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Distal villous hypoplasia
MINI-SYMPOSIUM: PLACENTAL AND TROPHOBLASTIC PATHOLOGY
Distal villous hypoplasia
process of villous development is disrupted the result may be intrauterine growth restriction (IUGR). IUGR is a serious pregnancy complication that may result in intrauterine fetal death, indicated preterm delivery for reasons of fetal protection, adverse neurodevelopmental outcomes and increased risks of adult cardiovascular disease.1e3 Causes of IUGR include environmental, maternal, uteroplacental and fetal factors,1,4,5 while placental pathologies associated with IUGR include infection, chronic villitis of unknown etiology, chronic intervillositis, massive perivillous fibrinoid deposition/maternal floor infarction, fetal thrombotic vasculopathy and lesions of uteroplacental malperfusion. In this review we concentrate on villous maldevelopment and specifically on distal villous hypoplasia (DVH) as a cause for IUGR, because a greater understanding of the events that regulate the formation of gas-exchanging terminal villi could assist with the development of screening methods for at-risk pregnancies and reduce the rate of stillbirth due to placental vascular insufficiency.
Brendan Fitzgerald John Kingdom Sarah Keating
Abstract Distal villous hypoplasia is a form of placental villous maldevelopment that has the potential to cause significant intrauterine growth restriction with adverse consequences for fetal viability, neurodevelopmental outcome and adult cardiovascular health. It is characterized by a sparse, poorly developed distal villous tree with abnormally shaped, elongated, slender villi and widening of the intervillous space. Generally, villi show widespread trophoblast abnormalities with thinning of the villous trophoblast layer, reduction in cytotrophoblast numbers, evidence of a widespread increase in syncytiotrophoblast nuclear senescence and wave-like syncytial knots. Investigation of pregnancies with false positive serum screening tests for fetal aneuploidy/structural defects can help identify pregnancies at risk of placental insufficiency, particularly when combined with ultrasound assessment of placental morphology at 19e22 weeks. Identification of pregnancies with multiple abnormal tests of placental function permits high-risk specialist referral to optimize maternal-fetal outcome.
Pathology of distal villous hypoplasia Severe, early onset IUGR is typically identified before 32 weeks gestational age in association with abnormal umbilical artery Doppler studies [absent or reduced end diastolic flow (AREDF)]. This Doppler flow abnormality is a consequence of increased impedance to fetal blood flow caused in part by underdevelopment of the peripheral placental vascular bed. The dominant corresponding villous pathology, know as DVH, is characterized by a hypoplastic, sparse villous tree with a predominantly non-branched villous capillary network.6e8 This results in reduced numbers of abnormally shaped, long, slender villi with accompanying relative prominence of the intervillous space.6,7 In diagnostic pathology, DVH may be observed in two overlapping clinicopathological scenarios. When DVH is extensive it is associated, as will be discussed in this review, with severe, early onset IUGR. When present in small areas of the placenta, DVH may not be the dominant pathological process and instead its presence may be combined with that of other placental lesions such as decidual vasculopathy and infarction to provide evidence for a global diagnosis of maternal vascular underperfusion (MVU).9 As IUGR and preeclampsia frequently co-exist clinically and have common elements in their pathogenesis, it is not surprising that DVH and lesions associated with MVU may also co-exist, with their relative prominence in a given placenta varying depending on the clinical presentation.
Keywords abnormal umbilical Doppler; distal villous hypoplasia; intrauterine growth restriction; maternal serum screening; placental insufficiency; placental ultrasound; wave-like syncytial knots
Introduction Successful pregnancy outcome requires much more than mere transformation of the uteroplacental arteries by the invasive extravillous trophoblast. Even though there is high volume flow of maternal blood into the intervillous space, low fractional extraction by the fetus means that the elaboration of chorionic villi is rate limiting for fetal growth. By the end of the first trimester, the developing villi are vascularized and thereafter, the villous tree grows, to exponentially expand the surface area available for active and diffusional exchange; when this normal
Brendan Fitzgerald MSc FRCPath is a Consultant Histopathologist at Cork University Hospital, Cork, Ireland. Conflicts of interest: none declared.
Gross features One of the most common pathological features in IUGR is a reduction in placenta size.10 When DVH is extensive it is likely to be associated with a small placenta but when DVH is focal the placental weight may be normal. Not all small placentas will show DVH however, as both appropriate villous development and distal villous immaturity may be seen in this situation. It is therefore appropriate to distinguish placental hypoplasia from DVH. As abnormally small placentas appear to result from excessive regression of the chorion frondosum in early gestation,11 placentas from IUGR infants with AREDF may also show
John Kingdom MD is a Professor, Department of Obstetrics and Gynecology, University of Toronto; and Staff Obstetrician, Maternal-Fetal Medicine Division, Mount Sinai Hospital, Toronto, Ontario, Canada. Conflicts of interest: none declared. Sarah Keating MD MSc is an Associate Professor, Department of Laboratory Medicine and Pathobiology, University of Toronto; and Staff Pathologist and Head of Perinatal Pathology Program, Mount Sinai Hospital, Toronto, Ontario, Canada. Conflicts of interest: none declared.
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MINI-SYMPOSIUM: PLACENTAL AND TROPHOBLASTIC PATHOLOGY
other features thought to be related to this abnormal chorion regression such as marginal cord insertions.12 Because development of the villous tree is stunted in DVH, the intervillous space is widened and the cut surface of the placental parenchyma may appear to have a loose texture or appear ragged (Figure 1). The parenchyma may also show focal lesions that are secondary to the DVH itself or that are related to MVU. Organizing thrombi that form as a patchy layer on the fetal aspect of the basal plate have been described in placentas showing DVH.13 Called basal plate plaques these may be recognized in placental cross sections as areas of thickening and discolouration of the basal plate. We have also observed cases of massive subchorionic thrombohematomas (Breus’ mole) in placentas with DVH. In both these scenarios it may be that the increased intervillous space characteristic of DVH, leads to abnormal intervillous circulation and an increased risk of these patterns of thrombosis. Because DVH and lesions of MVU often co-exist, gross evidence of parenchymal injury may also be present, for example placental infarcts or areas of increased perivillous fibrinoid. Microscopic features In standard histological sections distal gas-exchanging villi in DVH are few and widely spaced, with an apparent increase in the intervillous space (Figure 2). As terminal villi are normally scarce immediately beneath the chorionic plate, interpretation of villous spacing should be made in central area of lobules in the lower 3/4 a full thickness placental section.9 Care should thus be taken with fragmented specimens or incomplete sections to ensure that correct regions of the villous tree are being evaluated. Since the villi contain simple, long, non-branched capillary networks the overall villous shape, which is in part determined by the type of angiogenesis, is also long, slender and finger-like (Figure 3). In conventional two-dimensional H&E sections, these villi are represented in their long axis by long, unbranched longitudinal profiles and by cross-sectional profiles with abnormally small diameters.14 The villous stroma can show increased density as a result of deposition of collagens and laminins.7 In many cases the overlying syncytiotrophoblast layer is thinned (Figure 4b) and shows a general increase in nuclear
Figure 2 Low power appearance of DVH. Panel a shows the typical appearance of DVH in this second trimester placenta. Distal villi are small in calibre and widely spaced resulting in prominence of the intervillous space. In panel b the reduction in distal villous development has resulted in abnormal clustering of more proximal stem villi (arrowheads). Wavelike syncytial knots give a ragged, saw-tooth appearance to the edge of stem villi (arrow). [H&E, 50 original magnification].
