The cervix

The cervix is predominantly a fibrous organ with only 10% of uterine muscle cells in the substance of the cervix. Eighty percent of the total protein in the non-pregnant state consists of collagen, but by the end of pregnancy the concentration of collagen is reduced to one-third of the amount present in the non-pregnant state. The principal function of the cervix is to retain the conceptus (Fig. 3.2).

The characteristic changes in the cervix during pregnancy are:

The isthmus

The isthmus of the uterus is the junctional zone between the cervix and the body of the uterus. It joins the muscle fibres of the corpus to the dense connective tissue of the cervix both functionally and structurally. By the 28th week of gestation, regular contractions produce some stretching and thinning of the isthmus, resulting in the early formation of the lower uterine segment.

The lower segment is fully formed during labour and is a thin, relatively inert part of the uterus. It contributes little to the expulsive efforts of the uterus and becomes in effect an extension of the birth canal. Because of its relative avascularity and quiescence in the puerperium, it is the site of choice for the incision for a caesarean delivery.

The corpus uteri

The uterus changes throughout pregnancy to meet the needs of the growing fetus both in terms of physical size and in vascular adaptation to supply the nutrients required:

In the non-pregnant uterus, blood supply is almost entirely through the uterine arteries, but in pregnancy 20–30% is contributed through the ovarian vessels. A small contribution is made by the superior vesical arteries. The uterine and radial arteries are subject to regulation by the autonomic nervous system and by direct effects from vasodilator and vasoconstrictor humoral agents.

The final vessels delivering blood to the intervillous space (Fig. 3.3) are the 100–150 spiral arterioles. Two or three spiral arterioles arise from each radial artery and each placental cotyledon is provided with one or two. The remodelling of these spiral arteries is very important for successful pregnancy. Cytotrophoblast differentiates into villous or EVT. The latter can differentiate further into invasive EVT, which in turn is interstitial, migrating into the decidua and later differentiating into myometrial giant cells, or endovascular that invade the lumen of the spiral arteries. The intrauterine oxygen tension is very low in the first trimester, stimulating EVT invasion.

In the first 10 weeks of normal pregnancy, EVT invades the decidua and the walls of the spiral arterioles, destroying the smooth muscle in the wall of the vessels, which then become inert channels unresponsive to humoral and neurological control (Fig. 3.4). From 10–16 weeks, a further wave of invasion occurs, extending down the lumen of the decidual portion of the vessel; from 16–24 weeks this invasion extends to involve the myometrial portion of the spiral arterioles. The net effect of these changes is to turn the spiral arterioles into flaccid sinusoidal channels.

Failure of this process, particularly in the myometrial portion of the vessels, means that this portion of the vessels remains sensitive to vasoactive stimuli with a consequent reduction in blood flow. This is a feature of pre-eclampsia and intrauterine growth restriction with or without pre-eclampsia.

The uterus has both afferent and efferent nerve supplies, although it can function normally in a denervated state. The main sensory fibres from the cervix arise from S1 and S2, whereas those from the body of the uterus arise from the dorsal nerve routes on T11 and T12. There is an afferent pathway from the cervix to the hypothalamus so that stretching of the cervix and upper vagina stimulates the release of oxytocin (Ferguson’s reflex). The cervical and uterine vessels are well supplied by adrenergic nerves, whereas cholinergic nerves are confined to the blood vessels of the cervix.

Uterine contractility

The continuation of successful pregnancy depends on the fact that the myometrium remains quiescent until the fetus is mature and capable of sustaining extrauterine life. Pregnant myometrium has a much greater compliance than non-pregnant myometrium in response to distension. Thus, although the uterus becomes distended by the growing conceptus, intrauterine pressure does not increase, although the uterus does maintain the capacity to develop maximal active tension. Progesterone maintains quiescence by increasing the resting membrane potential of the myometrial cells while at the same time impairing the conduction of electrical activity and limiting muscle activity to small clumps of cells. Progesterone antagonists such as mifepristone can induce labour from the first trimester, as can prostaglandin F2_α, which is luteolytic. Other mechanisms include locally generated nitric oxide, probably acting through cyclic guanosine monophosphate (cGMP) or voltage-gated potassium channels, while several relaxatory hormones such as prostacyclin (PGI₂), prostaglandin (PGE₂) and calcitonin gene-related peptide, which act through the G_s receptors, increase in pregnancy.

