It is well established that development of the chorionic villous tree and fetal vasculature is abnormal in PET and IUGR (1; 2; 152) compared to normal pregnancy, and more recently in placentas from infants succumbing to SIDS (82). Consistent with the clinical implications, it has become apparent that the severity, timing-of-onset, and umbilical artery Doppler (absent versus positive) are associated with divergent pathways of villous maldevelopment in these pregnancy complications. Given that PET and IUGR are both associated with uteroplacental insufficiency, the placenta responds differently to the expected ‘intra-placental hypoxia’. Oxygen is therefore a key regulator of villous development and different pathways of villous maldevelopment have been proposed based on the origin of fetal hypoxia (153).
Following analysis of placental villi in complicated pregnancies, the origin of fetal hypoxia has been classified as pre-placental, uteroplacental, or post-placental (153). In pre-placental hypoxia, the mother, placenta, and fetus are potentially hypoxic due to a reduced oxygen content of the maternal blood, such as in pregnancy at high altitude and maternal anaemia (103). In contrast, in uteroplacental hypoxia, maternal blood flow is normoxic but the placenta and fetus may become hypoxic due to compromised flow into the IVS, i.e. malinvasion of the maternal spiral arteries. In post-placental hypoxia, maternal blood flow is normal in combination with normal or reduced flow into the IVS, but a severe defect in fetoplacental perfusion prevents the fetus from receiving sufficient oxygen, and hence is at serious risk of becoming hypoxic (153).
1.5.4.1 IUGR
In situations of pre-placental hypoxia or uteroplacental hypoxia, the placenta may undergo excessive branching angiogenesis and trophoblast proliferation in order to produce greater amounts of vascularised terminal villi as part of an adaptive response so as to maintain adequate fetoplacental diffusional exchange; maternal supply and fetal demand are therefore carefully balanced by the development of the terminal villi. This type of villous adaptation is associated with late-onset pre-eclampsia (154), and in some
but not all cases of IUGR (150), which have been shown to display increased capillary volume fractions, and degree of branching (for review see (155)). Because such changes are not observed in severe early-onset IUGR, these placentas are thought to represent
‘failure to adapt’, since they appear to have lost their ‘hypoxic’ angiogenic drive (153) conferring severe functional consequences to the potentially hypoxic fetus (post-placental hypoxia).
Stereological and morphometric analyses have led to the agreement that the small placentas from IUGR pregnancies are associated with a failure in the development of the gas-exchanging villi, due to malformation of the fetal capillaries in terminal villi secondary to failed branching angiogenesis in the third trimester of pregnancy and the predominance of non-branching angiogenesis. Stereological studies reveal consistent reductions in the elaboration of mature intermediate and terminal villi (102; 152; 156-159) (volumes, surface areas, and lengths) and reduced terminal villous capillarisation (160; 161). 3D scanning electron microscopy and vessel casts confirmed reductions in the numbers of ‘malformed’ (1), congested, elongated, poorly-branched gas-exchanging villi and underlying fetal vasculature (2). These observations are evident in placentas from both early- (2; 152) and late-onset IUGR (102; 152; 156-159; 161; 162).
The malformed capillaries in severe IUGR placentas confer high vascular impedance which is associated with abnormal umbilical artery Doppler (150), representing a severe form of reduced fetoplacental blood flow inferred by absent or reverse end-diastolic flow velocity waveforms (AREDV). Those pregnancies destined to develop severe IUGR are therefore typically associated with severe abnormalities in umbilical artery Doppler, which has become an established test of fetal wellbeing in the second trimester of pregnancy (19-23 weeks) (129).
The compromised fetoplacental circulation is understood to result in reduced extraction of oxygen from maternal blood in the intervillous space leading to poor oxygenation of the severe IUGR fetus (hence the term postplacental fetal hypoxia), evidenced by the
(142). This led to the term placental ‘hyperoxia’, although this is still debated by some investigators (Figure 1-7).
