Introduction

In healthy, non-pregnant women, cyclical variations occur in a range of homeostatic mechanisms across the ovarian cycle, including thirst, fluid balance, appetite, temperature, cardiovascular, haemodynamic, metabolic and respiratory regulation. Following fertilization, luteal changes are accentuated and other physiological and behavioural adaptations unfold in response to distinct neurohormonal interactions that characterize successive phases of pregnancy and lactation. These altered regulatory mechanisms accommodate changing maternal needs and those of the conceptus, during implantation, and embryo formation, while changes occur in a variety of maternal systems to anticipate the distinct needs of the fetus and neonate.

Detailed information on the time course of specific changes and improved understanding of the coordinating factors have increased the potential number of tools to measure key adaptations and assess maternal health. For example, higher plasma concentrations of progesterone and relaxin in early pregnancy are associated with lower mean systolic blood pressure in the second and third trimester, and a positive correlation exists between the extent of plasma volume expansion and fetal growth, reduced risk of pregnancy complications, and pre-term labour (Khraibi et al 2003, Kristiansson & Wang 2001, Steer 2000). Some pre-existing and potential maternal health problems in early pregnancy may be identified through assessment of different hormone levels; and raised body mass index (BMI) (Duvekot et al 1995, Lain et al 2008, Maccarrone & Finazzi-Agro 2004).

This chapter will outline the time course and regulation of adaptive responses of maternal cardiovascular, renal and haemodynamic systems to pregnancy; adaptive responses of maternal hypothalamic–pituitary regulation of prolactin and growth hormone, and adaptive responses of maternal hypothalamic–pituitary–adrenal (HPA) axis to early and late pregnancy (Brunton et al 2008, Douglas 2010). It will conclude by examining the time course and regulation of the adaptive response of the uterus and mammary gland during pregnancy. See also website for more information.

Pulmonary and cardiovascular adaptations

During the infertile cycle, regulation of fluid balance, cardiovascular volume and blood pressure varies during different phases (Chapman et al 1997). This includes some degree of hyperventilation and changing alveolar and arterial tensions of carbon dioxide (CO₂) levels influenced by oestrogens and progesterone (see website).

When conception occurs, hyperventilation increases and the magnitude of decline in PCO₂ correlates with arterial concentrations of progesterone (Chapman et al 1998, Jensen et al 2005).

During the luteal phase, mean arterial pressure (MAP) declines significantly, leading to a reflexive rise in cardiac output, while blood volume remains constant (Chapman et al 1997, Williams et al 2001). In most studies, systolic blood pressure is slightly raised compared to the follicular phase, while diastolic pressure is 5% lower. Following conception, the largest change in blood pressure occurs before 8 weeks’ gestation. At this point, 80–90% of the total pregnancy-related fall of around 10 mmHg in MAP has already taken place (Duvekot & Peeters 1998). After 8 weeks, MAP continues to fall, reaching its lowest level by 24 weeks (Robson et al 1989). This pregnancy-related decline in MAP is largely due to the fall in diastolic pressure that begins during the luteal phase (Duvekot & Peeters 1998). Systolic blood pressure remains constant until 20 weeks, rising significantly during the second half of pregnancy, while diastolic pressure reaches its lowest point at 24 weeks and rises significantly for the remainder of pregnancy (Mabie et al 1994, Volman et al 2007) (see Figs 31.1 and 31.2).

Figure 31.1 Systemic haemodynamic changes before and during pregnancy. Mean arterial pressure (MAP) decreases and cardiac output (CO) increases significantly by 6 weeks’ gestation in association with a decline in systemic vascular resistance (SVR).

(Reproduced with permission from Chapman et al 1998: Fig. 1; 2059.)

Figure 31.2 Changes in (A) systolic and (B) diastolic blood pressure from 8 weeks’ gestation

(Reproduced from Kristiansson & Wang 2001; Figs 1 and 2: 15, with kind permission of OUP. www.oup.com)

Adaptations in fluid regulation

Osmotic thresholds for thirst and vasopressin secretion decline during the luteal phase (see website) leading to a comparable reduction in plasma osmolality, through a fall in plasma sodium and its associated anions, primarily chloride and bicarbonate (Chapman et al 1997, Vokes et al 1988). When conception occurs, plasma osmolality continues to decline to 8–10 mOsmol/kg below mid-follicular values by 10 weeks’ gestation, and this new setpoint for thirst and vasopressin secretion is maintained throughout pregnancy and labour (Chapman et al 1998, Davison et al 1981). These changes are stimulated by a primary renal and systemic vasodilation, which creates a fall in total vascular resistance (Fig. 31.3).