hyperchromasia that is suggestive of nuclear senescence/ progression to apoptosis.7,15,16 Although not readily appreciated in routine H&E sections, a reduction in the numbers of underlying cytotrophoblast cells has been demonstrated.7,15 Even though the overlying syncytiotrophoblast is generally thinned, increased numbers of focal bulbous aggregates of syncytiotrophoblast nuclei (syncytial knots) are usually present (Figure 4).7,15,16 The syncytial knots in DVH appear to result from aggregation of senescent/apoptotic syncytial nuclei in transversely arranged ridges15 that can be readily-observed by scanning electron microscopy (SEM). Kaufmann and Huppertz described these distinctive structures in cases of severe IUGR with AEDF as “wave-like apoptotic shedding”16 and they correspond to the syncytial “wrinkles” described in the scanning electron microscopy studies of Krebs et al.6 We prefer the term wave-like syncytial knots (WLSK) to describe these nuclear aggregations since nuclear aggregates such as these may retain transcriptional activity and thus may not all be apoptotic.17,18 It is proposed that WLSK form by aggregation of syncytial nuclei along lines of nuclear organization that are intrinsic to the
Figure 1 Gross section of a placenta with DVH. The ragged appearance of the placental texture is apparent on the right of the image. The white arrows indicate areas of basal plate discolouration corresponding to basal plate plaques. The white arrowheads highlight a large subchorionic thrombohematoma that appears to be progressively filling an abnormally large space beneath the chorionic plate (red arrowhead). Such a placenta would appear thick on placental ultrasound but the amount of functional villous tissue is small.
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MINI-SYMPOSIUM: PLACENTAL AND TROPHOBLASTIC PATHOLOGY
there is increased villous branching resulting in an increase in syncytial knots caused by tangential sectioning (Tenney-Parker change). DVH may occur in the absence of WLSK although these other trophoblast abnormalities are not well characterized. It is difficult to know if they reflect a different pathological mechanism or a just an earlier phase of the same process. One illustration is the presence of prominent, demarcated areas of trophoblast necrosis in the absence of villous agglutination or infarction.15 With further research other specific patterns of trophoblast pathology may emerge. In the meantime it may be prudent to simply describe the overall villous developmental anomaly first (DVH) and to then add a qualifier to describe the appearance of the covering trophoblast e.g. distal villous hypoplasia with wave-like syncytial knots; distal villous hypoplasia with prominent trophoblast necrosis etc.
Pathogenesis The strongest determinant of placental weight percentile at delivery is surface area of attachment to the uterine wall; since the distinction between definitive placenta (chorion frondosum) and membranes (chorion leave), and thus placental size, is defined during implantation in the first trimester11 it is likely that the risk of a small placenta is conferred during the period of embryogenesis. The implanting placenta secretes pregnancyassociated placental protein A (PAPP-A) into maternal blood; PAPP-A is now routinely measured at 10e13 weeks gestation as part of first trimester screening for trisomy 21 and follow-up of false-positive screen tests in large cohorts, especially in younger women, reveal significant associations with adverse pregnancy outcomes that were unrelated to aneuploidy, especially stillbirth and IUGR. The risk of stillbirth is 40-fold increased in women with low PAPP-A and subsequent elevated alpha-fetoprotein (AFP) [at the 16-week screening blood test to screen for neural tube and abdominal wall defects].20 Interestingly, ultrasound evaluation at 19e22 weeks in pregnancies with low PAPP-A levels <0.3 multiples of median (MOM) reveals that small placental size, often with eccentric cord insertion, correlates with extreme preterm delivery or stillbirth due to severe IUGR.21 Low first-trimester PAPP-A levels have also been associated in placental morphometric studies with smaller terminal villous volume in IUGR pregnancies.22 Therefore, an important concept emerging is that DVH is part of a more fundamental defect in placentation that begins in the first trimester. Villous growth is dependent on co-ordination of trophoblast and vascular proliferation through complex mechanisms that likely involve the intervening mesenchymal cells. As would be expected from this, defects in trophoblast differentiation and turnover have been implicated in intrauterine growth restriction.23e25 While defects in extravillous trophoblast would lead to defective placental implantation, defects in villous trophoblast would have direct effects on villous growth. Such a link between abnormal villous trophoblast differentiation and abnormal villous development is supported by the presence of DVH in a group of pregnancies with adverse outcomes where there was elevation of second trimester screening markers Inhibin-A and human chorionic gonadotropin (hCG). As both markers are produced by syncytiotrophoblast, the increased inhibin-A and
Figure 3 Abnormal distal villous development. Panel a shows the H&E appearance of a typical, abnormally long, slender and non-branching villous of DVH [200 original magnification]. The villous also shows increased stromal density and low vascularity. Panel b shows a scanning electron microscopy (SEM) image of two such villi, highlighting their filiform shape. A corresponding SEM image of a vascular cast shows that the capillaries loops run the length of the villous with little or no branching evident.