The development of myometrial activity

The myometrium functions as a syncytium so that contractions can pass through the gap junctions linking the cells and produce coordinated waves of contractions. Uterine activity occurs throughout pregnancy and is measurable as early as 7 weeks gestation, with frequent, low intensity contractions. As the second trimester proceeds, contractions increase in intensity but remain of relatively low frequency. In the third trimester they increase in both frequency and intensity, leading up to the first stage of labour. Contractions during pregnancy are usually painless and are felt as ‘tightenings’ (Braxton Hicks contractions) but may sometimes be sufficiently powerful to produce discomfort. They do not produce cervical dilatation, which occurs with the onset of labour.

In late gestation, the fetus continues to grow, but the uterus stops growing, so tension across the uterine wall increases. This stimulates expression of a variety of gene products such as oxytocin and prostaglandin F2_α receptors, sodium channels and the gap junction protein. Pro-inflammatory cytokine expression also increases. Once labour has begun, the contractions in the late first stage may reach pressures up to 100 mmHg and occur every 2–3 minutes (Fig. 3.5). See Chapter 11 for a discussion of labour and delivery.

Cardiac position and size

As the uterus grows, the diaphragm is pushed upwards and the heart is correspondingly displaced: the apex of the heart is displaced upwards and left laterally, with a deviation of ~15%. Radiologically, the upper left cardiac border is straightened with increased prominence of the pulmonary conus. These changes result in an inverted T wave in lead III and a Q wave in leads III and aVF.

The heart enlarges by 70–80 mL, some 12%, between early and late pregnancy, due to a small increase in wall thickness but predominantly to increased venous filling. The increase in ventricular volume results in dilatation of the valve rings and hence an increase in regurgitant flow velocities. Myocardial contractility is increased during pregnancy, as indicated by shortening of the pre-ejection period, and this is associated with lengthening of the myocardial muscle fibres.

Cardiac output

Non-invasive methods, such as echocardiography, are now available, allowing standardized sequential studies of cardiac output throughout pregnancy.

There is a small rise in heart rate during the luteal phase increasing to 10–15 beats/min by mid-pregnancy; this may be related to the progesterone-driven hyperventilation (see below). There is probably a fall in baroreflex sensitivity as pregnancy progresses and heart rate variability falls. Stroke volume rises a little later in the first trimester than heart rate, increasing from about 64 to 71 mL during pregnancy. Women who have an artificial pacemaker and thus a fixed heart rate compensate well in pregnancy on the basis of increased stroke volume alone.

These two factors push the cardiac output up. Most of the rise in cardiac output occurs in the first 14 weeks of pregnancy, with an increase of 1.5 L from 4.5 to 6.0 L/min. The non-labouring change in cardiac output is 35–40% in a first pregnancy, and ~50% in later pregnancies. Twin pregnancies are associated with a 15% greater increase throughout pregnancy.

Cardiac output can rise by another third (~2 L/min) in labour. The cardiac output remains high for ~24 h postpartum and then gradually declines to non-pregnant levels by ~2 weeks after delivery.

Table 3.1 summarizes the percentage changes in some cardiovascular variables during pregnancy.

Total peripheral resistance

Total peripheral resistance (TPR) is not measured directly, but is calculated from the mean arterial pressure divided by cardiac output. The total peripheral resistance has fallen by 6 weeks gestation, so afterload falls. This is ‘perceived’ as circulatory underfilling, which is thought to be one of the primary stimuli to the mother’s circulatory adaptations. It activates the renin–angiotensin–aldosterone system and allows the necessary expansion of the plasma volume (PV; see below: Renal function). In a normotensive non-pregnant woman the TPR is around 1700 dyn/s/cm; this falls to a nadir of 40–50% by mid-gestation, rising slowly thereafter towards term, reaching 1200–1300 dyn/s/cm in late pregnancy. The fall in systemic TPR is partly associated with the expansion of the vascular space in the uteroplacental bed and the renal vasculature in particular; blood flow to the skin is also greatly increased in pregnancy as a result of vasodilatation.

The vasodilatation that causes the fall in TPR is not due to a withdrawal of sympathetic tone, but is hormonally driven by a major shift in the balance between vasoconstrictor and vasodilator hormones, towards the latter. The vasodilators involved in early gestation include circulating PGI₂ and locally synthesised nitric oxide, and later, atrial natriuretic peptide. There is also a loss of pressor responsiveness to angiotensin II (AngII), concentrations of which rise markedly (see: Endocrinology). The balance between vasodilatation and vasoconstriction in pregnancy is a critical determinant of blood pressure and lies at the heart of the pathogenesis of pre-eclampsia.

