**4. The uterus**

224 From Preconception to Postpartum

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

(Hermansen

It is well known that muscle performance may decline with prolonged or intense muscle activity, especially if there is a shortage of 02 (Allen et al. 1995; Westerblad et al. 2002). This decline is known as muscle fatigue. The causes of fatigue are probably multiple, but the consequence is that the power output may be drastically reduced. The consequence of lost power is obvious during sporting activity, for example, in endurance sports. It is almost impossible to maintain a marathon race if the muscles are exhausted. When a muscle goes from rest to high-intensity exercise a marked acidification occurs because of the shortage of 02. The energy demand exceeds the capacity from available aerobic metabolism. The metabolism will enter the anaerobic pathway and the ATP required will come from anaerobic metabolism. Anaerobic breakdown of glycogen leads to intracellular accumulation of inorganic acids such as, for example, lactic acid. Lactic acid is a strong acid and dissociates easily to lactate and H+ at physiological temperature. Lactate might therefore have limited effect of its own on the muscle contractions. The traditional thinking was that H+ is produced together with lactate,

Recently presented data provide substantial support for that increased inorganic phosphate (Pi) having a key role in muscle fatigue (Westerblad et al. 1991; Westerblad et al. 1998; Westerblad 2002; Westerblad & Allen 2003), especially at physiological temperature (Westerblad et al 1997). For acidosis, on the other hand, most recent data indicate that its depressive effect on muscle contraction is limited. Other studies express doubts about the effect of Pi, and indicate that it is

The way in which human uterine smooth muscle cells metabolize and meet the energy demands during labor is still obscure. Energy is produced by glycolysis, ending with the formation of ATP and pyruvate. It has in different studies been demonstrated that the human uterus utilizes glucose as its main energy substrate at term pregnancy. It seems that smooth muscle cells in uterus are capable of producing lactate at a higher rate under aerobic

Fatigue has many sources that may be present in different sites in the muscle cells (Taggart & Wray 1998). Many constituents of muscle metabolism change during fatigue and for each of these metabolites we need to know which role they have in the regulation of the muscle contraction. Despite nearly 200 years of muscle function research, the question of muscle

Earlier, lactate was considered to be transported across the membrane only via passive diffusion, depending on a pH gradient, (Crone 1963; Brooks 2002; Philp et al. 2005). Subsequent publications revealed a carrier-mediated transport of lactate across membranes.

of the `lactate shuttle hypothesis´ (Brooks GA.1986; Brooks 2000; Brooks 2002).

and H+ created the pH change and was the important cause of fatigue.

too early to dismiss H+ as an important factor in muscle fatigue (Fitts 2003).

conditions compared with striated muscle cells.

fatigue still remains partly unresolved.

**3.2 Lactate shuttles** 

**3.1 Muscle fatigue** 

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 working muscle with a high level of activity.

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 demand for adequate circulation.

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,

Lactate Level in Amniotic Fluid, a New Diagnostic Tool 227

The knowledge that amniotic fluid (AF) contains high concentration of lactate has been published for the first time in the 1970's. Some publications have suggested that the source of lactate in AF is the fetus itself, mainly through urine and lung excretion. Several reports have suggested the myometrium as the most important lactate producer. The lactate concentration in amniotic fluid is reported to be 4 - 6 times higher as compared with fetal and maternal blood. However, from the literature it is not clear from where the high AF

"*In Africa the sun should never rise twice during labor, then it's dangerous*", an Old African saying was recounted by an African obstetrician at `Federation International Gynecologie

Normal childbirth is a retrospective diagnosis that refers to spontaneous delivery starting after a full-term pregnancy, with absence of risk factors and/or complications. The goal of

In the first stage of labor, uterine contractions increase in frequency and strength. Since Freedman's work in the 1950s, it is considered that normal cervical dilatation during the first stage of labor is 1 cm/hour which gives a mean duration of first stage of 4.5 hours. An opening stage with a 2-3 hours delay is considered as extended or dystosic (Friedman 1955).

