**2. Energy metabolism**

The main substrate for energy metabolism is glucose (Meyer 1920). Under normal conditions, with sufficient oxygen supply, aerobic metabolism occurs. Here glucose is broken down along the glycolytic pathway, and the resulting pyruvate enters the citric acid cycle (Fig.1). Energy is produced along the glycolytic pathway, together with carbon dioxide (CO2) and water (H2O). Nicotinamide adenine dinucleotid (NAD+) is a powerful hydrogen ion acceptor. In the citric acid cycle NAD+ accepts an H+ to produce NADH. In the reaction O2 is consumed, and a large amount of energy is released (36 ATP).

Fig. 1. From: Intrapartum Fetal Hypoxia and Biochemical Markers; a review (Nordstrom & Arulkumaran 1998).

If oxygen supply reaches a critical low level, the metabolism will change to become anaerobic. Here, instead of entering the citric acid cycle, pyruvate is reduced to lactic acid and H+. This reaction is catalyzed by the enzyme lactate- dehydrogenase (LDH), and also involves the oxidation of NADH to NAD+. NADH is generated in glycolysis, and reoxidised into NAD+. Under anaerobic conditions, this oxidation is impaired, resulting in accumulation of NADH, promoting the conversion of pyruvate to lactate.

In normal conditions there is a steady state relation between lactic acid/pyruvate (L/P). If oxygen supply is limited, a progressive lactate acidemia (metabolic acidosis) develops. Anaerobic metabolism produces less energy (2 ATP/glucose) compared with aerobic conditions (36 ATP/glucose).

#### **2.1 Cellular energy production**

With prolonged lack of energy due to anaerobic metabolism, there is difficulty in maintaining cellular integrity. Cellular functions rely on ion gradients across cell membranes. Ion pumps require ATP to function. Regeneration of sufficient amount of ATP can no longer be sustained if anaerobic metabolism continues. In this catabolic situation, the basic cellular functions start to fail. Three different cellular energy statuses are described (Nordstrom & Arulkumaran 1998). The first one is aerobic when there is sufficient amount of oxygen and a lot of energy is produced in the form of ATP. This is an efficient way of energy production. The two others are dependent on the level of oxygen supply, and if the situation is compensated or not. Lack of oxygen forces the cell into an anaerobic metabolism with production of lactate and H+. Energy is produced but to a limited amount. If the demand of energy is still sufficient, the cellular energy status is compensated. This can continue as long as energy demand and production is in balance. If the situation is progressing, regeneration of ATP can no longer be keep up with demands and the cellular energy status will be decompensated

#### **2.2 Buffering systems**

222 From Preconception to Postpartum

The main substrate for energy metabolism is glucose (Meyer 1920). Under normal conditions, with sufficient oxygen supply, aerobic metabolism occurs. Here glucose is broken down along the glycolytic pathway, and the resulting pyruvate enters the citric acid cycle (Fig.1). Energy is produced along the glycolytic pathway, together with carbon dioxide (CO2) and water (H2O). Nicotinamide adenine dinucleotid (NAD+) is a powerful hydrogen ion acceptor. In the citric acid cycle NAD+ accepts an H+ to produce NADH. In the reaction

Fig. 1. From: Intrapartum Fetal Hypoxia and Biochemical Markers; a review (Nordstrom &

If oxygen supply reaches a critical low level, the metabolism will change to become anaerobic. Here, instead of entering the citric acid cycle, pyruvate is reduced to lactic acid and H+. This reaction is catalyzed by the enzyme lactate- dehydrogenase (LDH), and also involves the oxidation of NADH to NAD+. NADH is generated in glycolysis, and reoxidised into NAD+. Under anaerobic conditions, this oxidation is impaired, resulting in

In normal conditions there is a steady state relation between lactic acid/pyruvate (L/P). If oxygen supply is limited, a progressive lactate acidemia (metabolic acidosis) develops. Anaerobic metabolism produces less energy (2 ATP/glucose) compared with aerobic

With prolonged lack of energy due to anaerobic metabolism, there is difficulty in maintaining cellular integrity. Cellular functions rely on ion gradients across cell

accumulation of NADH, promoting the conversion of pyruvate to lactate.

O2 is consumed, and a large amount of energy is released (36 ATP).

**2. Energy metabolism** 

Arulkumaran 1998).

conditions (36 ATP/glucose).

**2.1 Cellular energy production** 

In a normal state, the buffering systems of the organism have the capacity to maintain pH within a physiological range. It is important for the organism to maintain stability in pH, i.e. H+ concentrations. A fluctuation of H+ is dangerous for the cell. If the concentration of H+ rises it may disturb cellular function and affect the activity of cellular enzymes.