Arterial blood pressure

Blood pressure changes occur during the menstrual cycle. Systolic blood pressure increases during the luteal phase of the cycle and reaches its peak at the onset of menstruation, whereas diastolic pressure is 5% lower during the luteal phase than in the follicular phase of the cycle.

The fall in TPR during the first half of pregnancy causes a fall of some 10 mmHg in mean arterial pressure; 80% of this fall occurs in the first 8 weeks of pregnancy. Thereafter, a small additional fall occurs until arterial pressure reaches its nadir by 16–24 weeks gestation. It rises again after this, and may return to early pregnancy levels. The rate of rise is amplified in women who go on to develop pre-eclampsia.

Posture has a significant effect on blood pressure in pregnancy; pressure is lowest with the woman lying supine on her left side. The pressure falls during gestation in a similar way whether the pressure is recorded sitting, lying supine or in the left lateral supine position, but the levels are significantly different (Fig. 3.7). This means that mothers attending for antenatal visits must have their blood pressure recorded in the same position at each visit if the pressures are to be comparable. Special care must be taken to use an appropriate cuff size for the measurement of brachial pressures. This is especially important with the increasing incidence of obesity among young women. The gap between the fourth and fifth Korotkoff sounds widens in pregnancy, and the fifth Korotkoff sound may be difficult to define. Both these factors may cause discrepancies in the measurement of diastolic pressure in pregnancy. Although most published studies of blood pressure are based on the use of Korotkoff fourth sound, it is now recommended to use the fifth sound where it is clear and the fourth sound only where the point of disappearance is unclear. Automated sphygmomanometers are unsuitable for use in pregnancy when the blood pressure is raised, as in pre-eclampsia.

Profound falls in blood pressure may occur in late pregnancy when the mother lies on her back. This phenomenon is described as the supine hypotension syndrome. It results from the restriction of venous return from the lower limbs due to compression of the inferior vena cava and hence a fall in stroke volume. It must be remembered that aortic compression also occurs and that this will result in conspicuous differences between brachial and femoral blood pressures in pregnancy. When a woman turns from a supine to a lateral position in late pregnancy, the blood pressure may fall by 15%, although some of this fall is a measurement artefact caused by the raising of the right arm above the level of the heart.

There is progressive venodilatation and rises in venous distensibility and capacitance throughout a normal pregnancy. Central venous pressure and pressure in the upper arms remain constant in pregnancy, but the venous pressure in the lower circulation rises progressively on standing, sitting or lying supine because of pressure from the uterus and the fetal presenting part in late pregnancy. The pulmonary circulation can absorb high rates of flow without an increase in pressure so pressure in the right ventricle, and the pulmonary arteries and capillaries, does not change. Pulmonary resistance falls in early pregnancy, and does not change thereafter.

Erythrocytes

There is a steady increase in red cell mass in pregnancy and the increase appears to be linear throughout pregnancy. Both cell number and cell size increase. The circulating red cell mass rises from around 1400 mL in non-pregnant women, to ~1700 mL during pregnancy in women who do not take iron supplements. It rises more in women with multiple pregnancies, and substantially more with iron supplementation (~29% compared with 18%). Erythropoietin rises in pregnancy, more if iron supplementation is not taken (55% compared with 25%) but the changes in red cell mass antedate this; human placental lactogen may stimulate haematopoiesis.

Haemoglobin concentration, haematocrit and red cell count fall during pregnancy because the plasma volume rises proportionately more than the red cell mass (‘physiological anaemia’, see Table 9.1). However, in normal pregnancy the mean corpuscular haemoglobin concentration remains constant. Serum iron concentration falls but the absorption of iron from the gut rises and iron-binding capacity rises in a normal pregnancy, since there is increased synthesis of the β1-globulin, transferrin. Maternal dietary iron requirements more than double. Plasma folate concentration halves by term, because of greater renal clearance, although red cell folate concentrations fall less. In the late 1990s, 20% of the female population aged 16–64 years in the UK was estimated to have serum ferritin levels below 15 µ g/L, indicating low iron stores; no similar survey appears to have been undertaken since then. Pregnant adolescents seem to be at particular risk of iron deficiency. Even relatively mild maternal anaemia is associated with increased placental : birth weight ratios and decreased birth weight.

