**4. Discussion**

172 From Preconception to Postpartum

Fig. 1. Means (circles) and standard deviations (bars) of UVB constituents in pathological group and sub-groups (number of samples 5). Values are expressed as number of standard deviations (SDs) from the mean of control group. Shaded area indicates extent of reference

range for the different variables.

During its intra-uterine life, the conceptus can be exposed to various agents (physical, chemical and infectious) which may interfere with its development. However, they are responsible for only 5% of the congenital malformations observed, as around 5% are attributable to chromosome anomalies, 10 to 20% to hereditary diseases, and 70% due to indeterminate causes (Gallot, 2002). The fetus' response to an aggression depends mainly on its level of maturity.

We have studied 53 pathological pregnancies, for which a fetal blood sampling was performed following confirmation by ultrasound of one or more fetal malformation(s), or a risk of malformation; the population studied is characterised by its heterogeneity, as previously described.

The fetal karyotype was found to be normal in all cases.

In this context, the obstetrical decision as to whether or not to continue the pregnancy, depends principally on the prognosis associated with the malformation.

The acid-base parameters measured allow a state of fetal distress to be diagnosed, the metabolic parameters assessed characterise the level of energy supply to fetus affected by morphological anomalies, some 20% of which also presented growth restriction.

The fetal origin of the umbilical venous blood taken was carefully checked in our study protocol, in particular with the measurement of hCG serum concentration; reference values in the fetal blood were established previously for this parameter (Bon et al., 1999).

#### **4.1 Acid-base balance and gasometric data**

The pH is not significantly different, on average, from that of the control group; however, the analysis of results showed a state of acidemia to be present in 12 fetuses, i.e. 22% of the group; this relates mainly to cases of cardiac malformation, central nervous system malformations, pulmonary malformations, one case of effusion with anasarca, and one case of hepatic tumour.

The plot on a Davenport diagram of the pH and total CO2 shows that acidosis is usually mixed: gaseous and metabolic. However, gaseous acidosis is predominant as the pH is significantly correlated with the pCO2 (r = -0.866, p < 0.001), while the correlation between pH and plasma bicarbonate concentration is less significant (r = 0.402, p = 0.003). The pCO2 is significantly increased in the event of cardiac malformations.

In the presence of effusion with fetoplacental anasarca and flooding with amniotic fluid, acidosis is of essentially metabolic origin, due to the high level of lactic acid in the amniotic fluid.

The most frequent gasometric anomaly is the fall in the partial oxygen pressure, present in over 40% of observations. The state of hypoxemia is not specific to any pathology; it is found in all types of malformation, with the exception of anomalies of the limbs and extremities.

Strictly fetal causes - anemia or cardiovascular failure - can be the cause of fetal hypoxia, responsible for a deviation in the metabolism towards anaerobia.

hypoxia, with a significant negative correlation between pO2 and lactate in the UVB (r = -0.420, p < 0.02). The rise in lactate may also be associated with poor lactate clearance by

Umbilical venous concentrations of free fatty acids were found to be significantly lowered in

Few data are available on the maternal-fetal metabolism of free fatty acids during

In a group of 24 patients with a pregnancy complicated by intra-uterine growth restriction (Ortega - Senovilla, 2010), an increase in free fatty acid and retinol concentrations was found in the maternal plasma, in comparison with the results of the control group; the authors put forward the hypothesis of a limitation in the transplacental transfer of retinol and free fatty acids, lower concentrations of which are found in the fetal plasma. A similar mechanism can be mentioned in the case of pregnancies complicated by fetal malformations, or alternatively an accelerated turnover of free fatty acids in the fetal compartment could be implicated.

Umbilical venous concentrations of ketone bodies and in particular beta-hydroxybutyrate are very scattered in the pathological group and do not differ, on average, from those of the control group. However, in some pregnancies, namely around 15% of cases, a moderate increase in ketone bodies concentration was found in the umbilical venous blood: in three cases of renal malformations, two cases of digestive malformations, three cases of malformations of the central nervous system and one case of pulmonary

Fetal ketone bodies can be supplied by transplacental transfer from the maternal blood (Pere et al., 2003), and there is also probably an intrinsic fetal production (Tannirandorm et al., 1999). The teratogenic action of beta-hydroxybutyrate has been suspected in certain diabetic

Cholesterol, an essential constituent for embryo development and growth, is found at a reduced umbilical venous concentration in some pathological pregnancies: in the presence of renal malformations (2 cases out of 14), pulmonary malformations (2 cases out of 3), ascites with anasarca (1 case), hepatic tumour (1 case), and malformations of the central nervous system (7 cases out of 11); in this final sub-group, umbilical venous cholesterolemia

