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2


The regulation of human parturition
Roger Smith, Sam Mesiano, Richard Nicholson, Vicki Clifton,
Tamas Zakar, Eng-Cheng Chan, Andrew Bisits and Warwick Giles
Mothers and Babies Research Centre, John Hunter Hospital, Newcastle, Australia




Preterm birth accounts for 70% of neonatal mortality and is a common cause for
intellectual handicap among survivors. Approximately 50% of cases of cerebral
palsy are associated with preterm birth, in turn preterm birth increases the risk
of cerebral palsy by 40 times! (Goldenberg, 2002). Preterm labor thus af¬‚icts indi-
viduals at the very beginning of their lives, depriving them of opportunities
and increasing health and educational costs for families and society in general.
Unfortunately the rates of preterm birth have not changed for over 30 years due to
an inability to predict the event and lack of effective therapies.
This clinical problem has driven research into the mechanisms that regulate the
timing of human birth and the disorders which cause preterm birth.
For reasons of ethics most research in the past has focused on animal work, espe-
cially in the sheep. Unfortunately studies have revealed substantial differences
between parturition in humans and that in other animals. Thus animal studies pro-
vide us with clues as to how systems operate to regulate delivery in mammals but
frustrate us with uncertainty as to whether particular mechanisms operate in the
human. Experimental in vivo studies provide the strongest evidence for cause and
effect, yet the closer we come to the human state in our near relatives the apes, the
larger the ethical constraints on experimental studies become. This biological
equivalent of Heisenberg™s Uncertainty Principle dif¬culty continues to restrict
opportunities for interventional, experimental studies of relevance to human par-
turition. Recent observational studies have started to clarify the mechanisms
regulating the process and timing of human birth. Complemented by in vitro
experimental studies using human tissue which can examine cause and effect rela-
tionships progress is occurring. Only when we have a good understanding of the
normal physiology which determines the timing of human birth, can we hope to
understand the disturbances that occur in pathology leading to preterm birth. With
such an understanding we may be in a position to rationally identify predictors of
preterm delivery, methods of preventing preterm delivery and, when these fail,
74
75 The regulation of human parturition


methods of successfully intervening to generate a healthy newborn able to fully par-
ticipate in our society. This chapter outlines the progress made over the last decade.


Clues from parturition in mammals

In the overwhelming majority of mammals parturition is associated with a fall in
circulating progesterone concentrations and often a rise in circulating estrogens
(see Figure 2.1). This is seen as a type of switch from the pro-pregnancy environ-
ment created by high concentrations of progesterone to the parturition inducing
phenotype created by estrogen. Different mammals use different mechanisms to
create the withdrawal of progesterone. In goats luteolysis initiated by endometrial-
derived prostaglandin PGF2 plays a key role. In mice PGF2 also plays a key role
in luteolysis and COX1 induction in the myometrium is present at labor; neither
occurs in humans (Bethin et al., 2003). In sheep pioneering work by Mont Liggins
indicated a fetal mechanism involving the fetal hypothalamic“pituitary“adrenal
(HPA) axis (Liggins, 1973a, b; 1994). This model has contributed much to our
understanding.
In the sheep, progesterone levels are high for the majority of pregnancy (Figure
2.1). The sheep placenta converts cholesterol to progesterone but is unable to produce
estrogen because it lacks the 17 -hydroxylase, 17,20 lyase enzyme required for
this conversion. Late in pregnancy, possibly stimulated by placentally derived


Birth Birth Birth
Cow Goat Guinea pig




Sheep Birth Pig Birth Human Birth




Gestational age

Figure 2.1 Variations in the pattern of estrogen and progesterone during pregnancy in different
mammals; solid lines represent estrogen and dashed lines represent progesterone
76 R. Smith et al.


prostaglandin E2 (Young et al., 1996), the fetal hypothalamus releases increased
amounts of the neuropeptide corticotropin-releasing hormone (CRH). The CRH
stimulates fetal pituitary adrenocorticotropic hormone (ACTH) secretion which in
turn drives fetal adrenal synthesis of cortisol. Rising concentrations of fetal cortisol
induce placental expression of 17 -hydroxylase leading to conversion of progesterone
into estrogen (see Figure 2.2). Maternal progesterone levels consequently fall while
estrogen rises. Rising levels of estrogen initiate transcription of many contraction-
associated genes in the myometrium, such as that coding for the oxytocin receptor.
These changes lead to the onset of labor in the sheep. Damage to the sheep fetal hypo-
thalamus, pituitary, or adrenal leads to a failure of parturition and the continuation of
the pregnancy even to the extent of maternal death related to continued fetal growth
and abdominal compression. Importantly, these events do not occur in human preg-
nancy. Clinical conditions occur where the fetal hypothalamus, pituitary, or adrenal
fail to develop; yet labor occurs close to the normal time. Pregnant women do not
remain pregnant inde¬nitely, regardless of the presence of pathology, while preterm
delivery is common. The process in sheep cannot be extrapolated to the human. Why
is this so?

Con¬‚ict as a source of evolutionary drive

The astonishing variety of processes observed in mammalian pregnancy has stim-
ulated debate on the evolutionary pressures which have produced this situation.

Fetus Placenta Mother




Corticotropin-releasing
hormone Cholesterol


Progesterone
Adrenocorticotropin
hormone
Myometrial contractility,
Cortisol
P450c17 cervical softening

Liver,
lungs, Estrogens

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