The white cells

The total white cell count rises during pregnancy. This increase is mainly due to an increase in neutrophil polymorphonuclear leukocytes that peaks at 30 weeks’ gestation (Fig. 3.8). A further massive neutrophilia normally occurs during labour and immediately after delivery, with a fourfold increase in the number of polymorphs.

There is also an increase in the metabolic activity of granulocytes during pregnancy, which may result from the action of oestrogens. This can be seen in the normal menstrual cycle where the neutrophil count rises with the oestrogen peak in mid-cycle. Eosinophils, basophils and monocytes remain relatively constant during pregnancy, but there is a profound fall in eosinophils during labour and they are virtually absent at delivery. The lymphocyte count remains constant and the numbers of T and B cells do not alter, but lymphocyte function and cell-mediated immunity in particular are depressed, possibly by the increase in concentrations of glycoproteins coating the surface of the lymphocytes, reducing the response to stimuli. There is, however, no evidence of suppression of humoral immunity or the production of immunoglobulins.

Platelets

Longitudinal studies show a significant fall in platelet count during pregnancy. The fall in platelet numbers may be a dilutional effect, but the substantial increase in platelet volume from ~28 weeks suggests that there is increased destruction of platelets in pregnancy with an increase in the number of larger and younger platelets in the circulation. Platelet reactivity is increased in the second and third trimesters and does not return to normal until ~12 weeks after delivery.

Clotting factors

There are major changes in the coagulation system in pregnancy, with an increased tendency towards clotting (Box 3.1). In a situation where haemorrhage from the uterine vascular bed may be sudden, profuse and life-threatening, the increase in coagulability may play a life-saving role. On the other hand, it increases the risk of thrombotic disease.

Many clotting factors remain constant in pregnancy but there are notable and important exceptions (Fig. 3.9). Factors VII, VIII, VIII:C, X and IX (Christmas factor) all increase during pregnancy, whereas factors II and V tend to remain constant. Factor XI falls to 60–70% of the non-pregnant values and concentrations of factor XIII fall by 50%. Protein C, which inactivates factors V and VIII, is probably unchanged in pregnancy, but concentrations of protein S, one of its co-factors, fall during the first two trimesters.

Plasma fibrinogen levels increase from non-pregnant values of 2.5–4.0 g/L to levels as high as 6.0 g/L in late pregnancy and there is an increase in the concentration of high-molecular-weight fibrin/fibrinogen complexes during normal pregnancy. The erythrocyte sedimentation rate rises early in pregnancy, mainly due to the increase in fibrinogen. An estimated 5–10% of the total circulating fibrinogen is consumed during placental separation, and thromboembolism is one of the main causes of maternal death in the UK. On the other hand, there is a reduction in plasma fibrinolytic activity during pregnancy; the rapid return to non-pregnant levels of activity within 1 hour of delivery suggests that this inhibition is mediated through the placenta.

Physiology

Both renal blood flow (RBF) and glomerular filtration rate (GFR) increase during an ovulatory menstrual cycle, and this increase is maintained should conception occur. Renal blood flow increases by 50–80% in the first trimester, is maintained at these levels during the second trimester, and falls by ~15% thereafter (Fig. 3.11). Creatinine clearance is a useful indicator of GFR but gives values that are significantly less than those obtained by inulin clearance (gold standard). The 24-hour creatinine clearance has increased by 25% 4 weeks after the last menstrual period and by 45% at 9 weeks. In the third trimester, there is some decrease towards non-pregnant values, but less than the fall in RBF. The filtration fraction thus falls in the first trimester, is stable in the second, and rises towards non-pregnant values towards term.

Water retention must occur to allow the increase in plasma volume. The osmotic threshold for drinking falls between weeks 4 and 6, which stimulates water intake and thus dilution of body fluids. There is a marked fall in plasma osmolality (~10 mOsm/kg). However, arginine vasopressin (AVP) continues to circulate at concentrations that allow water to be reabsorbed in the renal medullary collecting ducts until the P_osm falls below the new osmotic thirst threshold, when a new steady state is established. Water retention is facilitated by the sodium retention of pregnancy (see below). Standing upright is significantly more antidiuretic than in non-pregnant subjects.

