Recently we have been testing the hypothesis that the fetal/placental signals in pre-eclampsia may not merely be ''toxic side effects'' but rather a directed fetal response to reduced placental perfusion. This hypothesis proposes that the poorly perfused placenta generates signals that attempt to overcome the reduced fetal/placental nutrient availability. These signals function to modify maternal metabolism and physiology in a manner that increases nutrient availability. We further posited that the signal(s) may also modify placental transport to increase nutrient availability. An extension of this hypothesis is that some women because of their constitution cannot tolerate these changes and pre-eclampsia results (Figure 12.3).
The hypothesis is consistent with the heritability of pre-eclampsia. The survival value of the condition is not the pre-eclampsia but the directed fetal/ placental signal(s) that increases fetal nutrient availability (and in women with constitutional risk factors, pre-eclampsia). It could also explain why abnormal vascular remodeling is present in the vast majority of placental bed biopsies of pre-eclamptic women but growth restriction in only 30%. Furthermore, it is consistent with the excess of large for gestational age infants in women with pre-eclampsia delivered after 37 weeks gestational age (Xiong et al., 2000).
It is also possible that the reduced nutrient availability resulting in the putative fetal/placental signal is mediated not solely by reduced placental perfusion but also by reduced maternal stores or reduced intake of appropriate nutrients. This could explain why the role of maternal nutrition, long suspected as having a role in growth restriction,
Normally grown fetus
Figure 12.3 Fetal maternal adaptation to reduced placental perfusion: reduced placental perfusion may result in abortion, preterm birth pre-eclampsia or growth restriction. This model posits another possibility, that there are fetal-maternal adaptive responses that result in normally grown fetuses and that the relationship to pre-eclampsia is not direct. The model proposes that an appropriate response to reduced placental perfusion is the generation of fetal/placental signals that modify maternal metabolism and physiology to increase nutrient delivery to the poorly perfused placenta. Some women cannot tolerate the response and pre-eclampsia is the result. In two-thirds of women with pre-eclampsia this does not result in intrauterine growth restriction, but in one-third of the cases, either because of profoundly reduced perfusion that cannot be overcome by the fetal signal or with maternal adverse physiological responses further reducing perfusion, growth restriction results. The model also posits intrauterine growth restriction in the absence of pre-eclampsia as a failure of production of the putative fetal/placental signal. It further predicts normally grown infants despite reduced placental perfusion.
has been so difficult to establish. The reduced nutrient intake could be countered by fetal/ placental signals that in rare women would result in pre-eclampsia.
This hypothesis predicts that there will be women with reduced fetal/placental nutrient availability who, because of the fetal/placental signal which they are able to tolerate, have normally grown infants. This concept is supported by findings that 10% of women with normally grown infants will have abnormal uterine artery Dopplers at term accompanied by failed vascular bed remodeling on placental bed biopsy (Aardema et a/., 2001). Also it is consistent with the observation that 50% of women with abnormal uterine artery Dopplers in early pregnancy will have normal pregnancy outcomes despite evidence of oxidative stress in many of them (Chappell et a/., 2002; Morris et a/., 1998; Savvidou et a/., 2003).
Determination of the fetal signal could have therapeutic implications for pre-eclampsia and IUGR. What are the possible candidates? The placenta produces a number of molecules that might potentially modify maternal physiology and metabolism and placental function. These include norepinephrine (Manyonda et al., 1998; Sarkar et a/., 2001; Sodha et a/., 1984), acetylcholine (Sastry, 1997), CRH (Fadalti et a/., 2000; Karteris et a/., 2001, 2003) and leptin (Ashworth et a/., 2000; Domali and Messinis, 2002; Mantzoros, 2000; Poston, 2002; Sagawa et a/., 2002) to name a few.
We believe that of the placental hormones listed, leptin holds special promise as one of the putative signals to modify maternal and placental function to augment nutrient delivery. Leptin has numerous effects to alter energy metabolism and influence adiposity (Harris, 2000). Many of these are quite relevant to the metabolic adaptations of pregnancy that are accentuated in pre-eclampsia. Leptin acts centrally to increase sympathetic outflow, increasing the breakdown of triglycerides and glycogen and also resulting in generalized increased sympathetic activity, as seen pre-eclampsia (Haynes et al., 1997). Leptin interacts with insulin, increasing insulin sensitivity in brown fat and muscle but reducing insulin sensitivity of white fat (Wang et al., 1999).
The prime tissue for the production of leptin in humans is adipose tissue. The placenta is the only other tissue with a concentration of mRNA equivalent to that of adipose tissue in humans (Ashworth et al., 2000). Leptin concentration doubles during normal pregnancy and drops dramatically post delivery consistent with a placental origin (McCarthy et al., 1999). Leptin produced by the placenta can be upregulated by hypoxia (Mise et al., 1998) and in vitro perfusion studies indicate secretion almost exclusively to the maternal compartment (Linnemann et al., 2000).
Consistent with the effect of hypoxia to increase placental leptin, placental mRNA (Mise et al., 1998) and maternal circulating leptin are increased in pre-eclampsia (McCarthy et al., 1999). Paradoxically, leptin is not increased in maternal blood in pregnancies complicated by SGA (Chappell et al., 2002). Leptin receptors are present on the maternal (villus) surface of syncytiotrophoblast (Bodner et al., 1999). Recent data indicates that exposure of villus fragments to leptin increases amino acid uptake (Jansson et al., 2003).
Leptin has effects in several tissues to modify energy metabolism and uptake; in the placenta leptin can increase amino acid uptake. Leptin is produced by the placenta and increased by hypoxia, as might be expected in placental and fetal tissues with poor placental perfusion. In keeping with the effect of hypoxia, leptin is increased in the blood of women with pre-eclampsia and in the placentas from these pregnancies (McCarthy et al., 1999; Mise et al., 1998; Teppa et al., 2000). Paradoxically and consistent with a fetal signal not expressed in response to reduced nutrient and oxygen delivery in IUGR, leptin is not increased in mothers destined to have SGA pregnancies (Chappell et al., 2002).
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