structure of the syncytiotrophoblast. These lines of nuclear organization are present even in normal placentas but the linear nuclear pattern is difficult to appreciate as it is only visible in rare foci where the syncytiotrophoblast is sectioned through its nuclei in a plane parallel to its syncytial surface (Figure 5). It is only when nuclei aggregate in a pathological manner, to form WLSK, that the organizational pattern becomes more obvious.15 Although true syncytial nuclear aggregations exist at points of villous growth (syncytial sprouts) or as packaged apoptotic nuclei about to be shed to the maternal circulation, most syncytial knots, have been shown to be artefacts due to tangential sectioning of the complex placental villous tree.19 Towards term, as branching angiogenesis progresses, villous tree complexity increases and these knots become more frequent. Villi in DVH have been referred to as “hypermature” or as showing “accelerated maturation” as they show a superficial resemblance to this normal maturation pattern because of their small size and prominent syncytial knots. We suggest that these terms should be avoided in DVH as there is no equivalent villous appearance in a normal mature placenta and because the syncytial knots in DVH form by a different mechanism. WLSK in DVH form not as an artefact related to villous tree complexity but as a manifestation of generalized pathological changes in villous trophoblast in a hypoplastic villous tree. Use of the term accelerated maturation should be restricted to situations where
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MINI-SYMPOSIUM: PLACENTAL AND TROPHOBLASTIC PATHOLOGY
Figure 4 Wave-like syncytial knots (WLSK). WLSK are often more readily appreciated along the edge of stem villi (arrowheads, panel a). In panel b the thinness of the trophoblast can be appreciated together with the generalized syncytial nuclear condensation indicative of nuclear senescence. A cytotrophoblast nucleus is highlighted for comparison (arrow). WLSK are also present (arrowhead). In panel c WLSK are seen in cross section (arrows) while arrowheads highlight the wave-like configuration of these knots along the long axis of the villous. [H&E, original magnifications (a) 200, (b) 400, (c) 200].
Sonographic correlates
hCG levels in this situation were proposed to be due to excessive syncytiotrophoblast production at the expense of cytotrophoblast proliferation, a situation that would eventually lead to cytotrophoblast depletion, global trophoblast depletion and impaired villous growth.15 A global trophoblast defect may thus reduce both implantation site size (resulting in placental hypoplasia) and villous growth (resulting in villous hypoplasia). The combination of small placental size and DVH will severely limit maternal-fetal exchange and cause IUGR independently of the maternal blood supply. This is supported by the finding that placental dysmorphology on ultrasound was found to be more predictive of adverse outcome due to IUGR than abnormal uterine artery Doppler.21
Maternal uterine artery and fetal Doppler monitoring play an important role in the diagnosis and management of pregnancy complications.26,27 The original pathological descriptions of the villous abnormalities that characterize DVH were facilitated by case-control studies of placental tissues from pregnancies with abnormal vs. normal umbilical artery Doppler studies.8 The recognition that AREDF in the umbilical arteries is associated with DVH has stimulated interest in direct sonographic evaluation of the placental size and structure, as opposed to Dopplerbased assessment of uteroplacental blood flow. Though the optimal technique of placental morphologic assessment has yet to be agreed upon it can be combined with both PAPP-A/AFP
Figure 5 Linear nuclear patterning. (a) Shows the normal linear arrangement of nuclei within the syncytioplasm. The arrow highlights a group of condensed, apoptotic nuclei. In b it is apparent how singly arranged nuclei may be inconspicuous (arrow) but accumulation of nuclei in the same linear pattern would eventually lead to ridge formation and WLSK (arrowheads). [H&E, original magnification 400].
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Research directions
blood testing and uterine artery Doppler to determine perinatal risk in cohorts of clinically high-risk pregnant women.28 We routinely use this approach at Mount Sinai Hospital, Toronto (www.mountsinai.on.ca/care/placenta-clinic) and offer a “placental ultrasound study” in a 19e22-week window to obstetricians worried about the potential risk of “placental insufficiency” in their patients, based upon age, medical and or obstetrical risk factors. Correlation of antenatal ultrasound findings with pathology at delivery has great potential to refine the optimal method/s of ultrasound assessment of the placenta. For example, when assessing the volume of placental “tissue” seen at 19e22 weeks, pathologic placentas with small areas of attachment may appear thick compared with normal placentas, with a greater degree of projection into the uterine cavity. These small, abnormally thick and wobbly/jelly-like placentas have been associated with poor obstetric outcome29 and increased thickness/width ratio is recognized as a marker of adverse outcome in women with low PAPPA.21 While it could be assumed that increased thickness is an attempt at compensating for a small placental implantation footprint, the increased sonographic volume may not be due to increased villous tissue. Our correlation between sonographic thickness and post-delivery thickness in these pathologic placentas shows that in many cases these placentas were merely inflated by maternal blood, collapsing at delivery and exhibiting DVH at pathological examination [unpublished data]. This abnormal inflation may be a consequence of reduced structural integrity caused by hypoplasia of the villous tree, as in this situation, reduced numbers of anchoring villi or rupture of anchoring villi would allow the chorionic plate to be displaced further from the basal plate. Thus, correlation of sonographic findings and pathological examination has shown that one potential limitation of 3D ultrasound for evaluation of villous tissue volume is that apparently increased invivo volume may in some cases be due to a pathological degree of inflation of the maternal space surrounding a hypoplastic villous tree rather than the presence of additional function tissue.
Uncover the mechanisms that control villous growth. Identify maternal serum markers specific to DVH that may be detected as early as possible in gestation. Determine the nature of the global trophoblast defect that may underlie DVH. Identify therapeutic agents that may act on this defect to limit its effect and encourage normal villous growth.
