Many maternal adaptations to pregnancy, such as an increased heart rate and renal blood flow, are initiated in the luteal phase of every ovulatory cycle, and are thus proactive rather than reactive, simply being amplified during the first trimester should conception occur. This suggests very strongly that they are driven by progesterone. All physiological systems are affected to some degree and will also vary within a physiological range because of factors such as age, parity, multiple pregnancy, socioeconomic status and race.
After studying this chapter you should be able to:
Knowledge criteria
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Understand the immunology of pregnancy
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Describe the changes in the uterus, vagina and breasts that take place in pregnancy
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Describe the adaptations of the cardiovascular, endocrine, respiratory, renal and gastrointestinal systems to pregnancy
Clinical competencies
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Interpret the clinical findings and investigatory findings of various tests related to cardiovascular, respiratory, gastrointestinal and renal parameters in pregnancy
Professional skills and attitudes
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The impact of the physiological adaptation to pregnancy on the wellbeing of the mother
From a teleological point of view, there are two main reasons for these changes:
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To provide a suitable environment for the nutrition, growth and development of the fetus.
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To protect and prepare the mother for the process of parturition and subsequent support and nurture of the newborn infant.
Immunology of pregnancy
Pregnancy defies the laws of transplant immunology. The fetus is an allograft that, according to the laws that protect ‘self’ from ‘non-self’, ‘should’ be rejected by the mother. Furthermore, the mother continues to respond to and destroy other foreign antigens and confers passive immunity to the newborn while not rejecting the fetus. The uterus is not an immunologically privileged site, because other tissues implanted in the uterus are rejected.
Protection has to occur from the time of implantation when the endometrium decidualizes. The decidua contains all the common immunological cell types, e.g. lymphocytes and macrophages, but it also contains additional cell types, e.g. large granular lymphocytes. Only two types of fetoplacental tissue come into direct contact with maternal tissues: the villous and extravillous trophoblast (EVT), and there are effectively no systemic maternal T- or B-cell responses to trophoblast cells in humans. The villous trophoblast, which is bathed by maternal blood, seems to be immunologically inert and never expresses human leucocyte antigen (HLA) class I or class II molecules. EVT, which is directly in contact with endometrial/decidual tissues, does not express the major T-cell ligands, HLA-A or HLA-B but does express the HLA class I trophoblast-specific HLA-G, which is strongly immunosuppressive, HLA-C and HLA-E.
The main type of decidual lymphocytes are the uterine natural killer (NK) cells, which differ from those in the systemic circulation. They express surface killer immunoglobulin-like receptors (KIRs), which bind to HLA-C and HLA-G on trophoblast. The KIRs are highly polymorphic, with two main classes: the KIR-A (non-activating) and KIR-B (multiply activating). HLA-E and HLA-G are effectively monomorphic, but HLA-C is polymorphic, with two main groups: the HLA-C1 and the HLA-C2. Thus the very polymorphic KIR in maternal tissues and the polymorphic HLA-C in the fetus make up a potentially very variable receptor–ligand system. It has been shown that if the maternal KIR haplotype is AA, and the trophoblast expresses any HLA-C2, then the possibility of miscarriage or pre-eclampsia, both associated with shallow invasion, is significantly increased. However, even one KIR-B provides protection. HLA-C2 is highly inhibitory to trophoblast migration, and thus appears to need ‘activating KIR’ to overcome it.
A population of NK-derived, CD56 + granulated lymphocytes is found in first trimester decidua. They release transforming growth factor-β2, which also has immunosuppressive activity.
The fetus expresses paternal antigens and these can stimulate the production of maternal antibodies. Conversely, maternal antibodies are present in the fetus, confirming that the placenta is not an impermeable immunological barrier. Pregnancy may also induce blocking antibodies, but these do not appear to be vital to the continuation of pregnancy.