Figure 31.3 Mean values (±SD) for plasma urea (P_urea), sodium (P_Na) and osmolality (P_osm) measured at weekly intervals during the infertile cycle and following conception to 16 weeks’ gestation

(Reproduced with permission from Baylis & Davison 1998; Fig. 10.17; 284.)

In the absence of any increase in plasma volume, the post-ovulatory fall in renal and systemic vascular resistance initiates a decline in ventricular afterload. This stimulates a reflex rise in cardiac output followed by a significant expansion in plasma volume by 6 weeks’ gestation, increasing rapidly to around 45–50% of non-pregnant values by 36 weeks (Chapman et al 1998). The fall in systemic vascular resistance from the luteal phase stimulates renal sodium and water retention, by activating fluid-retaining components of the renin–angiotensin–aldosterone system (RAAS) while blunting its vasoconstrictive effects (Chapman et al 1997, Chidambaram et al 2002, Sealey et al 1987).

When conception occurs, plasma renin activity, aldosterone and atrial natriuretic peptide (ANP) increase significantly by 6 weeks’ gestation (Chapman et al 1997, 1998, Sealey et al 1985). Despite higher basal activity of the RAAS during pregnancy, the early fall in plasma sodium sets a lower response threshold, and renal reactions to natriuretic stimuli like ANP and vascular responses to vasoconstrictor components, notably vasopressin and angiotensin II, are significantly blunted, as occurs during the luteal phase.

These responses are largely mediated by rising levels of hCG, oestrogens and progesterone (Fig. 31.4). Oestrogens stimulate hepatic synthesis of angiotensinogen (renin substrate) and promote formation of angiotensin-(1-7) [ANG-(1-7)] over angiotensin II (ANG II). ANG-(1-7) opposes the pressor effects of ANG II by releasing nitric oxide, bradykinin and prostacyclin (Valdes et al 2001, Zhang et al 2001). Rising levels of hCG in early pregnancy simultaneously attenuate the pressor effects of ANG II while progesterone counteracts its vasoconstrictive actions by decreasing mean arterial pressure. Progesterone also stimulates aldosterone synthesis, promoting water retention, while the natriuretic actions of progesterone are inactivated in the kidneys (Hermsteiner et al 2002, Quinkler et al 2001, Szmuilowicz et al 2006). Together, these modifications of the RAAS sustain volume expansion without an attendant increase in blood pressure (Duvekot & Peeters 1998, Nakamura et al 1988, Sudhir et al 1995).

Figure 31.4 Patterns of release of human chorionic gonadotrophin, progesterone and oestrogens from ovulation to birth

(Reproduced with permission from Blackburn 2007:100.)

Renal haemodynamic adaptations

Although the kidneys constitute less than 0.5% of total body weight, in resting non-pregnant adults, blood flow is equal to 25% of cardiac output, reflecting their key role in regulating fluid and electrolyte balance (Stanton & Koeppen 1993). From the mid-luteal phase of the cycle, significant changes occur in renal haemodynamics, as vascular resistance declines, while plasma flow and glomerular filtration rate increase significantly, by 6 weeks’ gestation, compared to values obtained during the mid-follicular phase of the cycle. Minimal renal vascular resistance occurs at 8 weeks’ gestation and this coincides with a peak rise in plasma flow of around 70%, which remains at slightly lower values for the remainder of pregnancy (Baylis & Davison 1998, Chapman et al 1998, Conrad & Novak 2004) (Fig. 31.5).

Figure 31.5 Renal haemodynamic changes before and during pregnancy. Changes in glomerular filtration rate, effective renal plasma flow and renal vascular resistance from mid-follicular phase until 36 weeks’ gestation.

(Reproduced with permission from Chapman et al 1998: Fig. 3; 2059.)

These findings suggest that hormonal changes in the corpus luteum, before and after conception, stimulate a primary fall in renal and systemic vascular resistance that initiates a chain of events leading to an early rise in cardiac output, renal sodium and water retention, despite the increase in glomerular filtration rate, leading to an expansion in plasma volume, before any increase in basal metabolic rate (Spaanderman et al 2000). A primary reduction in vascular resistance of non-reproductive organs may be initiated in preparation for the dramatic increase in uteroplacental blood flow during the second and third trimesters.

Considerable evidence suggests that the luteal decline in vascular resistance and plasma osmolality and the subsequent rise in plasma volume and total body water are positive indicators of maternal adaptations to pregnancy and long-term health, because of their strong association with increased fetal growth, reduced perinatal mortality and risk of cardiovascular disease in later life (Churchill et al 1997, Conrad et al 2001, Duvekot et al 1995, Steer et al 1995) (see website).