Plasma volume increases in pregnancy to a peak between 32 and 34 weeks, from a non-pregnant level of 2600 mL. The total increase is ~50% in a first pregnancy and 60% in a second or subsequent pregnancy. The bigger the expansion is, the bigger, on average, the birth weight of the baby. The total extracellular fluid volume rises by about 16% by term, so the percentage rise in plasma volume is disproportionately large. Multiple pregnancies are associated with a significantly higher increase in plasma volume and pregnancies exhibiting impaired fetal growth are associated with a poor increase in plasma volume.

The filtered load of sodium increases by 5000–10 000 mmol/day because of the increase in the GFR. Tubular reabsorption increases in parallel with the GFR (see: Renin–angiotensin system, below), with the retention of 3–5 mmol of sodium per day into the fetal and maternal stores. The total net sodium gain amounts to 950 mmol mainly stored in the maternal compartment. However, the plasma concentration of sodium falls slightly in pregnancy, because of the marked rise in plasma volume. A similar change occurs with potassium ions, with a net gain of approximately 350 mmol.

Renal tubular function also changes significantly during pregnancy. Uric acid is freely filtered through the glomerulus, but most is later reabsorbed. However, in pregnancy, uric acid filtration doubles, following the GFR, and there is a decrease in net tubular reabsorption, so serum uric acid concentrations fall by 25% to mid-pregnancy. The normal values in pregnancy range from 148–298 µmol/L, with an upper limit of ~330 µmol/L. In later gestation, the kidney excretes a progressively smaller proportion of the filtered uric acid, so some rise in serum uric acid concentration during the second half of pregnancy is normal. A similar pattern is seen in relation to urea, which is also partly reabsorbed in the nephron.

Glucose excretion increases during pregnancy and intermittent glycosuria is common in normal pregnancy, unrelated to blood glucose levels. Tubular reabsorption is probably less complete during pregnancy. The excretion of other sugars, such as lactose and fructose is also increased.

The tubular reabsorption of calcium is enhanced, presumably under the influence of the increased concentrations of 1,25-dihydroxyvitamin D. Even so, urinary calcium excretion is two- to threefold higher in normal pregnancy than in the non-pregnant woman. Renal bicarbonate reabsorption and hydrogen ion excretion appear to be unaltered during pregnancy. Although pregnant women can acidify their urine, it is usually mildly alkaline.

Both total protein and albumin excretion rise during pregnancy, to at least 36 weeks. Thus in late pregnancy, an upper limit of normal of 200 mg total protein excretion/24 h collection is accepted. Using dipsticks to assess proteinuria in pregnancy gives highly variable data.

Changes in plasma proteins

The total protein concentration falls by about 1 g/dL during the first trimester from 7 to 6 g/dL, even though there is increased nitrogen retention. This is partly due to the increased insulin concentrations, but also because of placental uptake and transfer of amino acids to the fetus for gluconeogenesis and protein synthesis. This fall is largely proportional to the fall in albumin concentration and is associated with a corresponding fall in colloid osmotic pressure. The fall is insufficient to affect drug-carrying capacity.

Amino acids

With the exception of alanine and glutamic acid, amino acid levels in maternal plasma decrease below non-pregnant values. There is active transport of amino acids to the fetus as building blocks for protein synthesis and gluconeogenesis.

Lipids

The total serum lipid concentration rises from about 600 to 1000 mg per 100 mL. The greatest changes are the approximate threefold increases in very low density lipoprotein (VLDL) triglycerides and a 50% increase in VLDL cholesterol by 36 weeks. Levels of free fatty acids are particularly unstable in pregnancy and may be affected by fasting, exertion, emotional stress and smoking. The levels are consistently raised above non-pregnant and early pregnancy values in late pregnancy. Birth weight and placental weight are directly related to maternal VLDL triglyceride levels at term.

The hyperlipidaemia of normal pregnancy is not atherogenic, although pregnancy can unmask pathological hyperlipidaemia. Mothers are usually protected from the potentially harmful effects of increasing lipid peroxidation in pregnancy by an increase in endogenous antioxidants, although this may be inadequate in pre-eclampsia. An adequate dietary intake of antioxidants such as vitamin A, the carotenoids and provitamin A carotenoids is also needed. Levels of fat-soluble vitamins rise in pregnancy whereas levels of water-soluble vitamins tend to fall.