A
REFERENCES 1 Bamfo JE, Odibo AO. Diagnosis and management of fetal growth restriction. J Pregnancy 2011; 2011: 640715. Epub 2011 Apr 13. 2 Baschat AA. Neurodevelopment following fetal growth restriction and its relationship with antepartum parameters of placental dysfunction. Ultrasound Obstet Gynecol 2011; 37: 501e14. 3 Thornburg KL, O’Tierney PF, Louey S. Review: the placenta is a programming agent for cardiovascular disease. Placenta 2010; 31(suppl): S54e9. 4 Roberts DJ, Post MD. The placenta in pre-eclampsia and intrauterine growth restriction. J Clin Pathol 2008; 61: 1254e60. 5 Cox P, Marton T. Pathological assessment of intrauterine growth restriction. Best Pract Res Clin Obstet Gynaecol 2009; 23: 751e64. 6 Krebs C, Macara LM, Leiser R, Bowman AW, Greer IA, Kingdom JC. Intrauterine growth restriction with absent end-diastolic flow velocity in the umbilical artery is associated with maldevelopment of the placental terminal villous tree. Am J Obstet Gynecol 1996; 175: 1534e42. 7 Macara L, Kingdom JC, Kaufmann P, et al. Structural analysis of placental terminal villi from growth-restricted pregnancies with abnormal umbilical artery Doppler waveforms. Placenta 1996; 17: 37e48. 8 Jackson MR, Walsh AJ, Morrow RJ, Mullen JBM, Lye SJ, Ritchie JWK. Reduced placental villous tree elaboration in small-for-gestationalage pregnancies: relationship with umbilical artery Doppler waveforms. Am J Obstet Gynecol 1995; 172: 518e25. 9 Redline RW, Boyd T, Campbell V, et al. Maternal vascular underperfusion: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol 2004; 7: 237e49. 10 Teasdale F. Idiopathic intrauterine growth retardation: histomorphometry of the human placenta. Placenta 1984; 5: 83e92. 11 Jauniaux E, Hempstock J, Greenwold N, Burton GJ. Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancies. Am J Pathol 2003; 162: 115e25. 12 Nordenvall M, Ullberg U, Laurin J, Lingman G, Sandstedt B, Ulmsten U. Placental morphology in relation to umbilical artery blood velocity waveforms. Eur J Obstet Gynecol Reprod Biol 1991; 40: 179e90. 13 Fitzgerald B, Shannon P, Kingdom J, Keating S. Basal plate plaque: a novel organising placental thrombotic process. J Clin Pathol 2011; 64: 1e5. 14 Kraus F, Redline R, Gersell D, Nelson M, Dicke J, eds. AFIP atlas of nontumor pathology: placental pathology. Washington: American Registry of Pathology, 2004. 15 Fitzgerald B, Levytska K, Kingdom J, Walker M, Baczyk D, Keating S. Villous trophoblast abnormalities in extremely preterm deliveries with elevated second trimester maternal serum hCG or inhibin-A. Placenta 2011; 32: 339e45.
Conclusion DVH is a developmental defect affecting the placental villous tree that when severe results in IUGR with potentially serious adverse consequences for pregnancy outcome. Maternal serum markers, normally used for prenatal screening for fetal aneuploidy and structural defects (PAPP-A, AFP, Inhibin-A and hCG) may be used in combination with ultrasound assessment of placental morphology at 19e22 weeks to identify women with pregnancies at risk for placental insufficiency, many of which would show DVH at placental pathological evaluation. Early identification of such pregnancies allows for referral to high-risk specialists and maximizes the possibility of successful pregnancy outcome. Correlation of maternal serological and antenatal ultrasound findings with villous and trophoblast pathology at delivery provides an opportunity to optimize these screening modalities and will provide a basis for laboratory investigations into disease pathogenesis. As at-risk pregnancies are identified earlier in gestation and as the pathological basis of the disease is better understood, the ultimate goal will be pharmacologic intervention to modify the course of the disease and thus prevent associated fetal morbidity and mortality.
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16 Kaufmann P, Huppertz B. Tenney-Parker changes and apoptotic versus necrotic shedding of trophoblast in normal pregnancy and pre-eclampsia. In: Lyall F, Belfort M, eds. Pre-eclampsia: etiology and clinical practice. New York: Cambridge University Press, 2007; 152e163. 17 Ellery PM, Cindrova-Davies T, Jauniaux E, Ferguson-Smith AC, Burton GJ. Evidence for transcriptional activity in the syncytiotrophoblast of the human placenta. Placenta 2009; 30: 329e34. 18 Burton GJ, Jones CJP. Syncytial knots, sprouts, apoptosis, and trophoblast deportation from the human placenta. Taiwan J Obstet Gynecol 2009; 48: 28e37. 19 Castellucci M, Kaufmann P. Basic structure of the villous tree. In: Benirshke K, Kaufmann P, Baergen R, eds. Pathology of the human placenta. New York: Springer, 2006; 50e120. 20 Smith GCS, Shah I, Crossley JA, et al. Pregnancy-associated plasma protein A and alpha-fetoprotein and prediction of adverse perinatal outcome. Obstet Gynecol 2006; 107: 161e6. 21 Proctor LK, Toal M, Keating S, et al. Placental size and the prediction of severe early-onset intrauterine growth restriction in women with low pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol 2009; 34: 274e82. 22 Odibo AO, Zhong Y, Longtine M, et al. First-trimester serum analytes, biophysical tests and the association with pathological morphometry in the placenta of pregnancies with preeclampsia and fetal growth restriction. Placenta 2011; 32: 333e8. 23 Chaddha V, Viero S, Huppertz B, Kingdom J. Developmental biology of the placenta and the origins of placental insufficiency. Semin Fetal Neonatal Med 2004; 9: 357e69. 24 Scifres CM, Nelson DM. Intrauterine growth restriction, human placental development and trophoblast cell death. J Physiol 2009; 587: 3453e8.
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25 Sharp AN, Heazell AEP, Crocker IP, Mor G. Placental apoptosis in health and disease. Am J Reprod Immunol 2010; 64: 159e69. 26 Ghidini A, Locatelli A. Monitoring of fetal well-being: role of uterine artery Doppler. Semin Perinatol 2008; 32: 258e62. 27 Mari G, Hanif F. Fetal Doppler: umbilical artery, middle cerebral artery, and venous system. Semin Perinatol 2008; 32: 253e7. 28 Toal M, Chan C, Fallah S, et al. Usefulness of a placental profile in high-risk pregnancies. Am J Obstet Gynecol 2007; 196: 363.e1e7. €rig P, Schneider H. The thick 29 Raio L, Ghezzi F, Cromi A, Nelle M, Du heterogeneous (jellylike) placenta: a strong predictor of adverse pregnancy outcome. Prenat Diagn 2004; 24: 182e8.
Practice points C
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DVH is characterized by the presence of stunted villous development with widely spaced, abnormally thin, long, nonbranching villi set in a relatively widened intervillous space. DVH is accompanied by widespread alterations in villous trophoblast that result in trophoblast thinning, nuclear senescence and wave-like syncytial knots. When DVH is extensive it is associated with intrauterine growth restriction with absent or reduced flow in the fetal umbilical arteries. Maternal serological markers and placental ultrasound may help identify pregnancies at risk of developing DVH and facilitate referral to high-risk pregnancy specialists, maximizing likelihood of successful outcome.
