Prelabour and labour hormonal and immunological mechanisms

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The multitude of biological substances which interact in the control of the human birth process seem to increase almost daily. To catalogue more than 60 such factors might

Table 7.1 A far from comprehensive list of substances and categories of substances which are known to participate in the birth process

Actin

Lipocortin

Adenylate cyclase

Lipopolysaccharide

Adhesion molecules

Lipoxygenase

(ICAM, VCAM, etc.)

Magnesium

Adrenaline

Matrix metalloproteinases

Bradykinin

Monocyte chemotactic protein-1

Calcium

Myosin

Calmodulin

Myosin light chain kinase

Chemokines

Neutrophil elastase

Chondroitin sulphate

Nitric oxide

Collagen

Noradrenaline

Collagenases

Oestrogens

Connexin 43

Oxytocin

Corticotrophin (ACTH)

Oxytocinase

Corticotrophin-releasing factor

Phosphatases

Cortisol

Phosphodiesterase

cAMP

Phospholipases

cGMP

Platelet-activating factor

Cyclo-oxygenase-1

Potassium

Cyclo-oxygenase-2

Progesterone

Cytokines

Prostacyclin

Dehydroepiandrosterone sulphate

Prostaglandin dehydrogenase

Dermatan sulphate

Prostaglandin E2

Endothelins

Prostaglandin F2a

Glycosaminoglycans

Proteoglycans

G proteins

Relaxin

Gravidin

Sodium

Inositol trisphosphate

Substance P

IL-8

Sulphatase

Leukotrienes

Surfactant

Vasopressin

Those shown in italic are discussed in detail in the text

Those shown in italic are discussed in detail in the text seem extravagant, yet such a list can readily be made (Table 7.1). A detailed description of the precise interactive roles of these factors is beyond the scope of this chapter. Discussion is mainly restricted to the roles of those shown in italic type in Table 7.1, since these are of special importance, both to the natural process and to its clinical manipulations. This description is inevitably a gross oversimplification of a hugely complex process, but one which may afford the clinician the appropriate insights with which to manage the problems of labour and delivery.

KEY SUBSTANCES

Everyday clinical experience, not least from the effective use of natural substances or drugs which interfere with their function, suggests that the following may deserve special prominence: progesterone, calcium, oxytocin and prostaglandins (especially PGE2 and PGF2«). Less obviously, to these may be added: connexin 43, cortisol,

Caldeyro Barcia
15 20 25 30 35 40

Weeks

Fig. 7.1 Schematic diagram of uterine contractility quantitation through the course of labour and delivery (from [2]).

cyclic adenosinemonophosphate(AMP), prostacyclin, the prostaglandin-degrading enzyme prostaglandin dehydrogenase, and various cytokines and chemokines, notably interleukin 8 (IL-8, the neutrophil attractant and activating peptide) and monocyte chemotactic peptide (MCP-1).

TRANSITION FROM PREGNANCY TO LABOUR

The classical studies of Caldeyro-Barcia [2] demonstrate thegradual 'coming to theboil' of myometrial contractility during 'prelabour' which occupies the last seventh or so of pregnancy (Fig. 7.1). Although the parameter shown on the vertical axis is Caldeyro's Montevideo unit whereby he quantifies uterine contractility as the product of the frequency and amplitude of contractions, the same figure pattern could be used, simply by altering the labelling, to illustrate a host of other events. These include the concentrations of myometrial gap junctions, those elements consisting of the protein connexin 43 which allow the spread of action potentials between smooth muscle cells by intercellular transmission of ions thereby allowing individual myometrial fibres to change from a disorganized rabble into a disciplined regiment marching to the same drum beat in labour. Equally the factor in question might be the myometrial sensitivity to oxytocin or the concentration of various receptors in the myometrium. Nor does the recipe for this broth contain only myometrial ingredients. To these can be added fetal endocrine changes (which may carry responsibility for initiating the process)

as well as a contribution from the cervix. The numerical expression of cervical ripening, the Bishop score, also fits Caldeyro's diagram during prelabour and labour almost perfectly.