While the fetus needs to avoid attack, this carries a cost as the partly suppressed immune state in pregnancy makes both new infections, parasitic diseases, e.g. malaria, and reactivation of latent virus potentially more dangerous. Infections are involved in some 40% of premature deliveries. The placental and decidual cells express most toll-like receptors (TLRs), and when there is TLR-ligand activation, various cytokines and chemokines, such as the interleukins, are expressed.
The thymus shows some reversible involution during pregnancy, apparently caused by the progesterone-driven exodus of lymphocytes from the thymic cortex and the Th1 : Th2 cytokine ratio shifts towards Th2. Conversely, the spleen enlarges during pregnancy possibly due to the accelerated production of erythrocytes and immunoglobulin-producing cells. The lymph nodes in the para-aortic chain draining the uterus may increase in size, although the germinal centres of these nodes may shrink with the shrinkage reversing after delivery.
The uterus
The non-pregnant uterus weighs ~40–100 g, increasing during pregnancy to 300–400 g at 20 weeks and 800–1000 g at term. Involution is rapid over the first 2 weeks after delivery, but slows thereafter and is not complete by 2 months. The uterus consists of bundles of smooth muscle cells separated by thin sheets of connective tissue composed of collagen, elastic fibres and fibroblasts. All hypertrophy during pregnancy. The muscle cells are arranged as an innermost longitudinal layer, a middle layer with bundles running in all directions and an outermost layer of both circular and longitudinal fibres partly continuous with the ligamentous supports of the uterus ( Fig. 3.1 ). Myometrial growth is almost entirely due to muscle hypertrophy and elongation of the cells from 50 µm in the non-pregnant state to 200–600 µm at term, although some hyperplasia may occur during early pregnancy. The stimulus for myometrial growth and development is the effect of the growing conceptus and oestrogens and progesterone.
The uterus is functionally and morphologically divided into three sections: the cervix, the isthmus and the body of the uterus (corpus uteri).
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:
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Increased vascularity.
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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.
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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 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:
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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 above: Immunology). This decidualization is essential for successful pregnancy.
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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.
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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 prepregnancy diameter (see below). Uterine blood flow increases from 50 mL/min at 10 weeks gestation to 500–600 mL/min at term.
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 (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.
The vagina
The vagina is lined by stratified squamous epithelium, which hypertrophies during pregnancy. The three layers of superficial, intermediate and basal cells change their relative proportions so that the intermediate cells predominate and can be seen in the cell population of normal vaginal secretions. The musculature in the vaginal wall also becomes hypertrophic. As in the cervix, the connective tissue collagen decreases, while water and glycosaminoglycans increase. The rich venous vascular network in the vaginal walls becomes engorged and gives rise to a slightly bluish appearance.
Epithelial cells generally multiply and enlarge and become filled with vacuoles rich in glycogen. High oestrogen levels stimulate glycogen synthesis and deposition and, as these epithelial cells are shed into the vagina, lactobacilli known as Döderlein’s bacilli break down the glycogen to produce lactic acid. The vaginal pH falls in pregnancy to 3.5–4.0 and this acid environment serves to keep the vagina clear of bacterial infection. Unfortunately, yeast infections may thrive in this environment and Candida infections are common in pregnancy.
The cardiovascular system
The cardiovascular system is one of those that shows proactive adaptations for a potential pregnancy during the luteal phase of every ovulatory menstrual cycle, long before there is any physiological ‘need’ for them. Many of these changes are almost complete by 12–16 weeks gestation ( Fig. 3.6 and Table 3.1 ).
| First trimester | Second trimester | Third trimester | |
|---|---|---|---|
| Heart rate | +11 | +13 | +16 |
| Stroke volume (mL) | +31 | +29 | +27 |
| Cardiac output (L/min) | +45 | +47 | +48 |
| Systolic BP (mm/Hg) | −1 | +1 | +6 |
| Diastolic BP (mmHg) | −6 | −3 | +7 |
| MPAP (mmHg) | +5 | +5 | +5 |
| Total peripheral resistance (resistance units) | −27 | −27 | −29 |
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.
Pregnancy imposes a significant increase in cardiac output and is likely to precipitate heart failure in women with heart disease.
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 PGI 2 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.