Ó 2012 Elsevier Ltd. All rights reserved.
Distal villous hypoplasia
process of villous development is disrupted the result may be intrauterine growth restriction (IUGR). IUGR is a serious pregnancy complication that may result in intrauterine fetal death, indicated preterm delivery for reasons of fetal protection, adverse neurodevelopmental outcomes and increased risks of adult cardiovascular disease.1e3 Causes of IUGR include environmental, maternal, uteroplacental and fetal factors,1,4,5 while placental pathologies associated with IUGR include infection, chronic villitis of unknown etiology, chronic intervillositis, massive perivillous fibrinoid deposition/maternal floor infarction, fetal thrombotic vasculopathy and lesions of uteroplacental malperfusion. In this review we concentrate on villous maldevelopment and specifically on distal villous hypoplasia (DVH) as a cause for IUGR, because a greater understanding of the events that regulate the formation of gas-exchanging terminal villi could assist with the development of screening methods for at-risk pregnancies and reduce the rate of stillbirth due to placental vascular insufficiency.
Brendan Fitzgerald John Kingdom Sarah Keating
Abstract Distal villous hypoplasia is a form of placental villous maldevelopment that has the potential to cause significant intrauterine growth restriction with adverse consequences for fetal viability, neurodevelopmental outcome and adult cardiovascular health. It is characterized by a sparse, poorly developed distal villous tree with abnormally shaped, elongated, slender villi and widening of the intervillous space. Generally, villi show widespread trophoblast abnormalities with thinning of the villous trophoblast layer, reduction in cytotrophoblast numbers, evidence of a widespread increase in syncytiotrophoblast nuclear senescence and wave-like syncytial knots. Investigation of pregnancies with false positive serum screening tests for fetal aneuploidy/structural defects can help identify pregnancies at risk of placental insufficiency, particularly when combined with ultrasound assessment of placental morphology at 19e22 weeks. Identification of pregnancies with multiple abnormal tests of placental function permits high-risk specialist referral to optimize maternal-fetal outcome.
Pathology of distal villous hypoplasia Severe, early onset IUGR is typically identified before 32 weeks gestational age in association with abnormal umbilical artery Doppler studies [absent or reduced end diastolic flow (AREDF)]. This Doppler flow abnormality is a consequence of increased impedance to fetal blood flow caused in part by underdevelopment of the peripheral placental vascular bed. The dominant corresponding villous pathology, know as DVH, is characterized by a hypoplastic, sparse villous tree with a predominantly non-branched villous capillary network.6e8 This results in reduced numbers of abnormally shaped, long, slender villi with accompanying relative prominence of the intervillous space.6,7 In diagnostic pathology, DVH may be observed in two overlapping clinicopathological scenarios. When DVH is extensive it is associated, as will be discussed in this review, with severe, early onset IUGR. When present in small areas of the placenta, DVH may not be the dominant pathological process and instead its presence may be combined with that of other placental lesions such as decidual vasculopathy and infarction to provide evidence for a global diagnosis of maternal vascular underperfusion (MVU).9 As IUGR and preeclampsia frequently co-exist clinically and have common elements in their pathogenesis, it is not surprising that DVH and lesions associated with MVU may also co-exist, with their relative prominence in a given placenta varying depending on the clinical presentation.
Keywords abnormal umbilical Doppler; distal villous hypoplasia; intrauterine growth restriction; maternal serum screening; placental insufficiency; placental ultrasound; wave-like syncytial knots
Introduction Successful pregnancy outcome requires much more than mere transformation of the uteroplacental arteries by the invasive extravillous trophoblast. Even though there is high volume flow of maternal blood into the intervillous space, low fractional extraction by the fetus means that the elaboration of chorionic villi is rate limiting for fetal growth. By the end of the first trimester, the developing villi are vascularized and thereafter, the villous tree grows, to exponentially expand the surface area available for active and diffusional exchange; when this normal
Brendan Fitzgerald MSc FRCPath is a Consultant Histopathologist at Cork University Hospital, Cork, Ireland. Conflicts of interest: none declared.
Gross features One of the most common pathological features in IUGR is a reduction in placenta size.10 When DVH is extensive it is likely to be associated with a small placenta but when DVH is focal the placental weight may be normal. Not all small placentas will show DVH however, as both appropriate villous development and distal villous immaturity may be seen in this situation. It is therefore appropriate to distinguish placental hypoplasia from DVH. As abnormally small placentas appear to result from excessive regression of the chorion frondosum in early gestation,11 placentas from IUGR infants with AREDF may also show
John Kingdom MD is a Professor, Department of Obstetrics and Gynecology, University of Toronto; and Staff Obstetrician, Maternal-Fetal Medicine Division, Mount Sinai Hospital, Toronto, Ontario, Canada. Conflicts of interest: none declared. Sarah Keating MD MSc is an Associate Professor, Department of Laboratory Medicine and Pathobiology, University of Toronto; and Staff Pathologist and Head of Perinatal Pathology Program, Mount Sinai Hospital, Toronto, Ontario, Canada. Conflicts of interest: none declared.
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Ó 2012 Elsevier Ltd. All rights reserved.