Fat is deposited early in pregnancy. It is also used as a source of energy, mainly by the mother from mid to late pregnancy for her high metabolic demands and those of lactation, so that glucose is available for the growing fetus. Total fat accretion is ~2–6 kg, mainly laid down in the second trimester, and is regulated by the hormone leptin. It is deposited mainly over the back, the upper thighs, the buttocks and the abdominal wall.

Calcium

Maternal total plasma calcium falls, because albumin concentation falls, but unbound ionized calcium is unchanged. Synthesis of 1,25-dihydroxycholecalciferol increases, promoting enhanced gastrointestinal calcium absorption, which doubles by 24 weeks, after which it stabilizes.

Postpartum weight

Immediately following delivery, there is a weight loss of ~6 kg, which is accounted for by water and fluid loss and by the loss of the products of conception. Diuresis occurs during the early puerperium, removing the water retained during pregnancy. From ~ day 3, body weight falls by ~0.3 kg/day until day 10, stabilizing by week 10 at ~2.3 kg above pre-pregnancy weight, or 0.7 kg in women who are continuing to lactate. By 6–18 months after delivery, 1–2 kg of pregnancy-related weight gain will still be retained, but in about one-fifth of women 5 kg or more can be retained. Obese women usually put on less weight during pregnancy, but retain more postpartum.

Weight gain is about 0.9 kg less in multigravidae than in primigravidae. However, a 5-year follow-up of nearly 3000 women found that parous women gained 23 kg more than nulliparae during this time.

Breast development during pregnancy

High oestrogen concentrations, with growth hormone and glucocorticoids, stimulate ductal proliferation during pregnancy (Fig. 3.15). Alveolar growth is stimulated in the oestrogen-primed breast by progesterone and prolactin. Secretory activity is initiated during pregnancy and is promoted by prolactin and placental lactogen so that from 3 to 4 months onwards and for the first 30 hours after delivery, a thick, glossy, protein-rich fluid known as colostrum can be expressed from the breast. However, full lactation is inhibited during pregnancy by the high levels of oestrogen and progesterone that block the alveolar transcription of α-lactalbumin.

The initiation of lactation

Prolactin acts directly on alveolar cells to stimulate the synthesis of all milk components including casein, lactalbumin and fatty acids. The sudden reduction of progesterone and oestrogen levels following parturition allows prolactin to act in an uninhibited manner and its release is promoted by suckling, with the development of the full flow of milk by day 5 and a further gradual increase over the next 3 weeks. Some 500–1000 mL of milk are produced daily, and the mother needs about 500 kcal extra per day to maintain this; a further 250 kcal/day are derived from the maternal fat stores. The administration of a dopamine agonist such as bromocriptine inhibits the release of prolactin and abolishes milk production.

Suckling also promotes the release of oxytocin from specialized neurones in the supraoptic and paraventricular nuclei of the hypothalamus, and this in turn results in the milk-ejection reflex as the oxytocin stimulates the myoepithelial cells to contract. The milk-ejection reflex can also be stimulated by the mother seeing the infant or hearing its cry or just thinking about feeding! It may also be inhibited by catecholamine release or by adverse emotional and environmental factors.

Placental hormones

Human chorionic gonadotrophin is the signal for pregnancy. The fetoplacental unit synthesizes very large amounts of oestrogen and progesterone, both being needed for uterine growth and quiescence, and for breast development. However, oestrogen also stimulate the synthesis of binding globulins for thyroxine and corticosteroids; cortisol-binding globulin (CBG) increases throughout pregnancy to reach twice non-pregnant levels, while thyroid-binding globulin (TBG) is doubled by the end of the first trimester and remains elevated throughout pregnancy. Oestrogens also stimulate vascular endothelial growth factor (VEGF) and its receptors, and angiogenesis. In turn, VEGF appears to interact with other placentally produced hormones and angiopoietin-2 in the development of the placental villous capillary bed. The peroxisome proliferator-activated receptor-γ (PPARγ) is expressed in human villous and extravillous cytotrophoblast and binds to, and is activated by, natural ligands such as eicosanoids, fatty acids and oxidized low-density lipoproteins.

The anterior and posterior pituitary glands have different embryological origins, the anterior pituitary arising from Rathke’s pouch in the developing oral cavity, while the posterior pituitary is derived from a downgrowth of neural tissue that forms the floor of the third ventricle. A specialized vascular portal system connects the two parts. The pituitary gland enlarges during pregnancy by ~30% in primigravid women and 50% in multiparous women. The weight increase is largely due to changes in the anterior lobe.