ACTIVATION OF THE MYOMETRIUM

The individual myometrial fibre contracts when the two filaments actin and myosin combine by phosphorylation by the enzyme myosin light chain kinase to form acti-nomyosin. This reaction requires increased availability of intracellular calcium, released from stores within the cell (mainly in the sarcoplasmic reticulum) which may be provoked by oxytocin or PGF2a or both via the second messenger inositol trisphosphate. Additionally, extracellular calcium may be transported into myometrial cells via calcium channels.

Conversely, contractility of the myometrial cell may be inhibited by progesterone and by the intracellular availability of cAMP, a mechanism which the use of f mimetic agents as tocolytics seeks to exploit.

RIPENING OF THE CERVIX

The substance most closely associated by clinicians with cervical ripening is PGE2 and this probably reflects a key biological role for this compound. Softening of the cervix entails not only degradation of stromal collagen, but also changes in the proteoglycan complexes and water content of the ground substance, which may be likened to glue or cement binding individual collagen fibrils into the rigid bundles which confer on the tissue its tensile strength. The process of cervical ripening remains improperly understood, but recent studies of a number of inflammatory mediators, notably IL-8 and MCP-1 have focused attention on neutrophils and monocytes recruited from the circulation as likely factors in the process. Neutrophils are a rich source of collagenases and neutrophil elastase as well as matrix metalloproteinase enzymes which play a crucial role in the breakdown of cervical collagen. One attractive hypothesis [3] implicates PGE2 as mainly responsible for vasodilatation of cervical capillaries and increasing their permeability to circulating neutrophils which are captured by surface adhesion molecules and drawn into the cervical stroma under the chemoattractant influence of IL-8. This chemokine is also responsible for stimulating their degranulation within the tissues to release these collagenolytic enzymes. Monocytes are also recruited into the cervix by MCP-1 and might potentially play a unifying role as a source of both PGE2 and IL-8. Both IL-8 and MCP-1 may prove in time to be effective agents in the pharmacological orchestration of cervical ripening.

INTEGRATION OF CONTROL PATHWAYS

Studies in humans, subhuman primates, domestic species (notably sheep), rodents, and especially guinea pigs have allowed concepts to be elaborated to explain the biological control of human parturition. As emphasized above, the transition from pregnancy maintenance to birth develops gradually during a month or more of 'prelabour'. From early naïve concepts which credited the mother as responsible for initiating labour by producing oxy-tocin from her posterior pituitary, the hypothesis has gradually been developed whereby the control is initiated and largely vested within the fetoplacental unit (Fig. 7.2). The key component appears to be the fetal brain whose influence is exerted on fetoplacental endocrinology via the hypothalamopituitary-adrenoplacental axis. Activation of corticotrophin (adrenocorticotrophic hormone or ACTH) stimulates adrenal production of (1) cortisol which brings about maturation of the fetal lungs with the generation of pulmonary surfactant; and (2) dehy-droepiandrosterone sulphate. The latter, a key precursor of placental oestradiol production, ordains a shift in the oestrogen to progesterone ratio in favour of oestrogen and provokes an endocrine dialogue between fetus, placenta, membranes and uterus (Fig. 7.3). Cortisol promotes maturation of the fetal lungs and this, together with similar events in the fetal kidneys, may modify the content of the amniotic fluid and thereby activate the fetal membranes (amnion and chorion), particularly in respect of prostaglandin synthesis. By means of such biological changes in the fetal components - fetus, placenta, amniotic fluid and the membranes - a new dialogue is created with the uterine (maternal) tissues which envelop them - the

Amnion

Decidua Myometrium Hypothalamus

Maternal, circulation

Amnion

Decidua Myometrium Hypothalamus

Maternal, circulation

Fetus Oxytocin Parturition

Cervix

Fig. 7.2 The fetoplacental unit and the intrauterine and uterine structures with which it interacts.