Hormonal regulation

Current findings suggest that the renal and systemic fall in vascular resistance and the rise in cardiac output are stimulated by the post-ovulatory increase in relaxin, oestrogens and progesterone from the corpus luteum followed by a significant rise in adrenomedullin, a long-lasting vasorelaxant, from a variety of tissues by 8 weeks’ gestation (Conrad et al 2001, Di Iorio et al 1999, Hermsteiner et al 2002, Nakamura et al 1988, Novak et al 2001, Sudhir et al 1995).

In pregnancy, relaxin is detectable in the peripheral circulation 6 days after the midcycle LH/FSH surge. By 11 days, concentrations are significantly higher in fertile than in non-fertile cycles and concentrations increase rapidly up to 20 weeks’ gestation (Johnson et al 1991, Stewart et al 1993). Limited human studies have demonstrated that higher plasma concentrations of relaxin and progesterone in early pregnancy are associated with lower mean systolic blood pressure in late pregnancy (Kristiansson & Wang 2001). Recent evidence suggests that while oestrogens have a stimulatory effect on cardiac output and oestrogens and progesterone stimulate systemic and uterine vasodilation, neither hormone seems to influence renal blood vessels, which show a marked degree of dilation following ovulation (Chapman et al 1997, Nakamura et al 1988, Sudhir et al 1995) (Fig. 31.6).

Figure 31.6 Serum relaxin concentrations from ovulation in a non-conceptive and a conceptive cycle.

(Reproduced with permission from Jaffe 1999: Fig. 27-16; 775.)

Cardiovascular adaptations

The maternal cardiovascular system undergoes an extensive expansion in response to pregnancy. The first event is decreased vascular resistance of non-reproductive organs, leading to a profound fall in systemic vascular resistance, which reaches its lowest point at the end of the first trimester (Poppas et al 1997). By reducing cardiac afterload, this primary adaptation stimulates an overall rise of approximately 40–50% in cardiac output (Duvekot et al 1995, Volman et al 2007). Longitudinal studies suggest that cardiac output rises significantly during the first trimester, and peaks at 20 to 32 weeks, with no significant changes thereafter, or continues to show further small rises until term (Chapman et al 1997, Desai et al 2004, Duvekot & Peeters 1998, Mabie et al 1994, Volman et al 2007). Measures of the pattern and relative contribution of heart rate (HR) and stroke volume (SV) to increased cardiac output suggest that HR rises progressively until 38 weeks while SV increases significantly by 8 weeks and rises further to reach maximum values between 20 and 37 weeks and declines slightly over the remainder of pregnancy (Desai et al 2004, Robson et al 1989, Volman et al 2007).

Stroke volume increases significantly by 8 weeks, peaks at 16–22 weeks and plateaus or shows further small increases during the third trimester (Volman et al 2007). This represents a rise of 21–22% over pre-pregnancy values. In different studies, HR has been found to increase significantly above pre-pregnancy values by 5 and 16 weeks’ gestation. Data on the remainder of pregnancy suggest that the increase peaks at 31–36 weeks and shows no significant change or a slight decline thereafter. Current evidence indicates that HR may increase by between 11% and 17% over pre-pregnancy values (Capeless & Clapp 1989, Duvekot et al 1993, Robson et al 1989, Volman et al 2007) (see website).

Peripheral arterial vasodilatation

Cardiac output rises in early pregnancy, in response to a fall in systemic vascular resistance that reduces afterload in the myocardial fibres during left ventricular ejection. Decreases in both MAP and total peripheral resistance are evident at 8 weeks’ gestation and reach their lowest point by the middle of pregnancy, before returning to similar or slightly above pre-pregnancy values at term (Desai et al 2004). The decline in peripheral vascular resistance is brought about by early reduced vasomotor tone; remodelling of resistance-sized arteries; relaxation of systemic, renal and pulmonary vascular tone and development of new vascular beds in the placenta during the second trimester (Conrad & Novak 2004, Kelly et al 2004, Schrier & Briner 1991).

The initial fall is induced during the luteal phase by rising levels of oestrogens and progesterone. Progesterone has been shown to reduce muscle tone in the vasculature (Magness & Rosenfeld 1989, Omar et al 1995). When fertilization occurs, the further fall in peripheral vascular resistance creates a state of relative hypovolaemia, causing a reflexive increase in stroke volume and heart rate (Clapp et al 1988, Davison & Noble 1981, Duvekot et al 1993, Schrier & Briner 1991).