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other features thought to be related to this abnormal chorion regression such as marginal cord insertions.12 Because development of the villous tree is stunted in DVH, the intervillous space is widened and the cut surface of the placental parenchyma may appear to have a loose texture or appear ragged (Figure 1). The parenchyma may also show focal lesions that are secondary to the DVH itself or that are related to MVU. Organizing thrombi that form as a patchy layer on the fetal aspect of the basal plate have been described in placentas showing DVH.13 Called basal plate plaques these may be recognized in placental cross sections as areas of thickening and discolouration of the basal plate. We have also observed cases of massive subchorionic thrombohematomas (Breus’ mole) in placentas with DVH. In both these scenarios it may be that the increased intervillous space characteristic of DVH, leads to abnormal intervillous circulation and an increased risk of these patterns of thrombosis. Because DVH and lesions of MVU often co-exist, gross evidence of parenchymal injury may also be present, for example placental infarcts or areas of increased perivillous fibrinoid. Microscopic features In standard histological sections distal gas-exchanging villi in DVH are few and widely spaced, with an apparent increase in the intervillous space (Figure 2). As terminal villi are normally scarce immediately beneath the chorionic plate, interpretation of villous spacing should be made in central area of lobules in the lower 3/4 a full thickness placental section.9 Care should thus be taken with fragmented specimens or incomplete sections to ensure that correct regions of the villous tree are being evaluated. Since the villi contain simple, long, non-branched capillary networks the overall villous shape, which is in part determined by the type of angiogenesis, is also long, slender and finger-like (Figure 3). In conventional two-dimensional H&E sections, these villi are represented in their long axis by long, unbranched longitudinal profiles and by cross-sectional profiles with abnormally small diameters.14 The villous stroma can show increased density as a result of deposition of collagens and laminins.7 In many cases the overlying syncytiotrophoblast layer is thinned (Figure 4b) and shows a general increase in nuclear
Figure 2 Low power appearance of DVH. Panel a shows the typical appearance of DVH in this second trimester placenta. Distal villi are small in calibre and widely spaced resulting in prominence of the intervillous space. In panel b the reduction in distal villous development has resulted in abnormal clustering of more proximal stem villi (arrowheads). Wavelike syncytial knots give a ragged, saw-tooth appearance to the edge of stem villi (arrow). [H&E, 50 original magnification].
hyperchromasia that is suggestive of nuclear senescence/ progression to apoptosis.7,15,16 Although not readily appreciated in routine H&E sections, a reduction in the numbers of underlying cytotrophoblast cells has been demonstrated.7,15 Even though the overlying syncytiotrophoblast is generally thinned, increased numbers of focal bulbous aggregates of syncytiotrophoblast nuclei (syncytial knots) are usually present (Figure 4).7,15,16 The syncytial knots in DVH appear to result from aggregation of senescent/apoptotic syncytial nuclei in transversely arranged ridges15 that can be readily-observed by scanning electron microscopy (SEM). Kaufmann and Huppertz described these distinctive structures in cases of severe IUGR with AEDF as “wave-like apoptotic shedding”16 and they correspond to the syncytial “wrinkles” described in the scanning electron microscopy studies of Krebs et al.6 We prefer the term wave-like syncytial knots (WLSK) to describe these nuclear aggregations since nuclear aggregates such as these may retain transcriptional activity and thus may not all be apoptotic.17,18 It is proposed that WLSK form by aggregation of syncytial nuclei along lines of nuclear organization that are intrinsic to the
Figure 1 Gross section of a placenta with DVH. The ragged appearance of the placental texture is apparent on the right of the image. The white arrows indicate areas of basal plate discolouration corresponding to basal plate plaques. The white arrowheads highlight a large subchorionic thrombohematoma that appears to be progressively filling an abnormally large space beneath the chorionic plate (red arrowhead). Such a placenta would appear thick on placental ultrasound but the amount of functional villous tissue is small.
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there is increased villous branching resulting in an increase in syncytial knots caused by tangential sectioning (Tenney-Parker change). DVH may occur in the absence of WLSK although these other trophoblast abnormalities are not well characterized. It is difficult to know if they reflect a different pathological mechanism or a just an earlier phase of the same process. One illustration is the presence of prominent, demarcated areas of trophoblast necrosis in the absence of villous agglutination or infarction.15 With further research other specific patterns of trophoblast pathology may emerge. In the meantime it may be prudent to simply describe the overall villous developmental anomaly first (DVH) and to then add a qualifier to describe the appearance of the covering trophoblast e.g. distal villous hypoplasia with wave-like syncytial knots; distal villous hypoplasia with prominent trophoblast necrosis etc.
Pathogenesis The strongest determinant of placental weight percentile at delivery is surface area of attachment to the uterine wall; since the distinction between definitive placenta (chorion frondosum) and membranes (chorion leave), and thus placental size, is defined during implantation in the first trimester11 it is likely that the risk of a small placenta is conferred during the period of embryogenesis. The implanting placenta secretes pregnancyassociated placental protein A (PAPP-A) into maternal blood; PAPP-A is now routinely measured at 10e13 weeks gestation as part of first trimester screening for trisomy 21 and follow-up of false-positive screen tests in large cohorts, especially in younger women, reveal significant associations with adverse pregnancy outcomes that were unrelated to aneuploidy, especially stillbirth and IUGR. The risk of stillbirth is 40-fold increased in women with low PAPP-A and subsequent elevated alpha-fetoprotein (AFP) [at the 16-week screening blood test to screen for neural tube and abdominal wall defects].20 Interestingly, ultrasound evaluation at 19e22 weeks in pregnancies with low PAPP-A levels <0.3 multiples of median (MOM) reveals that small placental size, often with eccentric cord insertion, correlates with extreme preterm delivery or stillbirth due to severe IUGR.21 Low first-trimester PAPP-A levels have also been associated in placental morphometric studies with smaller terminal villous volume in IUGR pregnancies.22 Therefore, an important concept emerging is that DVH is part of a more fundamental defect in placentation that begins in the first trimester. Villous growth is dependent on co-ordination of trophoblast and vascular proliferation through complex mechanisms that likely involve the intervening mesenchymal cells. As would be expected from this, defects in trophoblast differentiation and turnover have been implicated in intrauterine growth restriction.23e25 While defects in extravillous trophoblast would lead to defective placental implantation, defects in villous trophoblast would have direct effects on villous growth. Such a link between abnormal villous trophoblast differentiation and abnormal villous development is supported by the presence of DVH in a group of pregnancies with adverse outcomes where there was elevation of second trimester screening markers Inhibin-A and human chorionic gonadotropin (hCG). As both markers are produced by syncytiotrophoblast, the increased inhibin-A and
Figure 3 Abnormal distal villous development. Panel a shows the H&E appearance of a typical, abnormally long, slender and non-branching villous of DVH [200 original magnification]. The villous also shows increased stromal density and low vascularity. Panel b shows a scanning electron microscopy (SEM) image of two such villi, highlighting their filiform shape. A corresponding SEM image of a vascular cast shows that the capillaries loops run the length of the villous with little or no branching evident.
