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1999 Obstetrics & Gynaecology By Duy Thai

PHYSIOLOGY OF PREGNANCY AND PARTURITION Cross section through normal placenta

Umbilical cord containing 2 arteries, 1 vein

Chorionic villi with foetal vessels

Inter villous space filled with maternal blood

Placental septum

Anchoring villus



Spiral arteries supplying maternal blood rich in O2 and nutrients

• • •

Decidual vein to drain foetal CO2 and wastes into maternal circulation

The cells making up the anchoring villus are called intermediate trophoblast cells. These are special in that they behave much like a cancer cell and invade the spiral arteries, forming a layer on the endothelium By doing this, the spiral arteries are no longer influenced by maternal factors (e.g. sympathetic constriction) and hence provide a steady, uninterrupted flow of maternal blood into the placenta It is postulated that failure to invade these spiral arteries by the intermediate trophoblast cells may be a factor in IUGR (due to inadequate supply of maternal blood)

Functions of the placenta 1. Metabolic exchange • Nutrients and oxygen from the maternal blood enters the foetal veins in the villi • Foetal CO2 and wastes exit the foetal circulation via the arteries in the villi and are handled by the maternal circulation 2. Acts as an endocrine organ, mainly producing the placental hormones: • HCG • Oestrogen • Progesterone • HPL (human placental lactogen, aka human chorionic somatomammatropin) 3. Prevents rejection of the foetus The placental hormones 1. Human chorionic gonadotropin A. The normal menstrual cycle: • After ovulation, there is formation of the corpus luteum • The corpus luteum produces progesterone • LH secretion from the anterior pituitary is inhibited by progesterone via negative feedback • The loss of pituitary LH causes the corpus luteum to involute, resulting in reduction of progesterone • This progesterone withdrawal causes sloughing of the endometrium

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1999 Obstetrics & Gynaecology By Duy Thai

B. What happens if fertilisation occurs? • The implanted conceptus begins to produce HCG from the syncitiotrophoblast • HCG is structurally and functionally similar to LH, however, the half life of HCG is 24 hours compared to 30 min for LH • HCG prevents involution of the corpus luteum, even after the pituitary stops secreting LH • HCG levels peak at around 8 – 9 weeks, then decline and plateau at a lower level by 10 weeks. Why? • After 10 weeks, the corpus luteum is no longer required because the placenta can now sufficiently make enough progestogens and oestrogens on its own • Prior to 10 weeks, the placenta is still immature, and hence requires progestogens and oestrogens being produced from the corpus luteum

C. Clinical use of HCG • HCG can be measured (in blood or urine) and used to indicate pregnancy • Abnormal levels of HCG can also be used to identify certain conditions 1. Gestational trophoblastic diseases (hydatidiform mole and choriocarcinoma) result in very high levels of HCG. After surgical removal of these tumors, monitor HCG levels to see if they go down to indicate success of surgery. If no success, may need to consider chemo 2. If the rate of HCG rise is slower compared to normal pregnancy, this may indicate an ectopic pregnancy 2. Human placental lactogen • Single chain polypeptide • Produced by ST in very large amounts • Similar homology to GH • Blood levels correlate well with placental weight. Increases in linear fashion. Once used to measure placental function, but superceded by ultrasound • Functions: • Regulates glucose and amino acid concentrations in maternal blood • Increases lipolysis for placental and foetal use • Suppresses maternal glucose uptake into cells, thus increases glucose in the maternal blood so that the foetus can use it instead. Results in increased insulin production. If severe, may cause gestational diabetes • Others of no importance here 3. Progesterone synthesis • Progesterone is made by both the corpus luteum and placenta, at varying amounts during pregnancy • 3 phases: A. Corpus luteum dependent phase • Only the corpus luteum is producing progesterone • If the corpus luteum is lost, pregnancy cannot be sustained B. Transition phase at 6 – 10 weeks • Progesterone is being made by both the corpus luteum and the placenta C. Placental phase > 10 weeks • Placenta makes sufficient progesterone to sustain pregnancy • Corpus luteum no longer required, and so becomes smaller as a result of reduced levels of HCG at this time • How is progesterone synthesised by the placenta? • By about 6 weeks the placenta produces LDL receptors • LDL (containing cholesterol) from the maternal circulation is taken up by these receptors on the placenta • The cholesterol in the LDL is broken down into progesterone • Progesterone synthesis is not dependent on foetal well being. It is only dependent on the ability of the placenta to take up LDL • Progesterone withdrawal is related to labour onset • The main role of progesterone is maintaining uterine quiescence by:

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1999 Obstetrics & Gynaecology By Duy Thai