The compensatory rise in cardiac output produces a rise in vascular filling state characterized by a rise in left atrial diameter, a rise in glomerular filtration rate and little change in plasma renin, between 5 and 8 weeks’ gestation (Duvekot et al 1995). Studies have demonstrated that the fall in vascular resistance precedes the rise in circulating blood volume during pregnancy. This suggests that systemic vasodilatation is a primary adaptation to pregnancy that initiates a rise in cardiac output and maintains overall tissue perfusion and blood pressure, prior to significant increases in circulating blood volume (Capeless & Clapp 1989, Phippard et al 1986) (Fig. 31.7).

Figure 31.7 Changes in plasma volume, blood volume, red cell mass and haematocrit during normal pregnancy, expressed as a percentage of pre-pregnancy levels.

(Reproduced with permission from Rosso 1990:25.)

Adaptations in the vascular renin–angiotensin–aldosterone system

Current evidence suggests that plasma volume expansion is primarily stimulated by the decline in total peripheral vascular resistance, which activates multiple changes in different components of the maternal vascular renin–angiotensin–aldosterone system (August et al 1995, Irani & Xia 2008, Joyner et al 2007, Skinner 1993).

Angiotensinogen or renin substrate increases very early in pregnancy and closely mirrors levels of oestrogens in individual women (Skinner 1993). During pregnancy, placental oestrogens are largely converted in a series of enzymatic transformations from dehydroepiandrosterone (DHEA-S) and related androgens in the fetal zone of the adrenal glands and the fetal liver (Pasqualini 2005). When these androgens reach the placenta and membranes, they undergo enzymatic conversion to a form that serves as substrate for the synthesis of oestrogens (Ticconi et al 2006). Rising concentrations of oestrogens in the maternal circulation and the simultaneous fall in mean arterial pressure stimulates renal production of renin, and oestrogens provide the main stimulus for hepatic production of angiotensinogen, which acts as a substrate for renin (Romen et al 1991).

Aldosterone, progesterone and deoxycorticosterone

Aldosterone reduces sodium excretion primarily by acting on distal portions of the renal tubules, where it stimulates reabsorption of sodium ions. Plasma levels increase significantly by 12 weeks’ gestation and reach a plateau at 30 weeks that is three to five times higher than non-pregnant values. During the first half of pregnancy, effective renal plasma flow increases by 70–80%, and then declines slightly in the third trimester but remains 50–60% above non-pregnant values, which is greater than occurs in any other physiological state. The resulting increase in glomerular filtration rate increases the sodium load from 20,000 to 30,000 mmol/day (Skinner 1993). In pregnancy, aldosterone plays a key role in stimulating sodium retention (Quinkler et al 2001).

In the non-pregnant state, progesterone acts to enhance the excretion of sodium by decreasing its reabsorption in the proximal tubules and by blocking the increased reabsorption of sodium by aldosterone, in the distal tubules. Although progesterone concentrations exceed those of aldosterone at least 50-fold during pregnancy, the renal activity of aldosterone is preserved by the enzymatic conversion of progesterone to a number of different metabolites (Quinkler et al 2001). Current findings suggest that progesterone is effectively converted to various metabolites in the kidneys, which reduces its binding to mineralocorticoid receptors, thereby attenuating its capacity to competitively inhibit aldosterone (Quinkler et al 2001). Some of the increase in progesterone is also converted to deoxycorticosterone (DOC), which acts on the distal tubules to promote the reabsorption of sodium. Rising levels of DOC occur by approximately 8 weeks’ gestation and increase 10–15-fold, to a peak of approximately 100 mg/dL at term, which is higher than aldosterone. However, the salt-retaining properties of this hormone are 30–50 times less potent than aldosterone (Nolten & Rueckert 1981, Skinner 1993) (Fig. 31.8).

Figure 31.8 Mean adrenocorticosteroid levels in 11 women throughout pregnancy and postpartum (PP) compared to levels in non-pregnant (NP) women.

(Reproduced from Wintour et al 1978:399, with kind permission of OUP. www.oup.com)

Ventilation

Extensive anatomical and functional changes occur in the respiratory system. These accommodate both the progressive increase in gas exchange required by the rising blood volume and the growing space occupied by the uterus. From early pregnancy onwards, the overall shape of the chest alters, by a flaring of the lower ribs that seems to occur independently of any mechanical pressure from the growing uterus. This progressively increases the subcostal angle, from 68 degrees in early pregnancy to 103 degrees at term, and increases the transverse diameter of the chest by approximately 2 cm. Because of the flaring of the lower ribs, the diaphragm rises by a maximum of 4 cm while its contribution to the respiratory effort increases and shows no evidence of being impeded by the uterus. Studies on diaphragmatic movements during respiration – either sitting or lying down – have found them to be larger than in the non-pregnant state. This implies that breathing during pregnancy is more diaphragmatic than costal (de Swiet 1991a, Romen et al 1991) (Fig. 31.9).

