism while pure IUGR may not be [29]. Many imaging techniques permit exploration of placental morphology and function and have been used to predict complications or formulate a prognosis regarding perinatal outcome. Ultrasound, in all its modality (B-mode, colour, power and spectral Doppler, 3D/4D and contrast-agent enhanced) is unquestionably, at the moment, the optimal method of examination in a clinical setting but magnetic resonance imaging may also play a large role. Both MR and ultrasound will certainly evolve to a much more common use of contrast agents with dedicated target organs [94] with better insight on placental haemodynamics, placental transfer, early maternal–fetal connection and fetal development, allowing further understanding of their impact on the course of pregnancy.

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