structure of the syncytiotrophoblast. These lines of nuclear organization are present even in normal placentas but the linear nuclear pattern is difficult to appreciate as it is only visible in rare foci where the syncytiotrophoblast is sectioned through its nuclei in a plane parallel to its syncytial surface (Figure 5). It is only when nuclei aggregate in a pathological manner, to form WLSK, that the organizational pattern becomes more obvious.15 Although true syncytial nuclear aggregations exist at points of villous growth (syncytial sprouts) or as packaged apoptotic nuclei about to be shed to the maternal circulation, most syncytial knots, have been shown to be artefacts due to tangential sectioning of the complex placental villous tree.19 Towards term, as branching angiogenesis progresses, villous tree complexity increases and these knots become more frequent. Villi in DVH have been referred to as “hypermature” or as showing “accelerated maturation” as they show a superficial resemblance to this normal maturation pattern because of their small size and prominent syncytial knots. We suggest that these terms should be avoided in DVH as there is no equivalent villous appearance in a normal mature placenta and because the syncytial knots in DVH form by a different mechanism. WLSK in DVH form not as an artefact related to villous tree complexity but as a manifestation of generalized pathological changes in villous trophoblast in a hypoplastic villous tree. Use of the term accelerated maturation should be restricted to situations where
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Figure 4 Wave-like syncytial knots (WLSK). WLSK are often more readily appreciated along the edge of stem villi (arrowheads, panel a). In panel b the thinness of the trophoblast can be appreciated together with the generalized syncytial nuclear condensation indicative of nuclear senescence. A cytotrophoblast nucleus is highlighted for comparison (arrow). WLSK are also present (arrowhead). In panel c WLSK are seen in cross section (arrows) while arrowheads highlight the wave-like configuration of these knots along the long axis of the villous. [H&E, original magnifications (a) 200, (b) 400, (c) 200].
Sonographic correlates
hCG levels in this situation were proposed to be due to excessive syncytiotrophoblast production at the expense of cytotrophoblast proliferation, a situation that would eventually lead to cytotrophoblast depletion, global trophoblast depletion and impaired villous growth.15 A global trophoblast defect may thus reduce both implantation site size (resulting in placental hypoplasia) and villous growth (resulting in villous hypoplasia). The combination of small placental size and DVH will severely limit maternal-fetal exchange and cause IUGR independently of the maternal blood supply. This is supported by the finding that placental dysmorphology on ultrasound was found to be more predictive of adverse outcome due to IUGR than abnormal uterine artery Doppler.21
Maternal uterine artery and fetal Doppler monitoring play an important role in the diagnosis and management of pregnancy complications.26,27 The original pathological descriptions of the villous abnormalities that characterize DVH were facilitated by case-control studies of placental tissues from pregnancies with abnormal vs. normal umbilical artery Doppler studies.8 The recognition that AREDF in the umbilical arteries is associated with DVH has stimulated interest in direct sonographic evaluation of the placental size and structure, as opposed to Dopplerbased assessment of uteroplacental blood flow. Though the optimal technique of placental morphologic assessment has yet to be agreed upon it can be combined with both PAPP-A/AFP
Figure 5 Linear nuclear patterning. (a) Shows the normal linear arrangement of nuclei within the syncytioplasm. The arrow highlights a group of condensed, apoptotic nuclei. In b it is apparent how singly arranged nuclei may be inconspicuous (arrow) but accumulation of nuclei in the same linear pattern would eventually lead to ridge formation and WLSK (arrowheads). [H&E, original magnification 400].
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Research directions
blood testing and uterine artery Doppler to determine perinatal risk in cohorts of clinically high-risk pregnant women.28 We routinely use this approach at Mount Sinai Hospital, Toronto (www.mountsinai.on.ca/care/placenta-clinic) and offer a “placental ultrasound study” in a 19e22-week window to obstetricians worried about the potential risk of “placental insufficiency” in their patients, based upon age, medical and or obstetrical risk factors. Correlation of antenatal ultrasound findings with pathology at delivery has great potential to refine the optimal method/s of ultrasound assessment of the placenta. For example, when assessing the volume of placental “tissue” seen at 19e22 weeks, pathologic placentas with small areas of attachment may appear thick compared with normal placentas, with a greater degree of projection into the uterine cavity. These small, abnormally thick and wobbly/jelly-like placentas have been associated with poor obstetric outcome29 and increased thickness/width ratio is recognized as a marker of adverse outcome in women with low PAPPA.21 While it could be assumed that increased thickness is an attempt at compensating for a small placental implantation footprint, the increased sonographic volume may not be due to increased villous tissue. Our correlation between sonographic thickness and post-delivery thickness in these pathologic placentas shows that in many cases these placentas were merely inflated by maternal blood, collapsing at delivery and exhibiting DVH at pathological examination [unpublished data]. This abnormal inflation may be a consequence of reduced structural integrity caused by hypoplasia of the villous tree, as in this situation, reduced numbers of anchoring villi or rupture of anchoring villi would allow the chorionic plate to be displaced further from the basal plate. Thus, correlation of sonographic findings and pathological examination has shown that one potential limitation of 3D ultrasound for evaluation of villous tissue volume is that apparently increased invivo volume may in some cases be due to a pathological degree of inflation of the maternal space surrounding a hypoplastic villous tree rather than the presence of additional function tissue.
Uncover the mechanisms that control villous growth. Identify maternal serum markers specific to DVH that may be detected as early as possible in gestation. Determine the nature of the global trophoblast defect that may underlie DVH. Identify therapeutic agents that may act on this defect to limit its effect and encourage normal villous growth.