It should be borne in mind that cholesterol is essential for the development of the central

Cholesterol is mainly synthesised in the fetal compartment as maternal cholesterol does not

In the pathological pregnancies, the inadequate production of cholesterol by the fetal liver may be associated with hepatic immaturity, or alternatively with defective oxygenation conditions in the fetus; we noted the frequency of cases of hypoxemia in the group of fetuses

The possibility of a fetal liver disorder was reported by Roberts et al. in growth-restricted

is, on average, significantly lower than that of the control group.

nervous system and cerebral growth (Roux et al., 1997, 2000).

readily pass through the placenta (Carr et al., 1982).

the placenta and is one of the components of metabolic acidosis.

pathological pregnancies.

malformation.

studied.

fetuses.

pregnancies (Jovanovic et al., 1998).

the group of fetuses with malformations of the central nervous system.

Cerebral hypoxia is often associated with a poor neurological prognosis, and depending on its severity, can be the cause of an apoptotic process. A state of hypoxemia frequently accompanies malformations of the central nervous system.

The fall in the umbilical venous pO2 is associated in 15% of cases, with a rise in the pCO2, leading to a state of gaseous acidosis. An impaired transplacental diffusion of respiratory gases may be the cause; indeed, placental lesions (infarct and thromboses of the villositary vessels) were indicated in some observations.

The episode of acidosis may be secondary to anomalies in development, as a fetus with malformations probably has limited regulation abilities and insufficient resources to fight against acidosis.

Conversely, a state of hypoxemia and then acidemia was able to favour the occurrence of malformations, due to a greater sensitivity of the fetus to an external, infectious, toxic aggression. An episode of acidosis may facilitate a toxic drug being passed on to the fetus, with the pH gradient between maternal blood and fetal blood influencing the transfer of certain drugs, such as weak acids (Fontaine, 2001).

#### **4.2 Metabolic parameters**

Nutritional and metabolic anomalies are less frequent and often less severe than acid-base anomalies.

The umbilical venous glucose concentration, an essential energetic substrate for the fetus, does not differ, on average, from that of the control group, which means that the hormonal factors of glycemic regulation are functional in the pathological group, with the neoglucogenesis abilities being maintained.

However, ten cases of hypoglycemia are noted, often associated with hypoxemia. A fall in blood glucose may be secondary to a fall in the transplacental passage of glucose, in parallel to the reduced diffusion of oxygen, or alternatively to a fetal or placental over-consumption of glucose, associated with an acceleration of anaerobic glycolysis; these mechanisms were mentioned with regard to severe growth retardation (Economides et al., 1989, Nicolini et al., 1989).

Fetal glycemia is low in the presence of a multicystic hepatic tumour; it is accompanied by a fall in ketone bodies and cholesterol concentrations in the umbilical venous blood; these biological results are the consequence of hepatic dysfunction. In the case of effusion with fetoplacental anasarca, the fall in the umbilical venous glycemia is probably the result of dilution by amniotic fluid.

Umbilical venous glucose was found to be elevated in some cases, in particular concentrations of 6.8 and 7.1 mmol/l are associated with maternal venous concentrations of 7.2 and 7.8 mmol/l. At these conditions, these values are the expression of a pre-diabetic or diabetic state in the mother, and this can be implicated in the occurrence of the malformation (Boivin et al., 2002, Gabbe et al., 2003). al.,

Umbilical venous lactatemia is, on average, significantly higher in the pathological group than in the control group. Hyperlactatemia, present in 34% of observations, is secondary to

Cerebral hypoxia is often associated with a poor neurological prognosis, and depending on its severity, can be the cause of an apoptotic process. A state of hypoxemia frequently

The fall in the umbilical venous pO2 is associated in 15% of cases, with a rise in the pCO2, leading to a state of gaseous acidosis. An impaired transplacental diffusion of respiratory gases may be the cause; indeed, placental lesions (infarct and thromboses of the villositary

The episode of acidosis may be secondary to anomalies in development, as a fetus with malformations probably has limited regulation abilities and insufficient resources to fight

Conversely, a state of hypoxemia and then acidemia was able to favour the occurrence of malformations, due to a greater sensitivity of the fetus to an external, infectious, toxic aggression. An episode of acidosis may facilitate a toxic drug being passed on to the fetus, with the pH gradient between maternal blood and fetal blood influencing the transfer of

Nutritional and metabolic anomalies are less frequent and often less severe than acid-base

The umbilical venous glucose concentration, an essential energetic substrate for the fetus, does not differ, on average, from that of the control group, which means that the hormonal factors of glycemic regulation are functional in the pathological group, with the