Labor dystocia is a common worldwide obstetrical problem, and is one of the main indications for operative intervention during parturition. Labor dystocia is clinically defined as slow/arrest of progress during labor, i.e. cervical dilatation and descent of the presenting part. It is estimated that labor dystocia occurs in about 20% of all deliveries worldwide. However, it is difficult to find a precise definition of the diagnosis of dystocia. The usual method to identifying labor dystocia is to use a partogram with an `alert line´ representing cervical dilation of 1 cm per hour and an `action line´ drawn 2-4 hours to the right of the `alert line´ (Philpot 1972). The clinical method of identifying dystocia is when the graphically plotted rate of progress crosses

Labor dystocia is associated with increased risks, such as labor abnormalities, increased risk of instrumental/operative intervention, depressed Apgar score at 5´minutes and extended need for newborn care. Dysfunctional labor is also associated with a higher frequency of postpartum infections, higher estimated maternal blood loss and lengthened maternal and

According to World Health Organisation (WHO) every delivery in the world should have a partogram presented during labor (Kwast et al 1994). The partogram detects maternal and fetal complications and the progress of labor. The background of the partogram, the cervicoplot, was constructed by Friedman during the 1950´s. Friedman analyzed the average

all deliveries is healthy mother, healthy baby and a positive childbirth experience.

the action line or if no progress is made over the previous 2 hours (Lavender 2008).

lactate concentration is derived.

Obstetrique´ (FIGO) 2006.

**5.1 Normal delivery** 

**5.2 Labor dystocia** 

newborn hospital stay.

**5.3 Partogram** 

**5. Labor** 

e.g. metabolites. Extended knowledge about these metabolites seems to be of importance, especially in the light of the clinical expression of labor dystocia (Steingrimsdottir et al. 1995).

During the late 1980's and the 1990's several studies have been published on myometrial activity (Wedenberg et al. 1990; Wedenberg et al. 1991; Ronquist et al. 1993; Steingrimsdottir et al. 1995; Wedenberg et al. 1995). They have shown that the pregnant myometrium has a low energy charge (EC), described as an index of energy status, and compared with striated and cardiac muscles. The difference was considered to be due to the very special demand of the uterine muscle, compared to other muscles. The cardiac muscle has to work continuously, with only short periods of rest (diastole). Striated muscles must work instantly on command. The uterine muscle remains relaxed for long periods of time and then, only for short periods (labor), has to be transferred to a state in which strong contractions are required. This situation demand energy (Steingrimsdottir et al. 1993; Steingrimsdottir et al. 1995; Steingrimsdottir et al. 1997; Steingrimsdottir et al. 1999). Studies have shown an increased content of glucose in the pregnant smooth muscle in term pregnancy, compared with early pregnancy and the non- pregnant uterus. This finding along with a positive artriovenous difference in blood-glucose across the uterus (i.e. net uptake), indicates glucose to be the principal nutritive metabolite for the pregnant uterine muscle (Steingrimsdottir et al. 1999).

The anaerobic pathway seems to be more active in the myometrium than in striated muscles. The Lactate/Pyruvate ratio, an indicator of anaerobic metabolism, is reported to be higher in the pregnant myometrium compared with other muscles (Steingrimsdottir et al. 1995). The lactate content of pregnant uterine muscle has been reported to be doubled compare with the skeletal muscle, probably reflecting a vigorous glycolytic flow when the uterus is active.

The uterus undergoes a general metabolic preparation for a hypoxic condition in late gestation. A significant physiological alkalinisation of the muscle over the last few weeks of pregnancy has been shown (Parratt et al. 1995). This might therefore contribute to the mechanisms ensuring that strong and efficient contractions occur during labor, when acidity is added during normal myometrial contractions.

A number of papers have been published on myometrial acid-base balance, and correlation to inefficient contractions and dysfunctional labor. One finding is that acidification of the myometrium with accumulation of lactate, and a decrease of myometrial pH during contractions, could depress uterine contractions and thereby contribute to dysfunctional labor. It has been shown that lactate concentration of myometrial capillary blood is significantly higher in women having a caesarean delivery due to dystocia than in women having an elective caesarean section or being operatively delivered with normal contractions. Furthermore, reduced pH and raised lactate concentrations in myometrial strips change regular contractions to irregular ones with reduced amplitude in vitro studies. One of the suggested clinical explanations for this process was that during labor blood vessel supply might be occluded while the uterus is contracting. The irregular contractile pattern in dysfunctional labor might lead to extended occlusion of the uterine vessels. Extended occlusion might lead to a lowering of the myometrial oxygen levels and accumulation of lactic acid. Thus, despite the inefficient contractions, there is an inadequate reoxygenation of the uterus. There is a suggestion that that there is a variation in response to intermittent hypoxia in different women. The recovery period from the low oxygen episode after occlusion might differ.

The knowledge that amniotic fluid (AF) contains high concentration of lactate has been published for the first time in the 1970's. Some publications have suggested that the source of lactate in AF is the fetus itself, mainly through urine and lung excretion. Several reports have suggested the myometrium as the most important lactate producer. The lactate concentration in amniotic fluid is reported to be 4 - 6 times higher as compared with fetal and maternal blood. However, from the literature it is not clear from where the high AF lactate concentration is derived.