A
REFERENCES 1 Bamfo JE, Odibo AO. Diagnosis and management of fetal growth restriction. J Pregnancy 2011; 2011: 640715. Epub 2011 Apr 13. 2 Baschat AA. Neurodevelopment following fetal growth restriction and its relationship with antepartum parameters of placental dysfunction. Ultrasound Obstet Gynecol 2011; 37: 501e14. 3 Thornburg KL, O’Tierney PF, Louey S. Review: the placenta is a programming agent for cardiovascular disease. Placenta 2010; 31(suppl): S54e9. 4 Roberts DJ, Post MD. The placenta in pre-eclampsia and intrauterine growth restriction. J Clin Pathol 2008; 61: 1254e60. 5 Cox P, Marton T. Pathological assessment of intrauterine growth restriction. Best Pract Res Clin Obstet Gynaecol 2009; 23: 751e64. 6 Krebs C, Macara LM, Leiser R, Bowman AW, Greer IA, Kingdom JC. Intrauterine growth restriction with absent end-diastolic flow velocity in the umbilical artery is associated with maldevelopment of the placental terminal villous tree. Am J Obstet Gynecol 1996; 175: 1534e42. 7 Macara L, Kingdom JC, Kaufmann P, et al. Structural analysis of placental terminal villi from growth-restricted pregnancies with abnormal umbilical artery Doppler waveforms. Placenta 1996; 17: 37e48. 8 Jackson MR, Walsh AJ, Morrow RJ, Mullen JBM, Lye SJ, Ritchie JWK. Reduced placental villous tree elaboration in small-for-gestationalage pregnancies: relationship with umbilical artery Doppler waveforms. Am J Obstet Gynecol 1995; 172: 518e25. 9 Redline RW, Boyd T, Campbell V, et al. Maternal vascular underperfusion: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol 2004; 7: 237e49. 10 Teasdale F. Idiopathic intrauterine growth retardation: histomorphometry of the human placenta. Placenta 1984; 5: 83e92. 11 Jauniaux E, Hempstock J, Greenwold N, Burton GJ. Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancies. Am J Pathol 2003; 162: 115e25. 12 Nordenvall M, Ullberg U, Laurin J, Lingman G, Sandstedt B, Ulmsten U. Placental morphology in relation to umbilical artery blood velocity waveforms. Eur J Obstet Gynecol Reprod Biol 1991; 40: 179e90. 13 Fitzgerald B, Shannon P, Kingdom J, Keating S. Basal plate plaque: a novel organising placental thrombotic process. J Clin Pathol 2011; 64: 1e5. 14 Kraus F, Redline R, Gersell D, Nelson M, Dicke J, eds. AFIP atlas of nontumor pathology: placental pathology. Washington: American Registry of Pathology, 2004. 15 Fitzgerald B, Levytska K, Kingdom J, Walker M, Baczyk D, Keating S. Villous trophoblast abnormalities in extremely preterm deliveries with elevated second trimester maternal serum hCG or inhibin-A. Placenta 2011; 32: 339e45.
Conclusion DVH is a developmental defect affecting the placental villous tree that when severe results in IUGR with potentially serious adverse consequences for pregnancy outcome. Maternal serum markers, normally used for prenatal screening for fetal aneuploidy and structural defects (PAPP-A, AFP, Inhibin-A and hCG) may be used in combination with ultrasound assessment of placental morphology at 19e22 weeks to identify women with pregnancies at risk for placental insufficiency, many of which would show DVH at placental pathological evaluation. Early identification of such pregnancies allows for referral to high-risk specialists and maximizes the possibility of successful pregnancy outcome. Correlation of maternal serological and antenatal ultrasound findings with villous and trophoblast pathology at delivery provides an opportunity to optimize these screening modalities and will provide a basis for laboratory investigations into disease pathogenesis. As at-risk pregnancies are identified earlier in gestation and as the pathological basis of the disease is better understood, the ultimate goal will be pharmacologic intervention to modify the course of the disease and thus prevent associated fetal morbidity and mortality.
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16 Kaufmann P, Huppertz B. Tenney-Parker changes and apoptotic versus necrotic shedding of trophoblast in normal pregnancy and pre-eclampsia. In: Lyall F, Belfort M, eds. Pre-eclampsia: etiology and clinical practice. New York: Cambridge University Press, 2007; 152e163. 17 Ellery PM, Cindrova-Davies T, Jauniaux E, Ferguson-Smith AC, Burton GJ. Evidence for transcriptional activity in the syncytiotrophoblast of the human placenta. Placenta 2009; 30: 329e34. 18 Burton GJ, Jones CJP. Syncytial knots, sprouts, apoptosis, and trophoblast deportation from the human placenta. Taiwan J Obstet Gynecol 2009; 48: 28e37. 19 Castellucci M, Kaufmann P. Basic structure of the villous tree. In: Benirshke K, Kaufmann P, Baergen R, eds. Pathology of the human placenta. New York: Springer, 2006; 50e120. 20 Smith GCS, Shah I, Crossley JA, et al. Pregnancy-associated plasma protein A and alpha-fetoprotein and prediction of adverse perinatal outcome. Obstet Gynecol 2006; 107: 161e6. 21 Proctor LK, Toal M, Keating S, et al. Placental size and the prediction of severe early-onset intrauterine growth restriction in women with low pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol 2009; 34: 274e82. 22 Odibo AO, Zhong Y, Longtine M, et al. First-trimester serum analytes, biophysical tests and the association with pathological morphometry in the placenta of pregnancies with preeclampsia and fetal growth restriction. Placenta 2011; 32: 333e8. 23 Chaddha V, Viero S, Huppertz B, Kingdom J. Developmental biology of the placenta and the origins of placental insufficiency. Semin Fetal Neonatal Med 2004; 9: 357e69. 24 Scifres CM, Nelson DM. Intrauterine growth restriction, human placental development and trophoblast cell death. J Physiol 2009; 587: 3453e8.
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25 Sharp AN, Heazell AEP, Crocker IP, Mor G. Placental apoptosis in health and disease. Am J Reprod Immunol 2010; 64: 159e69. 26 Ghidini A, Locatelli A. Monitoring of fetal well-being: role of uterine artery Doppler. Semin Perinatol 2008; 32: 258e62. 27 Mari G, Hanif F. Fetal Doppler: umbilical artery, middle cerebral artery, and venous system. Semin Perinatol 2008; 32: 253e7. 28 Toal M, Chan C, Fallah S, et al. Usefulness of a placental profile in high-risk pregnancies. Am J Obstet Gynecol 2007; 196: 363.e1e7. €rig P, Schneider H. The thick 29 Raio L, Ghezzi F, Cromi A, Nelle M, Du heterogeneous (jellylike) placenta: a strong predictor of adverse pregnancy outcome. Prenat Diagn 2004; 24: 182e8.
Practice points C
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DVH is characterized by the presence of stunted villous development with widely spaced, abnormally thin, long, nonbranching villi set in a relatively widened intervillous space. DVH is accompanied by widespread alterations in villous trophoblast that result in trophoblast thinning, nuclear senescence and wave-like syncytial knots. When DVH is extensive it is associated with intrauterine growth restriction with absent or reduced flow in the fetal umbilical arteries. Maternal serological markers and placental ultrasound may help identify pregnancies at risk of developing DVH and facilitate referral to high-risk pregnancy specialists, maximizing likelihood of successful outcome.
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