However, ten cases of hypoglycemia are noted, often associated with hypoxemia. A fall in blood glucose may be secondary to a fall in the transplacental passage of glucose, in parallel to the reduced diffusion of oxygen, or alternatively to a fetal or placental over-consumption of glucose, associated with an acceleration of anaerobic glycolysis; these mechanisms were mentioned with regard to severe growth retardation (Economides et al., 1989, Nicolini et al.,

Fetal glycemia is low in the presence of a multicystic hepatic tumour; it is accompanied by a fall in ketone bodies and cholesterol concentrations in the umbilical venous blood; these biological results are the consequence of hepatic dysfunction. In the case of effusion with fetoplacental anasarca, the fall in the umbilical venous glycemia is probably the result of

Umbilical venous glucose was found to be elevated in some cases, in particular concentrations of 6.8 and 7.1 mmol/l are associated with maternal venous concentrations of 7.2 and 7.8 mmol/l. At these conditions, these values are the expression of a pre-diabetic or diabetic state in the mother, and this can be implicated in the occurrence of the

Umbilical venous lactatemia is, on average, significantly higher in the pathological group than in the control group. Hyperlactatemia, present in 34% of observations, is secondary to

accompanies malformations of the central nervous system.

vessels) were indicated in some observations.

certain drugs, such as weak acids (Fontaine, 2001).

neoglucogenesis abilities being maintained.

malformation (Boivin et al., 2002, Gabbe et al., 2003).

against acidosis.

anomalies.

1989).

**4.2 Metabolic parameters** 

dilution by amniotic fluid.

hypoxia, with a significant negative correlation between pO2 and lactate in the UVB (r = -0.420, p < 0.02). The rise in lactate may also be associated with poor lactate clearance by the placenta and is one of the components of metabolic acidosis.

Umbilical venous concentrations of free fatty acids were found to be significantly lowered in the group of fetuses with malformations of the central nervous system.

Few data are available on the maternal-fetal metabolism of free fatty acids during pathological pregnancies.

In a group of 24 patients with a pregnancy complicated by intra-uterine growth restriction (Ortega - Senovilla, 2010), an increase in free fatty acid and retinol concentrations was found in the maternal plasma, in comparison with the results of the control group; the authors put forward the hypothesis of a limitation in the transplacental transfer of retinol and free fatty acids, lower concentrations of which are found in the fetal plasma. A similar mechanism can be mentioned in the case of pregnancies complicated by fetal malformations, or alternatively an accelerated turnover of free fatty acids in the fetal compartment could be implicated.

Umbilical venous concentrations of ketone bodies and in particular beta-hydroxybutyrate are very scattered in the pathological group and do not differ, on average, from those of the control group. However, in some pregnancies, namely around 15% of cases, a moderate increase in ketone bodies concentration was found in the umbilical venous blood: in three cases of renal malformations, two cases of digestive malformations, three cases of malformations of the central nervous system and one case of pulmonary malformation.

Fetal ketone bodies can be supplied by transplacental transfer from the maternal blood (Pere et al., 2003), and there is also probably an intrinsic fetal production (Tannirandorm et al., 1999). The teratogenic action of beta-hydroxybutyrate has been suspected in certain diabetic pregnancies (Jovanovic et al., 1998).

Cholesterol, an essential constituent for embryo development and growth, is found at a reduced umbilical venous concentration in some pathological pregnancies: in the presence of renal malformations (2 cases out of 14), pulmonary malformations (2 cases out of 3), ascites with anasarca (1 case), hepatic tumour (1 case), and malformations of the central nervous system (7 cases out of 11); in this final sub-group, umbilical venous cholesterolemia is, on average, significantly lower than that of the control group.

It should be borne in mind that cholesterol is essential for the development of the central nervous system and cerebral growth (Roux et al., 1997, 2000).

Cholesterol is mainly synthesised in the fetal compartment as maternal cholesterol does not readily pass through the placenta (Carr et al., 1982).

In the pathological pregnancies, the inadequate production of cholesterol by the fetal liver may be associated with hepatic immaturity, or alternatively with defective oxygenation conditions in the fetus; we noted the frequency of cases of hypoxemia in the group of fetuses studied.

The possibility of a fetal liver disorder was reported by Roberts et al. in growth-restricted fetuses.

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**7. References** 

The decrease in cholesterolemia may be related to growth problems which are often associated with morphological anomalies. The fundamental role of cholesterol in embryo development is well established, and anomalies in cholesterol synthesis are involved in a number of human malformation syndromes (Porter et al., 2003; Guizzetti et al., 2005).
