Physiological changes in pregnancy

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:

• Increased vascularity.

• Hypertrophy of the cervical glands producing the appearance of a cervical erosion; an increase in mucous secretory tissue in the cervix during pregnancy leads to a thick mucus discharge and the development of an antibacterial plug of mucus in the cervix.

• Reduced collagen in the cervix in the third trimester and the accumulation of glycosaminoglycans and water, leading to the characteristic changes of cervical ripening. The lower section shortens as the upper section expands, while during labour there is further stretching and dilatation of the cervix.

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 twenty-eighth 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:

• As progesterone concentrations rise in the mid-secretory phase of an ovulatory menstrual cycle, endometrial epithelial and stromal cells stop proliferating and begin to differentiate, with an accumulation of maternal leukocytes, mainly NK cells (see Immunology earlier). This decidualization is essential for successful pregnancy.

• The uterus changes in size, shape, position and consistency. In later pregnancy, the enlargement occurs predominantly in the uterine fundus so that the round ligaments tend to emerge from a relatively caudal point in the uterus. The uterus changes from a pear shape in early pregnancy to a more globular and ovoid shape in the second and third trimesters. The cavity expands from some 4 mL to 4000 mL at full term. The myometrium must remain relatively quiescent until the onset of labour.

• All the vessels supplying the uterus undergo massive hypertrophy. The uterine arteries dilate so that the diameters are 1.5 times those seen outside pregnancy. The arcuate arteries, supplying the placental bed, become 10 times larger, and the spiral arterioles reach 30 times the pre-pregnancy diameter (see later). Uterine blood flow increases from 50 mL/min at 10 weeks’ gestation to 500–600 mL/min at term.

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 re-modelling of these spiral arteries is very important for a successful pregnancy. Cytotrophoblast differentiates into villous or EVT. The latter can differentiate further into invasive EVT, which in turn is either interstitial, migrating into the decidua and later differentiating into myometrial giant cells, or endovascular and invades 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 to 16 weeks, a further wave of invasion occurs, extending down the lumen of the decidual portion of the vessel; from 16 to 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 the potential for a 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 a 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, even though 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 receptor function appears to decrease towards term. 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 (PGI ₂ ), prostaglandin (PGE ₂ ) 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 70–80mL, some 12%, between early and late pregnancy, due in part 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 a shortening of the pre-ejection period, and this is associated with lengthening of the myocardial muscle fibres.

Cardiac output

Non-invasive methods, such as Doppler velocimetry, echocardiography and impedance cardiography, 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 10–15beats/min by mid-pregnancy; this may be related to the progesterone-driven hyperventilation (see later). There is probably a fall in baro-reflex 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 71mL during pregnancy. Women who have an artificial pacemaker and thus a fixed heart rate compensate well in pregnancy based on increased stroke volume alone.

These two factors push up the cardiac output and cardiac index (cardiac output related to body surface area). Most of the rise in cardiac output occurs in the first 14 weeks of pregnancy, with an increase of 1.5L from 4.5 to 6.0L/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. In a healthy pregnancy, the birth weight is associated with the increase in cardiac output and fall in total peripheral resistance (TPR) and augmentation index. Conversely, women with any type of hypertension in pregnancy who deliver babies with birth weights below the tenth centile show much smaller pregnancy-related changes in haemodynamics.

Cardiac output can rise by another third (≈2L/min) in labour. The cardiac output remains high for ≈24hours 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

TPR is not measured directly but is calculated from the mean arterial pressure divided by cardiac output. The augmentation index, a surrogate measure of arterial stiffness, is also measured indirectly from pulse wave analysis. Measured TPR and augmentation index both fall by 6 weeks’ gestation, so afterload is assumed to have fallen. This is ‘perceived’ as circulatory under-filling, 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 Renal function later). 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 1200–1300dyn/s/cm in late pregnancy. The fall in systemic TPR is partly associated with the expansion of the vascular space in the utero-placental bed and the renal vasculature; 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 from vasoconstrictor to vasodilator hormones. The vasodilators involved in early gestation include circulating PGI ₂ and locally synthesized 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 10mmHg 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 the 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 1400mL in non-pregnant women to ≈1700mL 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 PV 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 15μg/L, indicating low iron stores; no similar survey appears to have been undertaken since then. Pregnant adolescents seem to be at 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. The platelet count falls below 150,000 ×10 ⁹ /L in ≈10% of otherwise normal women in late gestation. Platelet reactivity is increased in the second and third trimesters and does not return to normal until ≈12 weeks after delivery.