Given that angiogenesis shapes villous development, the pathway of villous maldevelopment in severe early-onset IUGR is associated with changes in the molecular regulation of the principal angiogenic factors, VEGF and PGF. Whilst in normal pregnancy VEGF predominates in the first trimester and PGF predominates in the third, IUGR placentas demonstrate increased expression of PGF (113) (mRNA and protein) and decreased syncytial expression of VEGF (164). Because PGF mediates non-branching angiogenesis, this imbalance in angiogenic factors is thought to contribute to the poorly branched, elongated gas-exchanging villi that characterize IUGR pregnancies.
1.5.4.2 PET
Although pre-eclampsia is the most extensively studied pregnancy complication at term, its influence/impact on placental morphology is inconsistent and less well understood in early pregnancy. Severe early-onset pre-eclampsia, by definition, often co-exists with IUGR, conferring significant risk for perinatal survival compared to term complications.
Distinguishing the contributions of each disease on the pathway(s) of villous maldevelopment is thus hampered by this close association, but is presumed to involve considerable overlap. Consequently, the majority of stereological studies addressing the pathways of placental dysfunction in pre-eclampsia without IUGR focused on term pregnancies which revealed conflicting results.
Initially, stereological studies revealed one distinct pathway of placental dysfunction in pre-eclampsia compared to IUGR. At term, pre-eclamptic placentas displayed normal (102; 156; 161; 165) or ‘enhanced’ placental villi and vasculature morphology e.g.
increases in terminal capillarisation (adaptive branching angiogenesis due to intra-placental hypoxia), intra-placental volume and fetal birth weight in comparison to normal term controls. This led to the prevailing hypothesis that ‘pure’ pre-eclampsia at term has no overall effect on placental villous and vasculature development in comparison to IUGR. Furthermore, these placentas are typically associated with normal Dopplers represented clinically by preserved end-diastolic blood flow velocity waveforms
(PEDV) conferring minimal vascular impedance (153). IUGR at term is typically, but not exclusively, associated with normal umbilical artery Dopplers indicating normal fetoplacental blood flow associated with favourable perinatal outcome.
Figure 1-7: Pathways of villous maldevelopment
Pathways of villous angiogenesis according to villous oxygenation. Three different examples of oxygenation, postplacental hypoxia (top), normal pregnancy (middle) and pre-placental as well as uteroplacental hypoxia (bottom) are illustrated by their terminal capillarisation patterns (left) and by typical cross sections of terminal villi (right). The oblique lines refer to the position of the cross sections beneath (153).
Molecular evidence for intra-placental hypoxia in pre-eclampsia at term, (representing a form of uteroplacental hypoxia), came from the observation that expression of the hypoxia inducible transcription factors, HIF-1α and HIF-2α, is significantly increased in these placentas. However, due to the difficulty of measuring serum levels of VEGF (normal or increased) and PGF (normal or decreased), there are inconsistencies in the reported expression of these angiogenic factors in pre-eclampsia at term (155).
This concept was challenged by Egbor et al (152) who identified two distinct pathways of villous maldevelopment in pre-eclampsia, illustrating that early-onset pre-eclampsia without IUGR shares similar morphological features to the maldeveloped villi that are typically observed in both early- and late-onset IUGR placentas . This led to idea that the early phenotype of PET may have a different etiology compared to its late-onset phenotype, and that they may represent two different diseases.
1.5.4.3 SIDS
Protracted intrauterine hypoxia occurring during fetal development is also thought to be a primary pathophysiologic factor in SIDS (166). SIDS placentas may represent a form of pre-placental hypoxia due to the high incidence of maternal smoking associated with SIDS. However, previous stereological studies revealed that both SIDS-NBW and SIDS-LBW placentas are associated with altered placental villous (162) and vasculature (82) morphology. Changes observed include reduced volumes and surface areas of placental villi, and reduced surface areas of intermediate and terminal capillaries, which are contrary to the expected intra-placental hypoxia as noted in other forms of pre-placental hypoxia. Because villous development is also driven by the villous trophoblast, it hypothesized that different pathways of villous maldevelopment may reflect divergent villous trophoblast phenotypes.
1.6 Regulation and Maintenance of the Trophoblast Lineage during Pregnancy