There are different buffering systems within the organism. The two most important systems are the bicarbonate and the protein buffering systems. These two systems main functions are to neutralize H+ which has been produced through anaerobic metabolism. The role of the bicarbonate buffer is to establish equilibrium between CO2, H2CO3, bicarbonate (HCO3) and hydrogen ions (H+), via the equation shown below (Siggaard-Andersen 1971).

$$\text{CO}\_2 + \text{H}\_2\text{O} \rightarrow \text{H}\_2\text{CO}\_3 \rightarrow \text{H}^\* + \text{HCO} 3^\cdot$$

In this reaction CO2 is passing through and at the end is converted to bicarbonate, which leaves the red blood cells by means of an exchange of chlorides. The equation goes from left to right and back again several times until a steady state condition is established. At steady state total cellular CO2 production equals CO2 elimination.

#### **3. Lactate**

Knowledge about lactate is a rapidly changing field, and our understanding of the role of lactate metabolism has changed dramatically from the classical views held in the 19th century. The lactic acid era began in 1808 when Berzelius at the Karolinska Institute in Stockholm, discovered elevated concentrations of lactate in `the muscles of hunted stags´ (Berzelius 1808). Araki showed in 1891 that lactic acid concentration in exhausted animal muscles was proportional to the amount of exercise and was associated to O2 availability (Araki 1891). Some 100 years after Berzelius, Fletcher and Hopkins showed that lactic acid appeared in response to muscle contraction in human muscle (Fletcher & Hopkins 1907).They also showed that accumulated lactate disappeared when oxygen became available. Later on the `lactic-acid-cycle´ was described, and showed two distinct pathways in metabolism, the aerobic and the anaerobic. The coming period was called `the revolution in muscle physiology´. From the 1930's to the early

Lactate Level in Amniotic Fluid, a New Diagnostic Tool 225

An entire family of monocarboxylate transport proteins (MCT), which facilitate the transport of lactate in and out of the cells, has been described (Bonen et al. 1997; Brooks et al. 1999; Bonen 2000; Bonen 2001). During exercise lactate and H+ move in and out of tissue primarily via MCT1 and MCT4, diffusion of undissociated lactate constitutes a smaller component of the transport. It has been proposed that the force of smooth muscle contractions during labor is reduced by hypoxia in uterus, and studies have pointed out that

Lactate exchange is a dynamic process with simultaneous uptake and release between cells at rest and during exercise. At rest muscles slowly release lactate in to the surrounding fluids on a net basis, but cells may also show a small net uptake. During exercise, muscle tissue produces lactate rapidly. This results in an increased intracellular concentration of lactate and an increased net output of lactate from the muscle cells to the surrounding fluids. During recovery there is a net uptake of lactate from the ambient fluid by resting muscles, or other muscles that are exercising at low or moderate intensity. During prolonged exercise of low to moderate intensity, the muscles that originally released lactate on a net basis at the onset of exercise may actually reverse it to net lactate uptake. The conclusion from many recent studies is that lactate is a useful metabolic intermediate which can be exchanged rapidly between tissue compartments (Brooks 2002). Lactate can also be

The uterine muscle has a dualistic function. It has to shelter the growing fetus during pregnancy within the uterine cavity. To fulfil the demand of pregnancy/parturition the human uterus has a unique construction. The uterine cavity is surrounded by smooth muscle where the myocytes are arranged in bundles embedded in connective tissue. This arrangement gives uterus elastic properties and facilitates the transmission of contractile forces generated by individual muscle cells. The uterine muscle has a relatively relaxed state during pregnancy. Second, when labor starts the uterus becomes a strongly coordinated

Blood supply of the uterus is provided by the uterine and ovarian artery. The arteries meet on the surface of the uterus where they are connected. From this connection leaves the radial artery that penetrates the myometrium and supplies both the myometrium and the placenta during pregnancy and labor. During pregnancy the myocytes undergo hypertrophy and hyperplasia resulting in significant size and volume growth of the uterus and increased

In the last part of pregnancy the uterus in preparation for labor through changes in the ion and hormone balance to optimize the conditions for effective synchronized contractions. The number of gap junctions and calcium concentration in the uterine tissue increases. The relaxing NO decreases. Oxytocin and prostaglandins have an important stimulating role. Oxytocin contributes via oxytocin receptors to increased contractility of the myocytes. Earlier studies of contractile myometrial activity are mostly concerned with the hormonal control. We have knowledge about the effect of oxytocin (Rezapour et al. 1996), gestagens and estrogens (Roy & Arulkumaran 1991; Spencer et al. 2005), as well as the prostaglandins during labor (Challis 1974). Their ultimate effects are assumed to be modified by local factors in the tissue,

myometrial lactic acidosis is associated with dysfunctional labors.

used as a substrate in aerobic condition.

working muscle with a high level of activity.

demand for adequate circulation.

**4. The uterus** 

1970's lactic acid was largely considered to be a `dead-end metabolite of glycolysis after muscle hypoxia´ (Meyerhof 1920; Hill 1922). Lactic acid was also believed to be the major cause of muscle fatigue. Since the early 1970's, a `lactate revolution´ has occurred (Hermansen 1981; Wasserman 1984). At present we are in the midst of a `lactate shuttle era´ with the introduction of the `lactate shuttle hypothesis´ (Brooks GA.1986; Brooks 2000; Brooks 2002).