Hypothalamus

Corticotrophin releasing hormone (CRH) stimulates the release of ACTH. Both hypothalamus and placenta synthesise CRH. Plasma levels of CRH increase greatly in the third trimester, and may be one of the triggers for the onset of labour.

The thyroid

The thyroid gland enlarges in up to 70% of pregnant women, the percentage varying depending on iodine intake. In normal pregnancy, there is increased urinary excretion of iodine and transfer of iodothyronines to the fetus. This in turn results in a fall of plasma inorganic iodide levels in the mother. At the same time, the thyroid gland triples its uptake of iodide from the blood, creating a relative iodine deficiency which is probably responsible for the compensatory follicular enlargement of the gland (Fig. 3.16).

As a result of the increase in TBG, total tri-iodothyronine (T₃) and thyroxine (T₄) levels increase in pregnancy, although free T₃ and T₄ rise in early pregnancy and then fall to remain in the non-pregnant range. TSH may increase slightly but tends to remain within the normal range. T₃, T₄ and TSH do not cross the placental barrier and there is therefore no direct relationship between maternal and fetal thyroid function. However, iodine and antithyroid drugs do cross the placenta, as does the long-acting thyroid stimulator (LATS). Hence, the fetus may be affected by the level of iodine intake and by the presence of autoimmune disease in the mother.

Calcitonin is another thyroid hormone. It rises during the first trimester, peaks in the second and falls thereafter, although the changes are not large. It may contribute to the regulation of 1,25-di-hydroxy vitamin D.

The parathyroids

Parathyroid hormone (PTH) regulates the synthesis of 1,25-dihydroxy vitamin D in the proximal convoluted tubule. There is a fall in intact PTH during pregnancy but a doubling of 1,25-dihydroxy vitamin D. Placentally derived PTH-related protein (PTHrP) is also present in the maternal circulation and affects calcium homeostasis by acting through the PTH receptor.

The renin–angiotensin system (RAS)

The RAS is activated in the luteal phase, and is one of the first hormones to ‘recognize’ pregnancy. The increased GFR and high progesterone cause an increased sodium load at the macula densa, which stimulates renin release. At the same time, oestrogens stimulate angiotensinogen synthesis. The resultant increase in AngII stimulates aldosterone synthesis and release from the adrenal cortex, which counters the natriuretic effect of progesterone at the distal tubule and results in sodium retention and plasma volume expansion. The potential effect of the raised AngII on blood pressure is offset by a parallel, specific, reduction in vascular sensitivity to AngII. The decreased sensitivity to AngII in normal pregnancy is lost in pre-eclampsia, where sensitivity increases even before the onset of hypertension.

AngII acts through two directly opposing receptors, the AT1 and AT2 subtypes. AT1 receptors promote angiogenesis, hypertrophy and vasoconstriction and AT2 receptors promote apoptosis. AT2 expression dominates in the early placenta where the system may be involved in implantation and vascular remodelling.

The adrenal gland

The adrenal glands remain constant in size but exhibit changes in function.

The rising ACTH stimulates cortisol synthesis and plasma total cortisol concentrations rise from 3 months to term. Much of this cortisol is bound to CBG or to albumin; even so, mean free (active) cortisol concentrations do also increase during pregnancy, with the loss of diurnal variation. The normal placenta synthesizes a pregnancy-specific 11β-hydroxysteroid dehydrogenase, which inhibits transfer of maternal cortisol to the fetus; excess transfer is thought to inhibit fetal growth.

Plasma aldosterone from the zona glomerulosa rises progressively throughout pregnancy (see above: The renin–angiotensin system); there is also a substantial increase in the weak mineralocorticoid deoxycorticosterone that is apparent by 8 weeks gestation and may reflect production by the fetoplacental unit.

The oestrogen-induced increase in the production of sex-hormone-binding globulin (SHBG) results in an increase in total testosterone levels.

Improved measurement techniques have shown that plasma catecholamine concentrations fall from the first to the third trimesters. There is some blunting of the rise in noradrenaline (reflecting mainly sympathetic nerve activity) seen on standing and isometric exercise in pregnancy, but the adrenaline response (predominantly adrenal) is unaltered. However, there are often massive increases in both adrenaline and noradrenaline concentrations during labour as the result of stress and muscle activity.