Figure 31.9 The ribcage in pregnancy (coloured) and the non-pregnancy state (grey) showing the increased subcostal angle, the increased transverse diameter and the raised diaphragm in pregnancy.

(Reproduced with permission from de Swiet 1991a:88.)

The main functional change that occurs within the lungs is the gradual increase in the amount of air that is inspired or expired with a normal breath. This functional capacity (tidal volume) increases from 500 mL in the non-pregnant state to approximately 700 mL at term. As a result of this change, women breathe more deeply during pregnancy than in the non-pregnant state (Fig. 31.10).

Figure 31.10 Lung volume changes in pregnancy.

(Reproduced with permission from Blackburn 2007:316.)

Since the maximum amount of air that can be expired forcibly after maximum inspiration only increases by 100–200 mL, the increase in tidal volume is produced at the expense of the expiratory reserve volume. This means that a smaller amount of air remains in the lungs at the end of quiet expiration. As less residual air is mixed with the next inspiration of fresh air, this results in lower levels of PCO₂ that bring about a reciprocal rise in PO₂. PCO₂ declines from approximately 39 mmHg in the non-pregnant state to 31 mmHg during pregnancy, while PO₂ increases from 93.4 to 101.8 mmHg, over the same period (de Swiet 1991a).

Oxygen consumption

The progressive increases in cardiac output and pulmonary ventilation are proportionately greater than those occurring in maternal and fetal oxygen consumption during pregnancy. Oxygen consumption shows a linear increase with body weight as pregnancy advances, increasing to 38 mL/min (15%) above average values in the non-pregnant state (de Swiet 1991a). It is composed of the overall increase in tissue mass, higher metabolic rate of fetal and placental tissue, along with that of some maternal organs, particularly the heart, lungs and kidneys (Fig. 31.11).

Figure 31.11 Partition of the increased oxygen consumption in pregnancy among the organs concerned.

(Reproduced with permission from de Swiet, 1991a:91.)

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The increase in oxygen consumption is facilitated by a 40–50% increase in ventilation and by an 18% increase in the oxygen-carrying capacity of the blood. Because of this relative oversupply of oxygen, higher concentrations are returned to the heart from the venous circulation, making the arteriovenous oxygen difference significantly smaller than in the non-pregnant state. The extent of the arteriovenous oxygen difference is smallest in early pregnancy and does not reach average non-pregnant values until term (de Swiet 1991a).

The increase in ventilation during pregnancy reduces alveolar and plasma concentrations of carbon dioxide. Studies have demonstrated that arterial partial pressure of carbon dioxide (PCO₂) is about 30 mmHg in late pregnancy, compared to 39 mmHg during the follicular phase of the cycle. Since fetal PCO₂ remains at approximately 41 mmHg, the lower levels in the maternal circulation encourage the diffusion of CO₂ from fetal blood, across the placental membranes.

Reflective activity 31.1

Consider the changes that occur in maternal organ systems. How would you use this information to assess maternal health and fetal growth.

The mammary glands/breasts

See Chapter 43.

Uterine adaptations

The uterus changes from being a small pelvic organ, with a cavity of around 10 mL and weighing approximately 50 g. By 36 weeks, its weight has increased to an estimated 1100 g, representing almost a 20-fold increase in mass, and its average volume is 5 litres. It is then in contact with the anterior abdominal wall and extends as far as the xiphisternum. During pregnancy, the uterus is a central recipient of the increases in circulating blood volume. In the follicular phase of the cycle, uterine blood flow is approximately 45 mL/min (Burton et al 2009). This changes very little during early pregnancy, but rises sharply from about 20 weeks, to reach approximately 750 mL/min at term, when it receives nearly 20% of total cardiac output (Burton et al 2009, Steer 1991).

Uterine growth is characterized by a highly regulated process of myometrial cell differentiation:

Growth is stimulated by hCG, progesterone, growth factors, oestrogens and oxytocin, and by progressive distension exerted by the fetus, placenta and amniotic fluid, particularly during the third trimester. These factors promote synthesis of structural and contractile proteins (Blackburn 2007, Shynlova et al 2009, Ticconi et al 2006 (see website). During the first few months of pregnancy, growth is accompanied by increasing thickness of the myometrium in the corpus and the fundus. As the organ increases in length from around 12 weeks, the isthmus is gradually formed as an area with reduced density of muscle fibres (Steer 1991).