A. Suppressing formation of gap junctions linking uterine myocytes. This prevents the uterus from being able to synchronise contraction of the whole uterus B. Suppressing prostaglandin formation by blocking enzymes in the PG synthesis pathway C. Suppressing formation of oxytocin receptors on myocytes D. Prevent the activity of collagenolytics and smooth muscle cell contractility • Myocytes surrounded by extracellular matrix are less likely to contract E. Formation of a mucous plug in the cervical canal to prevent vaginal contaminants entering the uterus 4. Oestrogen synthesis • 3 types of oestrogens • Estrone (E1) • Estradiol (E2) • Estriol (E3) • The placenta does not possess the enzymes required to make oestrogen (unlike progesterone) • The progestogens produced by the placenta is released into both the maternal circulation and the foetal circulation. • In the foetus, progestogens are taken to the foetal adrenals where they are converted to androgens (DHEA) • The androgens are sulfated to DHEAS to inactivate them, since you don’t want too many steroids around, especially if the foetus is female • Some DHEAS is taken back to the placenta and converted to E2 • The majority of DHEAS is taken up by the foetal liver and hydrolysed (by 16hydroxylase). This hydrolysed DHEAS is then taken up by the placenta and converted to E3. • Measurement of E3 in maternal blood or urine is a marker of foetal wellbeing since it relies on the foetal liver • Most of the oestrogens produced are very weakly potent or inactivated. Hence, oestrogen is not particularly important for maintenance of pregnancy - <10% of oestrogen production is still compatible with normal pregnancy. However it is important in the process of labour. • It is the balance between oestrogen and progestogen levels which is important – oestrogens may have the opposite action to progestogens • Function of oestrogen in labour: A. Cervical ripening (softening) – in conjunction with prostaglandins B. Increase expression of oxytocin receptors C. Increase production of prostaglandins Factors involved in labour 1. cAMP levels in uterine myocytes • Agents that increase cAMP levels causes relaxation E.g. Salbutamol 2. Prostaglandins • Derived from arachidonic acid which is generated from cell membranes (hence damage to cell membranes may release arachidonic acid) • Any infection of the uterus (from ROM) results in production of inflammatory mediators and cytokines which ↑ PG production, as does bacterial endotoxin. Hence infection can be a cause of pre term labour • Foetal tissues produce PGE2 • Maternal tissue (decidua) produces PGF2α • Myometrium produces PGI2 (prostacyclin) • Functions of prostaglandins A. Involved in cervical “ripening” – softening of the cervix B. Causes intense uterine contractions (esp PGF2α) irrespective of gestational age (unlike oxytocin – see below) • Giving PGs (e.g. misoprostil) can induce abortion if given early • Inhibitors of PG synthesis will delay delivery • Women taking aspirin will have a delayed labour • Indomethacin or mefanamic acid are used as tocolytics to stop pre term labour • However, these agents can cross the placenta and affect foetal organ development and causes closure of the ductus arteriosus Page 3 of 4

1999 Obstetrics & Gynaecology By Duy Thai

3. Oxytocin • Produced in the neurosecretory cells of the hypothalamus and stored in the posterior pituitary • Oxytocin is a potent stimulator of uterine contractions, only near term • However, the levels of oxytocin remain relatively constant even prior to the onset of labour • What happens is that the sensitivity of the uterus to oxytocin increases at labour, by increasing the number of receptors on the myocytes. That is why not much oxytocin is required to initiate contractions. There is a 100 – 1000 X increase in oxytocin receptors at term. • The expression of oxytocin receptors is dependent on the balance between progestogens and oestrogens – during labour, there is a (relative) reduction in progestogens (see later), which normally inhibits expression of oxytocin receptors. • Syntocinon is not effective until the 3rd trimester because prior to this, there is not enough oestrogen receptors • During stage II of labour, there is a massive surge of oxytocin since dilation of the cervix produces a positive feedback loop (via neuroendocrine reflex) increasing the release of oxytocin from the posterior pituitary • ANTOCIBAN is a new agent which blocks oxytocin receptors to stop pre term labour 4. CRH and the balance between oestrogens and progestogens • As mentioned previously, oestrogen and progestogens have antagonistic functions in pregnancy • Oestrogens try and promote labour, whilst progestogens try to inhibit it • The balance initially is in favour of progestogen, hence labour does not occur • What shifts this balance, thus triggering labour? • The levels of oestrogen and progestogens remain relatively constant throughout labour • Hence there is not reduction in progestogen or increase in oestrogens • The answer may lie with CRH levels and cortisol production • CRH levels have been found to increase during the 3rd trimester. Why? A. Foetal stress, resulting in CRH released from foetal pituitary B. Maternal stress, CRH being released from maternal pituitary C. Maturation of the foetal adrenal results in increased cortisol production. This positively feeds back on the placenta to produce more CRH • CRH drives the foetal adrenals to produce more cortisol • Cortisol has similar functions to progestogen, but is much less potent. It also has similar structure to progestogens • The massive surge of cortisone levels results in it competing with progestogens for its receptors. Since there is so much more cortisone, it binds in preference to progestogen, and because it is less potent, there is a relative reduction in progestogen activity à change in the balance between oestrogen and progestogen. Summary of factors triggering and maintaining labour

Relative ↓ in progestogen activity

Competes with progestogens Cervical ripening

↑ cortisol

Unopposed oestrogen activity

+ feedback Foetal adrenal maturation

Placenta ↑ oxytocin R on

↑ PGs

uterus CRH production

Foetal stress

Maternal stress

Oxytocin + feedback

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Uterine contraction

ROM/infection Bacterial endotoxins and cytokines