Kidney

Adrenal Lung

Placenta

Chorion

Pituitary

Cervix

Fig. 7.2 The fetoplacental unit and the intrauterine and uterine structures with which it interacts.

Hormones Initiate Labour
Fig. 7.3 Scheme of the principal biochemical factors participating in the control of human labour

decidua, myometrium and cervix - producing a positive cascade of interactions among prostaglandins, cytokines and oxytocin.

PROSTAGLANDINS - ESSENTIAL REGULATORS OF PARTURITION

Only one small group of compounds involved in labour, the prostaglandins, appear to play an essential command role. It is probably no exaggeration to state that without prostaglandins labour is impossible, whereas when they appear in abundance labour is irresistible. PGF2« appears to be the principal prostaglandin generating contractility of the myometrium, while PGE2 is more important in the process of cervical ripening. The main sources of these prostanoids within the uterus are, respectively, the decidua and the amnion. Conveniently placed in intimate contact between these structures lies the chorion, a rich source of the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (PGDH). Activation of uterine prostaglandins in labour is vested in the inducible isoform of cyclo-oxygenase, COX-2, and it seems likely that the high capacity of the chorion to metabolize prostaglandins represents a defence mechanism against the early and inappropriate production of prostaglandins before the scheduled time. The influences which may bring about this precocious production of prostaglandins include trauma, haemorrhage and (most importantly) infection, now recognized as a major factor in initiating many premature deliveries. The chorion may thus be regarded as a biological metabolic barrier rather like blotting paper designed to mop up unwelcome prostaglandins.

CERVICAL EFFACEMENT - THE KEY TO SUCCESSFUL DELIVERY

As is emphasized below, effacement of the cervix is an essential prerequisite to its dilatation and one which depends on the softening and ripening of its connective tissue. Attention has focused on the apparent obstacle presented by the chorion to PGE2 derived from the amnion. It must be conceded that the PGE2 required in cervical ripening might be synthesized within the cervical stroma itself, but an alternative and attractive hypothesis lies in the possibility that a selective loss of PGDH activity in that area of chorion overlying the cervix might afford access of PGE2 from the amnion and amniotic fluid to the precise part of the cervix where it is most required, namely the internal cervical os. Support for such a concept comes from the clinical observation that loss of the fetal membranes from that key site following either their spontaneous or their artificial rupture adversely prejudices the prospects of successful delivery. Recently we have provided evidence that the area of fetal membranes overlying the cervix changes from exhibiting the highest activity of PGDH during pregnancy to the lowest during labour ([4]; Fig. 7.4). Nature may thus have provided a mechanism whereby the long firm cervix is progressively softened and shortened from the top downwards during the process of 'taking up' or effacement. Beginning just below the fibromuscu-lar junction (Fig. 7.5) the softened tissue at the internal os is progressively transported outwards around the fetal presenting part and the 'fore-waters' thereby bringing the lower portions of the cervix into intimate contact with that fetal membrane source of PGE2.

SUBSEQUENT COURSE OF CLINICAL LABOUR

Clinical labour, as opposed to prelabour, is considered to begin with the onset of regular painful uterine contractions. The events of prelabour should have set everything in place for a comparatively short birth process, but not all labours will follow a straightforward course. In its simplest terms, labour consists of the muscle of the uterine corpus progressively stretching the cervix over the fetal head by means of rhythmic contraction and retraction. This process is usefully compared to pulling on a woollen jumper with a tight polo neck, where the action of the arms represent the contractions of the myometrium, while the changes in the neck of the garment replicate effacement and dilatation of the cervix. This analogy can be carried further with the observation that just as the first attempt at pulling on the garment is generally the most difficult, so too is the first labour. Furthermore, appropriate flexion of the head to present the cranial vertex to the neck of the garment, or the womb, is just as important for the wearer as it is for the fetus.

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Pregnancy And Childbirth

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